UNIT 1

THE CELL
(BLOOM AND FAWCETT)

CELLTISSUESORGANORGAN SYSTEMHUMAN

Histology- a branch of morphological science primarily concerned with tissues

- synonymous with microscopic anatomy

Cell - smallest unit of protoplasm capable of existing independently

- unit of structure and function of the human body

I. basic organization
2 major components:
A. Cytoplasm
1. Fluid - Cytosol
2. Formed elements
a1. Organelles
- metabolically active internal organs
- perform specific essential functions for cell metabolism
- bounded by membranes composed of lipid & protein
- capable of regeneration
- only 3 are viewed under LM: mitochondria, ergastoplasm, golgi complex
- importance:
Enhance efficiency of chemical rxns
 Amplify the area of physiologically active interfaces within the cell
Facilitate the control of cell metabolism
 Maintain separation of enzymes & substrates
 Permit their controlled rxns
 Vary permeability of a particular membrane
 Vary rate of active transport across the membranes
a2. Inclusions
- metabolically inert accumulations of cell products(pigment deposits, stored metabolites like CHO and lipids)
- dispensable and often temporary constituents of cells
- melanosomes have been found out to have enzymatic activities
- Secretory granules, formerly considered to be simply stores of cell product, are now found to be bounded by an enzymatic ally
active membrane.
a3. Cytoskeleton
- fibrillar elements in the cytoplasm
B. Nucleus
- largest organelle of the cell
- archive of the cell
- repository of genetic material (DNA)
- Functions:
controls the constructive cell metabolism
Essential for cell reproduction & hereditary transmission
-parts:
1. Nuclear Envelope
-LM - thin dark line surrounding the nucleus
-EM - double layered membrane with a space in within known as perinuclear space
- Fenestrated by nuclear pores
- Fxns:
participates in the organization of chromatin
controls the movement of macromolecules between nucleoplasm & cytoplasm
-membranes:
a. Outer nuclear membrane
- has ribosomes
- continuous with endoplasmic reticulum
b. Perinuclear cisterna
- space between the outer & inner nuclear membrane
c. Inner nuclear membrane
d. Nuclear pore complex
- collective term that includes the membranous & non-membranous structures of the nuclear pore(serves as avenues of
communication between the nucleoplasm and cytoplasm, closed by a pore diaphragm)
- composed of nucleoporins (3 glycoprotein units)
Lectin that binds to 1 of these nucleoporins completely inhibits transport into the nucleus
number & distribution changes as the cell differentiates or changes its activity
- 2 rings
Coaxial
Octagonally symmetrical
Perpendicular to the axis of the nuclear envelope plane
Each ring has:
8 subunits
8 radial spokes - converge at the plug responsible for specious appearance of the
1 central granule/plug pore diaphragm
 10nm = passive diffusion
10nm = energy-dependent transport mechanism
e. Nuclear lamina
- continuous meshwork of fine filaments
- interposed between the inner nuclear membrane & the peripheral heterochromatin
- composed of lamins
Polymers of polypeptides (before nuclear envelope disintegration during cell division)
Involved in the functional organization of the interphase nucleus
of 2 types which differ in location & chemical properties
 A type – inner aspect of the nuclear lamina
 B type – outer aspect of the nuclear lamina
- Responsible of binding to integral proteins that are specific to the inner nuclear membrane
2. Chromatin
-LM - dark irregular masses in the nucleoplasm
-EM - made up of filaments/strands of DNA
- (+) Feulgen rxn, deeply stained with acidic dyes since basophilic
- DNA resides in chromosomes
-Types:
a. heterochromatin
- stainable, electron-dense portion of the interphase chromosomes
- coiled, condensed, clumped, granular
- inactive portions that are being transcribed
- unexpressed genes
- in special preparations, appear as a beaded strand of regularly spaced discoid subunits
nucleosomes - the core is an octomer of 2 molecules each of histones: H4, 3, 2A, 2B
H1 is associated with the connecting segments of DNA.
b. euchromatin
- non-stainable, unidentifiable on LM
- dispersed portion
- uncoiled, loosely packed, conjectural
- active genes involved in protein synthesis
3. Nucleolus
-LM - rounded refractile body usually located eccentrically in the nucleus
-EM - tightly coiled filaments of RNA / has a 3D network of anastomosing dense strands
- (-) Feulgen rxn, deeply stained with basic dyes since acidophilic
- consist mainly of ribonucleoprotein
- disappears during cell division
- reappears during reconstruction
- Nucleolus-Associated Chromatin - intensely stained that surrounds the rim of the nucleolus
- the network:
1. Nucleolonema / Pars Granulosa
- ribonucleoprotein particles in a matrix of fine filaments
- anastomosing dense strands
- site of ribonucleoprotein particle accumulation
2. Fibrillar Centers
- fibrillar texture
- less dense rounded areas found at 2 or more sites in the nucleolus
- contain Nucleolar-Organizer Regions
possess the nucleolar genes
site of transcription of rRNA
3. Dense Fibrillar Component / Pars Fibrosa
- rim of electron-dense filaments that immediately surrounds fibrillar centers
- site of processing RNA precursor & RNA protein assembly
-types:
1. Pyknotic - dark chromatin (basophilic)
2. Vesicular - pale

Organelles
1. Cell Membrane / Plasma Membrane / Plasmalemma
-LM - not visible because very thin, outline may be seen
-EM - trilaminar appearance, thin dense line around the periphery of the cell (due to deposition of heavy metal in the
hydrophilic ends)
- appeaers as 2 electron-dense lines(2.5-3.0 nm.,due to deposition of heavy metals in the hydrophilic end) separated by an electron-lucent
intermediate zone(3.5-4.0 nm., represents the unstained hydrocarbon chain ).
- phospholipid bilayer
Hydrophilic portions at the outer and inner
Hydrophobic toward the middle
- permeable to water, oxygen, nitrogen & small uncharged polar molecules
- lipid are responsible for the form and permeability properties
- receptors, ion pumps & enzymatic activities reside in proteins
- transmembrane proteins(majority) extend through the bilayer
transport glucose & amino acids
form channels permitting passive diffusion of certain ions
functions as pumps, moving sodium, potassium, hydrogen & calcium into & out of cells against a concentration gradient
receptors that enable the cell to recognize & bind specific molecules
 Neurotransmitters - acetylcholine
Hormones
Certain essential nutrients
- proteoglycans consist of a core protein bearing multiple glycosaminoglycan side-chains that are linear polymers of disaccharide subunits
- CAMs / Cell Adhesion Molecules consist of a polypeptide chain linked to a carbohydrate such as sialic acid
involves in cell recognition during histogenesis
 Brain cells & muscles = N-CAM
 Liver cells = L-CAM
 Glial cells to neurons = NG-CAM
- Terminal oligosaccharides of the glycoproteins extend outward contributing to the surface coat/glycocalyx
- glycocalyx is conspicuous on the epithelium lining the GIT
Commonly stained by Alcian-blue & Ruthenium-Red
- Functions:
Permeability property permit diffusion of ions & gases in solution into and out of the cell
Serves as device for cell attachments and cell-to-cell communication
2. Endoplasmic Reticulum
- visible in tissue cultures using lipophilic, non-ionic, fluorescent dyes
a. Rough ER / Ergastoplasm / Granular
-LM - (cresyl violet) dark staining irregular basophilic masses/clumps
-EM - network of branching & anastomosing tubules with dark staining palade granules/Ribosomes attached on the surface
- tubules may be locally expanded into broad flat saccules called cisternae
- abundant in glandular cells
- Fxn: protein synthesis
b. Smooth ER / Agranular
-LM - can’t be seen
-EM - similar to rough ER minus the ribosomes
-abundant in steroid-secreting endocrine glands
- Fxns:
in liver, synthesis of fatty acids & other lipids (VLDL that are carriers of cholesterol in the blood),
site of detoxification & metabolism of lipid-soluble exogenous drugs
in skeletal & cardiac muscles, sequestration of calcium ions that control muscular contraction
3. Ribosomes
- RNA + 20 or more proteins
- sites where amino acids are assembled in protein synthesis
- must be associated with mRNA
- polyribosome/polysomes = ribosomes in clusters of 10 or more linked to mRNA

4. Golgi Complex
-LM - (silver stain / osmium acid) blackened area near the nucleus
-EM - consist of flattened membranous sacs that are usually stacked close together
- cisternae
Narrow lumen throughout most of the length
Tends to be slightly expanded at the ends
Correspond to Dictyosomes - arciform structures
a. convex outer surface / cis-face
1st element - highly fenestrated network of anastomosing tubules
True cisternae - may have central fenestration
Small vesicles transport materials from cis to trans
b. concave inner surface / trans-face
- wider lumen & may contain precipitated protein
- terminal cistern
Often has distended segments forming condensing vacuoles that are precursors of secretory vacuoles
others are highly fenestrated forming the trans-Golgi network
- compartments:
a. cis-compartment
- highly fenestrated initial cisterna
- heavily stained by prolonged exposure to osmium
b. intermediate compartment
- (+) NADPase / nicotinamide adenine dinucleotide phosphatase
- (+) AGT / N-acetyl glucosamine transferase
c. trans-compartment
- (+) TTPase / thiamine pyrophosphatase
- (+) ST / sialyl transferase
- (+) GT / galactosyl transferase
- Functions:
Further processing, concentration & packaging in secretory granules of protein synthesized by the ER
maintenance & renewal of all membranes
5. Mitochondria
-LM - slender filaments/rods (special stain)
-EM - membrane bound organelle
- powerhouses of the cell
- oxidative phosphorylation is the principal biochemical activity
- self replicating (resembles bacterial binary fission) with limited life span
- has own DNA, rRNA, mRNA, tRNA but not self-sufficient
 - parts:
a. outer membrane
- smooth
- contains protein that are freely permeable to small particles
b. intracristal space / membrane space
- narrow cleft between the outer & inner membranes extending inward between the 2 leaves of the cristae
- lateral extensions
c. inner membrane
- thick & slightly thinner
- parallel to the outer membrane
- impermeable
- has higher content of protein
d. cristae mitochondriales
- thin folds that project into the interior of the membrane
- increase the surface area of this enzyme-rich membrane
- # depends upon energy requirement of the cell
e. intercristal space
- large area within the inner membrane
e1. Mitochondrial matrix
e2. inner membrane subunits
- consist of a globular head
- have cisternae = folds that extend inward
- inside is the matrix which contains enzymes for function of mitochondria
- no proteins!
e3. Membrane granules
- maybe involved in regulation of ion concentration in matrix
- Function: energy production since it contains oxidative enzymes
provide energy for biosynthesis & motor activities of the cell
Energy generated is used to synthesize ATP from ADP & inorganic phosphate
6. Lysosomes
-LM - can’t be identified
-EM - membrane bound vesicles containing a large variety of hydrolytic enzymes
- heterogeneous
- hydrolytic enzymes:
glycosides, nucleases, sulfatases, proteases, phosphatases, phospholipids
acid pH
- has dense granules, crystals, concentric systems of lamellae (phospholipids), 40/more enzymes, residual bodies
- Fxns:
Intracellular digestion - degrade nearly all naturally occurring chemical constituents of cells
extracellular digestion
 Osteoclast digestion of bone matrix
 Acute inflammation
autolysis
 Disease states
 Normal regression (apoptosis) - mammary gland after weaning,
Endometrium of the uterus in mentruation
defense of organism against bacterial invasion (phagosome)
Elimination of organelles during cytoplasm reorganization (autophagic vacuole)
 Autophagy - controlled degradation of organelles in a healthy cell
 Heterophony - digestion of exogenous material taken into the cell
7. Peroxisomes / microbodies
- membrane-limited bodies which contain electron dense central core known as nucleoid (para-crystalline array of urate oxidase, not in birds & man)
- less dense than lysosomes
- mostly in the liver
- enzymes: urate oxidase, D-amino acid oxidase, catalase
- Function:
Generate energy but unable to store it in the form of ATP for subsequent use by the cell
Energy generated is dissipated as heat & may contribute to the maintenance of body temperature
-oxidation of fatty acids
- clinical interest lies on inherited disease
Ex. Deficiency of single enzyme (x-linked adrenoleukodystrophy) or several enzymes (Zellweger syndrome)

8. Centrosomes & Centrioles

-LM - pale area of cytoplasm near the nucleus usually beneath the golgi complex
-EM - cylindrical hollow structure made up of microtubules
- spherical area with a texture differing slightly from the cytoplasm
- location in some epithelia: supranuclear cytoplasm partially surrounded by golgi complex
apical cytoplasm immediately beneath the cell membrane
- rich in tubulin
- Centrosomes contain a pair of short rods in the center = centrioles(anlage is procentriole=annular condensation of dense material having the same
diameter as a centriole, but devoid of microtubules)
- may also contain small dense bodies = centriolar satellites
serve as microtubule organizing centers
Sites of nucleation of the microtubules that will form the mitotic spindle
 - centrioles are cylindrical structures with an electron-dense wall surrounding an electron-lucent central cavity
- 9 evenly spaced triplet microtubules are embedded in the wall
- each centriole is composed of 9 sets of microtubules triplets arranged in pinwheel manner
- vanes of turbine = each triplet is set an angle about 40degrees to its respective tangent
- subunits of each triplet:
A - nearest to the axis of the centriole
B
C
- do not replicate by division
- centrin = calcium-binding 20 kD protein
& unnamed related 165 kD
- Functions:
Serves as organizing center for mitotic spindle formation during cell division
 Device for ensuring that both daughter cells receive a pair
Serves as basal bodies / kinetosomes which are signs of attachment of cilia
Initiating tubulin polymerizatioin that results in formation of axoneme of a cilium
9. Annulate Lamellae
- consists of parallel lamellae/cisternae containing many pores
- tend to occur in rapidly dividing cells esp. in germ cells & other cell types in early stages of their differentiation
- Function: obscure

Inclusions:
1. Nutritive substances
a. glycogen - (+) PAS / Periodic Acid Schiff
- liver & muscle - principal sites of carbohydrate storage
- polymer of D-glucose
- tend to be more concentrated in smooth ER
 Membrane of smooth ER contains glycogen phosphorylase
- in diabetes & glycogen-storage disease, it may accumulate in the nucleus(normally confined in the cytoplasm)
b. lipids - membrane synthesis
- in tissues fixed with glutaraldehyde & osmium tetroxide: gray/black spherical globules
2. Secretory granules - protein stored in glandular cells
3. Pigment
a. exogenous - outside source
Carotene/Vit.A
b. endogenous - from within
Melanin - cellular activity
- skin, hair, neurons of substancia nigra in brain, epithelium of retina
Melanosomes = dense ellipsoidal granules in their cytoplasm
Tyrosine + dihydrophenylalanine
Bilirubin
Hemosiderin - cellular breakdown
- oxygen carrier pigment of RBC
- EM: dense masses of particles of ferritin
Lipofuschin - wear & tear pigment
- yellowish brown which accumulate due to indigestible residues of lysosomal activity
- Long lifespan in the cardiac muscle & brain
- bounded by membrane
4. Crystals
- located in the cytoplasm or within the lumen of expanded segments of rough ER
Crystaloid of Reinke - human leydig cells / interstitial cells of human testis
Charcot-bottcher - sertoli cells of human testis
Ferritin crystal - intestinal cells of insects
Guanine crystal - skin of amphibians

Cytoskeleton
-LM - (special) interlacing filaments in cytoplasm
-EM - filamentous structure made up of structural proteins
- 3D lattice of filaments which cause the gel-like consistency of cytoplasm
- detectable when they occur in coarse bundles
- Functions:
Form & shaping of cells
Stabilization of cell attachments
distribution of cell organelles
cell motility
- types based on diameter:
1. Microtubules
- 25 nm in diameter
- straight & slender
- wall is made up of 13 protofilaments of tubulin
- majority tend to radiate from the centrosome which appears to be the microtubule organizing center of the cell
- centriolar satellites serve as nucleation sites for polymerization of tubulin
- ephemeral structures
- can rapidly disassembled & reassembled in a new pattern
- in elongating, add subunits at 1 end (plus end) & depolymerize at the other end (minus end)
 - doublet microtubules (1 complete & 1 C-shaped that has 10 protofilaments)
in cilia of epithelial cells & flagellum of spermatozoa
- triplet (1 complete & 2 C-shaped) in wall of centrioles & basal bodies
- Fxn: directing the movement of organelles & small vesicles from place to place in the cytoplasm
-MAPS = microtubule-associated proteins:
Kinesin - movement of vesicles along microtubules
Dynein - moves vesicles toward the minus end
Dynamin - 100 kD polypeptide that forms cross-bridges between neighboring microtubules
Axonemal dynein - arms of the doublets which is a motor for ciliary motion
2. Intermediate filaments
- 10nm in diameter
- polypeptides associated:
Filaggrin
- epidermal cells
- binds to keratin filaments causing them to aggregate into bundles
plectin
- sites of intersection of vimentin intermediate filaments
- linkage of vimentin into cytoskeleton network
Synamin - muscle
- major classes:
a. keratin
- stratified squamous epithelium of skin
- don’t undergo rapid assembly & disassembly
- fxn is mainly mechanical, stabilizing the shape of the cell & strengthening its attachment to other cells & basal lamina
b. vimentin
- 58 kD protein
- mesenchymal cells, fibroblasts
c. desmin
- 53 kD acidic protein
- muscle tissue
d. neurrofilaments
- made up of 3 major polypeptides: 210, 160, 68 kD
- perikaryon, dendrites & axons of neurons/nerve cells
- functions:
provide internal support
maintain the gelated state of axoplasm
e. glial filaments
- 51 kD glial fibrillary acidic protein
- non-neural cells of the CNS: astrocytes, oligodendrocytes & microglial cells
3. Microfilaments
- 7nm in diameter
- consist of globular subunits of a 42 kD protein = G-actin
- F-actin = 2 identical strands that are helically coiled around 1 another
- actin - viscoelastic & contractile properties of the cytoplasm
- most aboundant in ectoplasm (cortex) of the cell
- stress fibers = larger bundles under the LM
-examples:
Myosin - muscle contraction
Profilin - binds to G-actin monomer, preventing polymerization
- maintain a supply of monomer that can be drawn on as needed to form new actin filaments
Capping protein - binds to the end of actin filament, limiting further increase in length
Fimbrin - binds adjacent actin filaments
filamin - forms flexible links between intersecting microfilaments, stabilizing a 3D network
gelsolin - insert between subunits of filament, breaking into shorter segments
vinculin & alpha-actinin - mediate the binding of actin filaments to the cell membrane at intercellular junctions & at the cell base

CELL ACTIVITIES

CELL DIVISION
-Amitosis- division of the nucleus of a cell by without spindle formation; not involving mitosis
-Interphase- period between 2 successive episodes of cell division
-Difference bet. Mitosis and meiosis.
MITOSIS(Asexual) MEIOSIS(Sexual)
Cells involved Somatic Cells Germ Cells
Chromosome 46(diploid) 23(haploid)
number
Crossing over Yes No
Stages: REDUCTION:
PROPHASE (Prophase 1)
-marked by appearance of chromosomes(START) A. LEPTOTENE- chromosomes become visible in the
-chromosomes continue to condense, shorten and thicken, nucleolus as long, thin, single strand
consist of CHROMATIDS(2 parallel strands joined @ the
CENTROMERE-a constricted segment common to both B. ZYGOTENE- homologous chromosomes come
strands) together in close lateral apposityion with
-KINETOCHORE- trilaminar disc @ the site of centromeres corresponding sites along their length of register;
 consisting of 2 dense layers separated by a polar middle layer
-CENTRIOLES replicate and migrate to opposite poles
-breakdown of nuclear envelope(END)
SYNAPSIS(pairing)
C. PACHYTENE- chromosomes coil, become shorter
snd thicker; homologous chromosomes may be seen
as 1 because of the close apposition.

D. DIPLOTENE- homologous chromosome separate,

has already replicated, and is nowe double-stranded;
chromosomes has now 4 chromatids; CROSSING
OVER(homologous chromatids cross one another in
the area CHIASMATA, break, and the fragments
recombine @ these sites so that segments have been
exchanged; for ensuring genetic diversity)

E. DIAKINESIS- shortening and thickening of

chromosomes continue; they clump together @ the
center of the nucleus; nucleolus fragment later
disappear.
METAPHASE (Metaphase 1)
-Alignment of chromosomes in the same plane in the middle - nuclear membrane breaks down
of the cell to form EQUATORIAL PLATE/METAPHASE - spindle is formed
PLATE(START) - alignment in equatorial plate
- development of MITOTIC SPINDLE(fusiform array of - kinetochore does not divide
microtubules)
-the only stage where chromosomes are accessible for
analysis.
ANAPHASE (Anaphase 1)
- separation of single kinetochore(EARLY) - whole chromosomes separate and move to separate
- sister chromatids(unbound) migrate to opposite poles and poles
become chromosomes
- kinetochore of each chromosome attaches to 1 or more
spindle fiber.
- microtubules are shorter by depolymerization @ one end by
DYNEIN
TELOPHASE (Telophase 1)
- chromosomes are clustered at the spindle poles - nuclei are briefly reconstituted
- segment of a nuclear envelope are formed around them - proceed to 2nd. Division/EQUATIONAL DIVISION
-chromosomes uncoil(signals COMPLETE KARYOKINESIS- where chromatids separate, kinetochores divide, and
division of nucleus) sister chromatids move apart to opposite poles
- nuclei are reformed
-nuclear envelope coalesce to become complete perinuclear
cisternae NOTE:
- constriction of cytoplasmCLEAVAGE FURROWdeepens BIOLOGICAL SIGNIFICANCE OF MEIOSIS:
until it encounters the microtubules if the spindle.
-MIDBODY= daughter cells remain connected by a narrow 1. ensures constancy of chromosome number from
cytoplasmic bridge occupied by residual spindle microtubules generation to generation by producing haploid male
bound together at the midpoint by dense amorphous and female gametes.
materials
- microtubules depolymerize 2. creates genetic diversity by crossing-over of the
-intercellular bridge is sundered at 1 side of the midbody chromosomes.
-2 halves are retracted @ the cytoplasm of the daughter
cells(signals COMPLETE CYTOKINESIS)

Note: in females, 1 of the x-chromosome remain condensed

during interphase, usually located adjacent to the nuclear
envelope, called BARR BODY; useful in diagnosis of certain
abnormality of sexual development.
PRODUCTS 2 diploid cells(same component) 4 haplod cells (diverse)

- Amniocentesis- aspiration of amniotic fluid for early detection of congenital anomalies before birth.
- Types of Chromosomes based on the location of the Centromere:
Metacentric- centromere in the middle, arms are equal in length
Submetacentric- centromere is between midpoint and 1 end.
Acrocentric- centromere is near 1 end.
Telocentric- centromere is @ the very end.
- Karyotyping- where homologous chromosomes are identified, juxtaposed and arranged in groups on the basis of length and position of centromere.
- Anomalies:
Aneuploidy
 Deletion- loss of a portion of a chromosome
-eg: Turner’s Syndrome=loss of an X-chromosome(44XO)
= results in phenotypic female whose ovaries are vestigial ans
usually devoid of germ cells
 Translocation- transfer of a segment of to a nonhomologous chromosome.

- Down’s Syndrome/Mongolism/Trisomy 21- congenital disorder where there’s an extra chromosome 21 due to failure of 1 member of that homologous pair to move to the
appropriate spindle pole in meiotic divisions during gametogenesis.
- Klinefelter’s Syndrome- extra X-chromosome in a phenotypic male (44XXY)
- characterized by underdevelopment of testis, sterility, and breast development(GYNECOMASTIA)

ENDOCYTOSIS
- an active process of ingestion of large molecules in membrane-bound invaginations of the cell membrane that close at their neck, forming a vesicle or vacuole that moves into
the cytoplasm.
- 2 forms:
A. PHAGOCYTOSIS
- eating by cells
-not common to all cells but highly developed in WBC’s
-cells capable of phagocytosis are called PHAGOCYTES.
-initiated by binding of a bacterium or an inanimate particle to receptors on the cell surfacestimulates pseudopodia formation
-lamellipodia- thin, undulating, fin-like processes extending from the surfaces of macrophages
- bacteria may bind to these preexisting processes and be engulfed and drawn into the cytoplasmwithout the necessity of forming blunt pseudopodia to
envelope the particle.

B. PINOCYTOSIS
- drinking by cell
-exhibited in nearly all cell type
-MACROPINOCYTOSIS- thin lamellipodia envelopes and interiorize sizable droplets of ECF; can be detected in phase contrast microscopes
-MICROPINOCYTOSIS- more common; fluid and solutes are taken up in minute vesicles; can only be detected in electron microscopes
-TRANSCYTOSIS-in capillary endothelium, fluid and solutes are transported across the vessel wall from the lumen to the basal surface of the cells, where they fuse
with membrane and discharge their content.
- important mechanism for moving solutes from the blood to the extracellular space.
-FLUID-PHASE PINOCYTOSIS- vesicles formed are smooth surfaced and contain ions and molecules in the same concentration as in the ECF; nonselective.
- RECEPTOR-MEDIATED PINOCYTOSIS-process of uptake of specific proteins, including hormones and other regulatory molecules; highly selective; selectivity depends
on the specific receptors in the portion of the membrane that is invaginated
-COATED PITS- shallow indentations of the membrane where ligand-receptor complexes aggregate after binding of molecules to their specific receptors; consist of
CLATHRIN, as polymerization of clathrin progresses, pit deepens and becomes COATED VESICLES that are free in the cytoplasm
-ENDOSOMES- membrane-bound transient organelles formed from the fusion of the depolymerzed clathrin and preexisting vacuoles; have irregular outlines and
short tubular extensions.
Early Endosomes- those in the periphery of the cytoplasm
- lower pH in early endosome results in dissociation of the ligands from their receptors and leave them free in the lumen, receptors are
recycled and returns back to the cell membrane.
Late Endosomes- those found deeper in the cytoplasm
- prelysosomal compartment in the endocytotic pathway.
- larger size, greater content of internal membrane, lower pH,(+) ACP

EXOCYTOSIS
- release of cell products into the extracellular compartment.
-REGULATED SECRETION- stimulus-dependent exocytosis
- characteristic of cells specialized for synthesis and release of a large volume of secretion.
-CONSTITUTIVE SECRETION- secretions/products that are not concentrated into conspicuous secretory granules but released continuously in small vesicles that fuse
with the plasma membrane.

CELL LOCOMOTION
-AMOEBOID LOCOMOTION
Eg: leukocytes, fibroblasts
Resemblance to the movements of amoeba
Depends on the gel-sol formation at the front, and a contraction of the cell body at the rear.
- CHEMOTAXIS
Diecional migration along a gradient of diffusible substance, from an area of lower concentration to an area of higher concentration.

MOVEMENT WITHIN CELLS

-dynein and kinesin
-myosin I- consist of the globular head of conventional myosin(myosin II) without the alpha-helical, coiled-coil tail that permits assembly of into filaments.

CELL DEATH
- 2 distinct processes:
NECROBIOSIS/APOPTOSIS NECROSIS
DUE TO -not a result of injury -mechanical injury, exposure to toxins
-active form of cell death
-early condensation of chromatin and degradation -anoxia due to impairment of blood supply
of DNA due to activation of end nucleases by
calcium
SWELLING No (decreased cell volume) Yes
MEMBRANE AND ORGANELLES Intact Deteriorated
NEUTROPHILS AND MACROPHAGES Not involved Involved
PREVENTION Compounds that inhibit protein synthesis ???

EPITHELIUM
(BLOOM AND FAWCETT)

GENERAL HISTOLOGY
Histogenesis = formation/development of tissues from the undifferentiated cells of embryonic germ layers
Tissue = aggregate of similarly specialized cells united in the performance of a particular function
Basic types of tissues found in man:
1. Epithelium
2. Connective
3. Muscle
4. Nervous
Basic components: cells, fluid, intercellular ground substance (extracellular matrix)

EPITHELIUM
- tissue composed of 1 or more layers of contiguous cells that line external or internal surfaces of the body including small cavities & lining of vessels, both ectodermal and
endodermal in origin

-Germ layers:
1. Ectoderm
corneal epithelium
epidermis of the skin
Invagination & proliferation – gives rise to tubes or solid cords that form the glandular appendages of the skin
sudoriparous, sebaceous, & mammary glands

2. Endoderm
lining the embryonic alimentary tract
intestinal glands
Liver
pancreas

3. Mesoderm
kidney
male & female reproductive tracts
continuous layer of cells lining the blood & lymph vessels (endothelium), peritoneal cavity & other serous cavities (mesothelium)

-functions:

Functions Epithelium Examples

Protection Stratified squamous skin
Absorption Simple columnar with striated border proximal tubules of kidney
small & large intestines
Secretion glandular sweat, salivary, exocrine glands (not endocrine!)
Excretion glandular lungs, kidney
Sensory reception Pseudostratified columnar organ of corti - internal ear
olfactory mucosa - nose
Reproduction ova & spermatozoa

-General characteristics:
1. Scanty intercellular substance
2. Rest on a lamina propria (support) with basement membrane between
3. Avascular but well supplied with nerves
4. May undergo METAPLASIA
Squamous metaplasia - in chronic inflammation of the bronchi, ciliated pseudostratified epithelium may become transformed to stratified squamous epithelium

-Characteristics of epithelial cells:

1. Nucleus conforms with the shape of cells
2. Inherent property (cohesiveness) to make extensive contact with each other
3. Manifest POLARITY - columnar absorptive cells
to carry out the vectorial functions of secretion or absorption
to regulate the transepithelial traffic in ions & solutes necessary to maintain a concentration gradient between the external environment & the body fluids or
between the compartments within the body
evident in the:
a. specializations that amplify the area of the free surface
b. supranuclear location of the centrosome & golgi complex
c. accumulation of secretory products in the apical cytoplasm
expressed in the:
 Ultrastractural level
a. sealing of the intercellular clefts by tight junctions located on the cell boundaries near the free surface
b. other specializations for attachment or cell-to-cell communication that are confined to the lateral cell surfaces
 Submicroscopic level
a. segregation of certain membrane proteins & lipids in functional distinct domains:
 Apical domain - rich in glycolipids & cholesterol
- contains H+-ATPase, hydrolytic enzymes, ion channels, transport proteins for specific nutrients
- site of release of products of the regulated secretory pathway
 Basolateral domain - contains Na+/K+-ATPase, anion channels, receptors for hormones,
 neurotransmitters
- principal site of constitutive secretion
- basal portion contains binding sites for molecular constituents of the basal lamina

Distal Basal
Secretory granules Nuclei of columnar cells
Golgi complex Filamentous mitochondria
Centrioles Endoplasmic reticulum

- Classifications:
1. # of cell layers
Simple - 1
Stratified - 2 or more
2. Shape of component cells
Squamous - flattened
Columnar - rectangular
Cuboidal - square
3. Specializations of their free surface

A. Simple Epithelium
1. Simple Squamous
- single layer of thin plate-like or flattened cells
- Top view: hexagonal polygons (irregular)
- Serrations - interlocking serrated borders
- Round nucleus at the center
- Section: cells are thin & fusiform, spindle-shaped / oval nucleus & cells
-Ex:
Pulmonary alveoli
Parietal layer of Bowman’s capsule - (spherical) outer cortex of kidney
Thin segments of Henle’s loop in the kidney
Rete testis
Inner aspect of the tympanic membrane in the middle ear
Endothelium lining the blood & lymph vessels
Lining of the heart - endocardium

Specific types Location Examples

Mesothelium lining serous membranes (mesentery) Heart - epicardium, pericardium
Lungs - pleuratoneum
Abdomen - peritoneum
Endothelium Blood vessels Artery
Vein
Heart - endocardium
Lymphatic vessels
Mesenchymal Spaces in the body that develop from the clefts of embryo Subdural space - dura matter
Subarachnoid space - pia matter
perilymphatic space

2. Simple cuboidal
- height of the cell is equal to the width
- Top: smaller cells, also hexagonal (irregular), not obvious nucleus
- Section: single row of square cells
- Round nucleus at the center
-Ex:
thyroid follicle
surface of the ovary
choroid plexus (brain)
capsule of the lens
pigment epithelium of the retina
Secretory acini of many glands (intralobular ducts) - tend to be more pyramidal than cuboidal

3. Simple columnar
- height > width
- Top: smallest, also hexagonal (irregular)
- Section: Long axis is perpendicular to the basal lamina
- Cells are tall & slender , nuclei tend to be aligned at the same level near the lamina propria
- Ex:
digestive tract from the cardia of the stomach to the anus, small & large intestines, gall bladder
Larger excretory ducts of some glands
Uterus, oviducts - ciliated
Pulmonary bronchi, paranasal sinuses - ciliated
 Central canal of spinal cord

B. Stratified Epithelium
- arranged into 3 layers of cells
- Component: arbitrarily divided
a. Basal - not all cells are attached to it unlike simple squamous
- cuboidal or columnar cells are attached to the basal membrane
b. Middle - polygonal / polyhedral
c. Superficial

Types:
1. Stratified squamous
- made up of several layers of cells in which the superficial layers are thin flattened cells
- Characteristics:
a. Epithelium is very thick - thickest of all
b. Best suited for protection
c. Provided with connective tissue papillae (areolar CT)
- superficial layers of cells lose their nuclei & the cytoplasm is largely replaced by the scleroprotein = keratin
- Keratinized stratified squamous - cells become dry , devitalized scales
- nonkeratinizing stratified squamous - contain keratin but not present in excess
-Ex:
epidermis of the skin
oral cavity (tongue & lips)
epiglottis
esophagus
conjunctiva
cornea
vagina
distal portion of urethra

2. Transitional (stratified cuboidal)

- organ is in empty space
- connective tissue papillae are absent
- cells in the surface are large & dome-shaped (umbrella-shaped)
- covers only organs of the body which are constantly filled with fluid
- Ex:
urinary bladder
Urinary tract from the renal calyces to the urethra (uroepithelium)
ureter

3. Stratified columnar
- superficial cell layers: rectangular cells
- connective tissue papillae are absent
- very rare
- Ex:
Fornix of conjunctiva - between palpibral & bulbar conjunctivae
Cavernous part of male urethra
Pharynx
Small areas of the anal mucous membrane
Large excretory ducts of some glands
Nasal surface of the soft palate, larynx, fetal esophagus - ciliated

C. Pseudostratified columnar epithelium

- false stratification
- 1 layer of cells
- nuclei lie at different layers
- all cells are attached to basal membrane but not all reached the superficial surface
- Component: (3 cell types) columnar, triangular, pyriform/fusiform/globular
nucleus is found in the broadest part except columnar cells
columnar cells only reached the free surface
- Ex:
Male urethra
excretory duct of the parotid gland, vas deferens
Trachea & primary bronchi of the respiratory tract, auditory tube, part of the tympanic cavity, lacrimal sac - ciliated

D. Specialized epithelium
- special functions
1. Glandular
- for secretion
- Component: cuboidal however as cells form acinus/acini (secretory end pieces), cells become pyramidal
Types:
Serous Mucous
Nucleus round flat
Cytoplasm granular reticulated
Size of lumen it surrounds small large
Intercellular Canaliculi present absent
Secretion produced watery mucoid/slimy
Staining acidophilic basophilic
Examples parotid gland deep esophageal gland
pancreas pyloric gland
serous gland of Von Ebner

2. Ciliated epithelium
- possess motile cytoplasmic processes on free surface
- move/transport a blanket of mucous & debris on the surface of epthelium (not phagocytosis)
-Ex:
Simple columnar ciliated - uterus, oviducts / fallopian tube, central canal of spinal cord
Pseudostratified columnar - bronchial tree: larynx to bronchi, trachea, Eustachian tube

3. Neuroepithelium
- made up of pseudostratified columnar
-will make the sensory organs
- Ex:
organ of corti - internal ear
Olfactory mucosa - nose

Functional Surfaces of Epithelial Cells (simple - all 3; stratified - 1&2 only)

I. Free Surface
A. Non-motile processes - Microvilli
Types Examples Function
1. Striated border (GIT) Lining epithelium of small & large intestines Absorption
2. Brush border (kidney) Proximal tubule Absorption
3. Stereocilia Ductus epididymis Absorption
4. Sensory hairs Sensory organs - organ of corti Sensory reception

B. Motile processes
1. Cilia
2. Flagella - spermatozoa
C. Condensed border
- transitional epithelium of urinary system
- prevents entry of hypotonic fluid on epithelial cells

STRIATED BORDER / BRUSH BORDER

-LM: exhibit fine vertical striations
-EM: consist of microvilli - slender, cylindrical, membrane-bounded cell processes
- closely packed in parallel array
- result in 15-30 fold increase in the area of cell membrane exposed to the lumen
- delicate branching filaments projecting at the tip form the glycocalyx
terminal oligosaccharides of integral membrane proteins
- contain a bundle of actin filaments that are attached to the membrane at the tip of the villus & extended down into the apical cytoplasm, where they are anchored
in a zone of transversely oriented filaments called the terminal web
- the actin filaments are cross-linked by a polypeptide called villin
- the core filaments stiffen the microvilli & help maintain their parallel orientation
- membrane is rich in enzymes that carry out the terminal stages of digestion of carbohydrates
- increase both the digestive & absorptive efficiency of the epithelium by greatly amplifying the area of membrane exposed to nutrients in the intestinal lumen

STEREOCILIA
-LM: a tuft of long, slender processes
- pseudostratified columnar epithelium of epididymis
- resemble microvilli but are very much longer
-EM: have a core bundle of actin filaments that extends into the apical cytoplasm but is less organized than microvilli of intestinal absorptive cells
- parallel at their base but become sinuous & entwined nearer their tips
- absorb 90% of the original volume of fluid secreted by the testis
- provide increased surface which contributes to the efficiency of the epithelium in concentrating the seminal plasma during its passage throughout the
epididymal duct
- also found on the hair cells of the inner ear
- narrow at their base & wider at their free ends

KINOCILIA
- specialized for transport of fluid or a film of mucus over the surface of an epithelium
- execute rapid to-and-fro oscillations
 - each cilium is observed to stiffen on the more rapid forward or effective stroke & to bend on the slower recovery stroke
- isochronal rhythm - all of the cilia on an epithelium beat synchronously
- metachronal rhythm - successive cilia in each row start their beat in sequence so that each is slightly more advanced in its cycle that the cilium behind in
that row
- results in the formation of waves that sweep slowly over the epithelial surface
-EM: axoneme - core complex consisting of longitudinal microtubules
- 2 single microtubules are in the center
 consist of 13 protofilaments each
 terminate at the base of the cilium
- 9 doublet microtubules uniformly spaced around the central microtubules
 Continuous with the 2 inner subunits of the triplet microtubules in the wall of the basal body
 Subunit A - 1 complete microtubule, circular cross section
 Subunit B - incomplete microtubule, C-shaped cross section
- consists of 10 protofilaments & shares 3 with subunit-A
- radial spoke extends from subunit-A of each doublet toward the central pair
- nexin - flexible links connecting subunit-A of 1 doublet to subunit-B of the next
- short outer & inner arms of dynein projects from subunit-A toward subunit-B of the next
 where ATPase activity reside
 motors of ciliary beat
- Kartagener’s syndrome - rare congenital disorder in which dynein arms are lacking on the doublets of the axoneme, resulting in immotile cilia & flagella
- consequent infertility & inability to clear the upper respiratory tract of mucus
- basal body
 may arise/developed from:
a. centrioles
b. deuterosomes or procentriole organizers
- nucleation sites for assembly of multiple annular procentrioles arranged radially around each organizing site
- ring-like procentrioles lenghten by polymeration of tubulin at their ends to form the 9 triplet microtubules that become the major structural
component of their wall
- serves as template during ciliogenesis

FLAGELLA
- same internal structure with cilia but are very much longer
- usually occur singly or in pairs on free-swimming cells
 Spermatozoa - propelled by a flagellum that extends posterior & moves the cell body forward
Protozoa - located at the anterior pole of the cell & have an undulatory motion in which waves of bending are propagated along the flagellum, pulling the
organism through its fluid medium
epithelial cells of mammals - occasionally have a single very short flagellum
with lumen - Renal tubules, ducts of some glands, rete testis, non-ciliated cells of the uterine epithelium
-Fxn: agitation of the fluid in the lumen of these organs
-no lumen - anterior lobe of the hypophysis, cells of islets of Langerhans of the pancreas, amacrine cells of the retina
-Vestigial flagellum projects into the intercellular clefts or into the connective tissue stroma
-Abortive flagella - smooth muscle cells & stromal cells of the endometrium

II. Lateral Surface

CELL COHESION & COMMUNICATION
- fundamental property of epithelial cells is their maintenance of extensive lateral contact to form continuous sheets of cells
- intercellular cement
- terminal bars (zonula occludens & zonula adherens)
-LM: vertical section - fusiform dark spot on each lateral cell boundary just below the free surface
subtangential horizontal section - dark band outlining the apex of the cell

A. Junctional complex
1. Zonula occludens / Tight Junction
- maintaining structural integrity of epithelium
- seals off intercellular space
- EM: membranes of adjoining cells converge & are in very close proximity for a distance of 0.1-0.3 m
- freeze-fracture preparation: thin intramembranous strands or fibrils that are more-or-less parallel but interconnected to form a loose network on the inner half-
membrane (P-face)
- pattern of shallow grooves is found on the outer half-membrane (E-face)
- transverse sections: # of rows of the fibrils corresponds to the # of sites of membrane fusion
- along each line of fusion, the membranes evidently share a single junctional fibril
- developed by aggregation & alignment of integral membrane proteins:
-ZO-I - localized immediately adjacent to the sites of membrane fusion
-Cinqulin - distributed more diffusely
- cell attachment is stronger
- efficiency varies in different epithelia being classifed as “leaky” or “tight” which depend in large measure on the # & pattern of linear membrane fusions in the zonal
-Relative permeable - rows of junctional fibrils are few & may show short discontinuities
-Tight - multiple rows of continuous junctional fibrils that completely close the paracellular route

2. Zonula adherens
- band-like specialization of the membrane & subjacent cytoplasm that encircles the apex of adjoining cells
- strongly bonds the cells together
- opposing membranes are 15-20 nm apart & the intercellular space is occupied by material of low electron density that may exhibit an exceedingly fine transverse
striation
 - section: plaque-like dense area of cytoplasm closely applied to the junctional membrane of adjacent cells
- high magnification: subplasmalemmal densities are resolved as a mat of fine filaments
- band of microfilaments around the apex of the cells generally has rather ill-defined inner limits
- in some epithelia, filaments are continuous with terminal web - thin transverse zone of cytoplasm rich in actin filaments crossing the cell a short distance below its
free surface
- actin & actin-associated proteins (-actinin & vinculin) localized in the subplasmalemmal dense band may be involved in the cross-linking & binding of the
microfilaments of the band to the junctional membrane
- adherens junction-specific cell adhesion molecule (A-CAM)
135 kD glycoprotein localized in the membranes or the interspace between them
antibody to this molecule is reported to prevent development of this type of junction
- major site of epithelial cell cohesion
- its association with the actin-rich terminal web & other elements of the cytoskeleton in columnar epithelia having a brush border suggests that it may also have a
role in stabilizing this specialization of the free surface

3. Macula adherens / Desmosomes

- do not form a continuous band encircling the cell apex
- LM: separate plaques correspond to dots or fusiform thickenings of the cell boundaries
- may also be found scattered over the lateral surfaces of epithelial cells, away from the junctional complex
- EM: bipartite structures consisting of a subplasmalemmal dense plaque 10-15 nm thick on the cytoplasmic side of the opposing membranes
- intercellular cleft is 15-20 nm wide & a thin dense line is often seen midway between the opposing membranes
- intense heavy metal staining: delicate transverse striation may also be detected
- intermediate filaments (tonofibrils) in the cytoplasm converge on the desmosomes & terminate in a satellite zone of moderate density on the inner aspect of the
dense plaque
- not only sites of cell attachment but also contribute to structural stability of the epithelium as a whole by linking the cytoskeleton of adjoining cells
- integrity of the desmosomes is calcium-dependent
- biochemical components:
a. glycoproteins
desmoglein-I - in the intercellular cleft & in the dense plaque
desmocollin-I, desmocollin-II - adhesive proteins located in the intercellular cleft
b. nonglycosylated proteins
pakoglobin, a 75 kD basic polypeptide - in the plaque
desmoplakin-I, desmoplakin-II - in the plaque & in the inner zone in which the intermediate filaments are anchored

NOTE: stratified squamous - atypical

- lacks zonula occludens & zonula adherens in the superficial cell layer
- impervious to substances in solution by the deposition of lipid in the intercellular spaces
- desmosomes are abundant in deeper layers & occur where short processes of the cells meet end-to-end
- between the desmosomes, the intercellular spaces are widened to form a labyrinthine system of interfacial canals
- at the basal surface, there are numerous hemi-desmosomes binding the epithelium to the underlying basal lamina
Columnar - puncta adherentes are less-conspicuous specializations which are occasionally found
- lack the clearly defined dense plaque
- there is a very small subplasmalemmal density in which thin cytoplasmic filaments terminate
- desmoplakins are not demonstrable but -actinin & vinculin can be detected
- minute punctate junctions which serve mainly as sites of attachment for the actin-based contractile system of the cytoplasm & probably of little
significance for maintaining cell cohesion

B. Nexus / Gap Junction / Communication Junction

- permit spread of excitation from 1 cell to the next
- region of intimate cell contact that is undetected with the light microscope
- permits passage of small molecules between cells, coordinating the activities of an epithelium
- section: resembles zonula occludens but there is no actual fusion of the membranes
- intercellular cleft is narrowed to ~3nm & is constant width throughout
- connexons can be seen bridging the gap
- freeze-fracture of P-face of the membrane: round area of closely packed particles
- negatively stained with electron opaque probe (lanthanum):
hexagonally packed annular units with a center-to-center spacing of 9 nm
cylindrical in form & ~7.5 nm in length
with a wall made up of 6 rod-like subunits around a central pore 1.5-2.0 nm in diameter
- connexons in the opposing membranes of the junction are in register & project ~1.5nm into the intercellular space, where they are linked end-to-end
- central pores form a continuous hydrophilic channel connecting the cytoplasm of contiguous cells
- ions, cAMP, amino acids & other molecules <2nm in diameter pass freely through the channels
- abundant in smooth & skeletal muscles where they provide low-resistance pathways through which excitation passes rapidly between the cellular units permitting
muscle to function as though it were a sanctum
- permeability is affected by pH & the concentration of free calcium ions
- influx of calcium due to cell injury causes a change in the configuration of the subunits in the wall of the connexons that results in closure of their channels

CELL ADHESION MOLECULES OR INTEGRINS (ICAMs)

- play a role in:
1. mutual recognition & aggregation of cells of the same type during embryonic development
2. Epithelial cell cohesion & attachment to substrate in postnatal life
- prerequisite for the development of other cohesion devices because specific blocking of their function prevents formation of the junctional complexes
- cadherins - principal class of epithelial ICAMs
- adhesive properties are dependent on calcium
- chelation of calcium results in dissociation of an epithelium
- ligands for the integrins that bind to the extracellular matrix: fibronectin, laminin, collagens
 -secreted by the cells & attached to the cells via the integrins in the cell membrane
- essential for cell migration during tissue repair

III. Basal Surface

- most are smooth contoured
- in transporting epithelia (kidney tubules), the cell base may be deeply infolded partitioning the basal cytoplasm into numerous narrow alcoves occupied by
mitochondria
- amplification of the cell base serves to increase the area of the membrane engaged in pumping ions to generate an osmotic gradient to move water across the
epithelium
- basement membrane - thin supporting layer between the epithelium & the underlying connective tissue (Slide 25 - trachea)
= basal lamina - not a lipid bilayer
= external lamina - surrounds smooth & striated muscle fibers, & certain other sessile cells of mesenchymal origin
- EM: 2 zones have generally similar thickness (40-50 nm)
Lamina lucida - pale zone of very low density immediately adjacent to the basal cell membrane
Lamina densa - outer zone of greater density exposed to the underlying connective tissue
- may be thicker
- Principal chemical constituents:
Type-IV collagen - exclusive in basal lamina & consists of 3 -chains retaining a terminal peptide that prevents their assembly into the cross-striated fibers
characteristic of other forms of collagen
-The chains are cross-linked to form the resilient 3D meshwork of the basal lamina
-Laminin - large glycoprotein is located mainly in the lamina lucida
-adherent to specific receptors in the basal membrane of the cells at 1 end & to the collagen of the lamina densa at the other end
proteoglycans
- Heparan sulfate - gives the lamina a strong anionic charge that may contribute to its function as a selective filter
- Fibronectin - can be detected on the side of the basal lamina away from the cells
- may be involved in its attachment to reticular fibers of the underlying stroma
-Anchoring fibers of type-VII collagen - course downward from the basal lamina looping around collagen fibers in the subjacent connective tissue &
terminating in anchoring plaques
(anchoring plaques = dense bodies in the extracellular matrix that have a substructure similar to that of the lamina
densa & contain both type-IV & type-VII collagen)
- abundant beneath the stratified squamous epithelium of the epidermis especially in those areas of the skin subject to frictional stress
-Functions:
1. to support the epithelium
- the meshwork of type-IV collagen in the lamina densa has considerable tensile strength & enough flexibility to permit stretching & recoil of
epithelia lining hollow organs that are subject to changes in volume
- in repair after injury to an epithelium, the persisting basal lamina provides a substrate that guides the migration of new cells from the margins
of the wound to restore epithelial continuity
2. Serves as a passive molecular seive or ultrafilter
- apparent in the kidney where urine is formed as an ultra filtrate of the blood passing through the glomerular capillaries
- basal lamina of the capillary endothelium is the filter holding back molecules on the basis of their size, shape & electrostatic charge
- pore size of the filter is determined in part by the fine mesh of type-IV collagen in the lamina densa
- charge-dependent selectivity of the filter is attributed to the polyanionic chains of the associated proteoglycans, which have large spheres of
hydration, leaving little space occupied by free water that would permit passage of macromolecules

UNIT 2

EPITHELIUM

Epithelium
- consists of contiguous cells, covering an external surface or lining an internal cavity

General Characteristics
- Made up of cells w/ scanty intercellular substance
- Has no intrinsic blood supply but is well-supplied with nerves
- Rests on a lamina propria w/ a basement membrane in between
- One surface of the epithelium is a free surface
- All epithelial tissues may undergo metaplasia

Origins of the epithelium

The ectoderm gives rise to the corneal epithelium and the epidermis of the skin. Invaginations of this epithelium gives rise to tubes or cords which the form the
glandula appendages of the skin.
Epithelia of endodermal origin give rise to the intestinal glands, liver, and pancreas.
Organs containing epithelia of mesodermal origin include the kidney and the male and female reproductive tracts, the cells lining the blood and lymph vessels, the
peritoneal cavity and other serous caivities.

Classification
Epithelia are classified according to the number of layers; simple, pseudostratified or stratified, and the shape of the uppermost layer; squamous, cuboidal or
columnar. If the cells have cilia on their free surface it is also noted on the classification as in simple columnar ciliated epithelium.

Epithelial Polarity
The cells of the epithelium are polarized in order for it to carry out its functions of secretion or absorption and to regulate transepithelial traffic of ions.

Apical plasma membrane Lateral plasma membrane Baso-lateral plasma Basal plasma membrane
membrane
-Hydrolases -Cell adhesion molecules -Anion channel (Cl+/HCO3 -Basement membrane
-Glycolipids -Junctional complexes (Zonula exchanger) receptors
-H+-ATPase occludens, Zonula adherens, -Na+-K+-ATPase
-Cl-channel Desmosomes, Gap junctions) -Growth factor receptors
-Na+-dependent transporters -Hormone and
neurotransmitter receptors

Distal End Basal End

- secretory granules - nucleus
- golgi complex - filamentous mitochondria
- centrosome - endoplasmic reticulum

Cell Cohesion and Communication

Epithelial cells maintain extensive lateral contacts to form continuous sheets of cells. These points of contact are seen in the electron micrographs as conspicuous local junctional
specializations that were designated the zonula occludens, zonula adherens, desmosomes, and gap junctions.

ZONULA OCCLUDENS
At this zone the membranes of adjoining cells are in very close proximity for a distance of 0.1 - 0.3 micrometers. The membranes in this segment fuse together at
from two to four points, diverging slightly between sites of fusion. There are a variable number of fibrils that form a loose network n the inner half membrane and a
corresponding pattern of shallow grooves on the outer half. These fibrils develop by aggregation and alignment of integral membrane proteins. Proteins designated as ZO-1 and
cinqulin, are exclusively associated with the zonula occludens.
It is in this zone that cell attachment is strongest and this zone serves as a permeability barrier (a zone that occludes the paracellular passage of large and small
molecules). This zone also serves as a barrier to diffusion of integral membrane proteins between tha apical and basolateral domains.

ZONULA ADHERENS
This zone is seen as a band-like specialization of the membrane and subjacent cytoplasm that encircles the apex of adjoining cells. In this zone the cells are 15 – 20
micrometers apart. The most conspicuous feature of this zone is a plaque-like dense area of cytoplasm closely applied to the junctional membrane of adjacent cells. Actin, α-
actinin, vinculin and the glycoprotein called adherens junction-specific cell adhesion molecule (A-CAM) have been localized in this zone.

This zone is a major site of cell attachment and also has a role in stabilizing the specializations of the free surface.

DESMOSOMES (MACULA ADHERENS)

This zone unlike the previous two, do not form a continuous band encircling the cell apex, but are seen as separate plaques arranged in a row around the cell, just
below the zonula adherens.
Desmosomes are not only sites of cell attachment but they also contribute to the structural stability of the epithelium as a whole by linking the cytoskeleton of
adjoining cells. The integrity of the desmosomes are calcium dependent and chelating agents can separate the two halves of the desmosomes causing the cells to dissociate.

GAP JUNCTION (NEXUS)

This junction permits passage of small molecules between cells, coordinating the activities of an epithelium. In some histological sections, minute structures, called
connexons, can be seen bridging the gap between two cells. These connexons are culindrical in form with a wall made up of six rod-like units with a central pore. This pore form a
hydrophilic channel connecting the cytoplasm of contiguous cells. Ions, cAMP, amino acids and other molecules smaller than 2 micra can freely pass through this channel. These
type of junctions are also abundant in smooth and skeletal muscles where they provide pathways through which excitation passess rapidly between cellular units permitting the
muscle to function as a syncitium.

The Basal Surface

At the boundary between the epithelium and the underlyin connective tissue, there is a thin supporting layer called the basal lamina. Two zones are distinguishable
within the basal lamina; lamina lucida, lamina densa. The lamina lucida lies immediately underneath the epithelium.
The principal chemical constituents of the basal lamina are type-IV collagen, laminin and proteoglycans. Type-IV collagen is exclusively found in the basal lamina.
Laminin is localized mainly in the lamina lucida and its molecules adhere to specific receptors on the cll membrane on one end and to the collagen of the lamina densa on the
other end. The proteoglycans of the lamiona densa include heparin sulfate which gives it a strong negative charge.
The primary function of the lamina is to support the epithelium. The basal lamina also serves as a passive ultrafilter.

Free Surface Specializations

STRIATED BORDER (BRUSH BORDER)

Striated borders consists of short microvilli closely packed in a parallel array with some 60 per square micra of epithelial surface resulting in a 15 – 30 fold increase in
the area of the cell membrane exposed to the lumen. At the tips of the microvilli are delicate branching filaments of glycocalyx which are the terminal oligosaccharides of
integral membrane proteins. This border serves to increase both the digestive and absorptive efficiency of the epithelium by greatly amplifying the membrane exposed to the
nutrients in the intestinal lumen.

STEREOCILIA
This specialization is found in the cells of the pseudostratified columnar epithelium of the epididymis. They resemble microvilli but are very much longer and because
they are nonmotile so they are calle stereocilia. This epithelium is known to absorb up to 90% of the original volume of fluid secreted by the testis. They can also be found on the
hair cells of the inner ear.

CILIA
The cells that are specialized for transport of fluid or a film of mucus over the surface of an epithelium have cilia on their free surface which execute rapid to-and-fro
oscillations responsible for the net movement of the fluid over their surface. When viewed from above, these waves are reminiscent of he waves that run before the wind across
a field of palay so char.
Electron micrographs of the cilia reveal a core complex known as the axoneme, which consists of microtubules that have a 9 + 2 arrangement or two single
microtubules surrounded by nine doublets uniformly spaced around. At the base of each cilium, there is a basal body similar in structure to the centrioles. The cilia’s active
strokes are fueled by the hydrolysis of ATP by the ATPase activity of the dynein arms. In humans with Kartagner’s syndrome in which the dynein arms are lacking on the doublets
of the axoneme results in immotile cilia and flagella with consequent infertility and inability to clar the URT of mucus.

Renewal and Regeneration

 Cells in the skin are continually being desquamated but are rapidly replenished by new cells by the rapidly mitosing stratum germinativum of the skin. The layer of
dead cells provide some degree of protection to the cells deeper from them.
In the git, damaged cells and senescent cells are continually exfoliated at the tips of the intestinal villi and are replaced by division of cells in the cryps.
During wound healing, the cells at the margins of the defect flatten into a thin sheet that spreads to fill the gap in the epithelium. Cell division begins later, at the
margins of the wound, to provide additional cells.

CONNECTIVE TISSUE

Connective Tissue
- a diverse group of tissues that share a common origin from the mesenchyme of the embryo
- well supplied with nerves and blood essels
- main bulk is ground substance
- has connective tissue fibers including collagen, fibrillin, and elastic fibers
- has fixed and free cells

The Ground Substance

- a highly hydrated gel where nutrients and waste products pass through in transit between blood vessels and the cells.
- metachromatic because of the glycosaminoglycans including chondroitin sulfate, keratin sulfate, heparin sulfate and hyaluronic acid

Fibers
Type I collagen – the most common collagen, occurring n the dermis, bone, tendon fascia and the capsules of organs

Type II collagen – found in hyaline and elastic cartilage, nucleus pulposus of the intervertebral discs and vitreous body of the eye

Type III collagen – abundant in loose connective tissue, walls of blood vessels, stroma of various glands and in the kidney, spleen and uterus, forms agryophilic fibers also known
as reticular fibers

Type IV collagen – specialized form and largely restricted to the basal lamina of epithelia

Type V collagen – associated with the external lamina of smooth and striated muscle fibers and the basal lamina of epithelia

Type VI collagen – present in small amounts where types I and II are found

Type VII collagen – most abundant in the dermo-epidernal junction of the skin

Type IX collagen – found mainly in cartilage

Type X collagen – also confines to cartilage

Fibrillin – appears as a beaded chain ion the electron microscope closely associated with elastic fibers or with the basal lamina of the epithelia, deficient in marfan syndrome

Elastic Fibers – found in areas where elasticity is needed, like in the walls of large arteries, elastic ligaments

Cells(fixed and free)

Mesenchymal cells – all connective tissue develop from embryonic mesenchymal tissue, present in small amounts in postnatal life and gives rise to other cell types as the need
arise

Fibroblasts – these cells are the cells producing the fibers and the ground substance that make up the ECM of connective tissue

Adipocytes – cells specialized for the storage and synthesis of fat

Macrophages – maintains the tissue by engulfing dead cells and foreign bodies, breaks them down and eliminates them

Connective tissue Histiocytes

Skin Histiocytes
Bone marrow Littoral cells
Liver von Kupffer cells
Lungs Heart failure cells/dust cells
Bone Osteoclasts
CNS Microglia/mesoglia
Blood Monocytes

Plasma cells – has a spoke of wheel appearances of the chromatin and is the cell that produces antibodies

Mast cells – produces heparin, and vasoactive amines

WBCs

Reticular cells – usually associated with reticular fibers

Pigment cells – synthesis and storage of pigments

 ADIPOSE TISSUE

Adipose Tissue
- tissue specialized for the storage of lipids
- provides mechanical support
- insulation reservoir of energy synthesis of fat

there are two types: white fat and brown fat

White Fat Brown Fat

Color White to yellowish Brown to reddish brown
Distribution Widely distributed Localized
Vascularity Less vascular Highly vascular
In starvation Easily lost Not easily lost
Fat droplet Coalesce Does not coalesce
Nucleus Flattened to the periphery Spherical slightly eccentric

UNIT 3

SKIN
- widest & heaviest organ (16% of body weight)

Functions - depend mainly on the properties of the epidermis

1. Protection
2. Permeability barrier - prevents dehydration
3. Thermoregulation - insulated against heat loss by hairs & adipose tissue facilitated by evaporation of heat in skin surface
4. Sensory perception - receive stimuli from the environment
5. Immunological fxns - physical barrier against invasion of microorganisms

Classification based on thickness of epidermis

1. Thick - soles of feet & palms of hand
2. Thin - abdomen & inner surfaces of extremities

Prinicipal Layers
A. Epidermis - stratified squamous keratinizing epithelium
- forms an uninterrupted investment over the entire surface of the body
- locally specialized for the production of the skin appendages
- also gives rise to 2 kinds of glands
- free surface of the skin is not smooth but is marked by shallow grooves & flexure lines which are deeper on thick hairless regions (elbows, knees, palms &
soles)
Dermatoglyphs - alternating ridges & grooves on finger pads
- distinctive pattern of arches, loops or whorls
- has a well-developed basal lamina
a. lamina densa - parallel to the membrane of basal cells of the epithelium
- fine meshwork of type-IV collagen, also containing heparan sulfate & glycoprotein
b. lamina lucida - transversed by exceedingly thin filaments crossing from the CM to lamina densa
- slender anchoring fibrils
* extend from the lamina downward, arching around collagen bundles in the dermis & terminating in anchoring plaques (small bodies having the
same density & substructure as the lamina densa)
* others connect neighboring anchoring plaques
* have beaded or cross-striated appearance characteristic of type-VII collagen
- cytokines - influence growth & differentiation
a. epidermal growth factor (EGF) & IL-1 - stimulatory
b. TGF - suppress keratinocyte proliferation & differentiation
- epidermal cells can synthesize TGF & may autoregulate their own growth

Epidermal layers - (best seen in thick skin!)

1. Stratum Basale / Germinativum - 1 layer of cuboidal or low columnar cells
- basophilic
- filaments occur singly & in conspicuous bundles that often end in desmosomes or in hemidesmosomes spaced at regular
intervals along the membrane adjacent to the basal lamina
- basal cells consist of a loose network of keratins K5 & K14
- supported by a typical basal lamina
- separated from dermis by basement membrane
- intense mitotic activity (basal cells are only capable of undergoing mitosis)
- Fxn: continuous renewal & replenishment of superficial cells which are desquamated
2. Stratum Spinosum / Malpighii - multiple layers of cuboidal cells
- prickle cells due to spiny appearance
- less intensely basophilic than stratum basale
- numerous bundles of cytokeratin intermediate filaments that radiate from the perinuclear region, to end in the dense
plague of numerous desmosomes
- synthesize 2 new keratins: K1 & K10
- cells also produce involucres & other “envelope proteins” that are deposited on the inner aspect of CM
 - membrane-coating granules or lamellar granules
* secretory granules
* have limiting membrane
* distinctive internal structure consisting of closely packed parallel lamellae
* made up of discoid flattened vesicles
* release complex lipid & lipoproteins into the intercellular spaces
3. Stratum Granulosum - 3 to 5 layers of flattened polygonal cells
- kerato-hyaline granules
* bodies of large size & very irregular shape
* intensely basophilic
* don’t have a limiting membrane
- greater # of lamellar granules, where they collect near the CM
* undergo exocytosis & their content coalesces to form a continuous multilayered coating of the CM
- increase in the size of extracellular spaces & this space is occupied by the lipid-rich secretory product of the cells
* a kind of waterproof sealant
* major component of the epidermal permeability barrier
- cease to produce keratins & envelope proteins
- instead synthesize:
* filaggrin - involved in the assembly of keratin filaments into still coarser bundles
* loricin - additional component of the cell envelope
- cells become permeable to calcium ions that activate an enzyme which cross-links the various envelope proteins to form a very tough
layer beneath the CM
4. Stratum Lucidum - layer of thin, lightly staining, refractile, 4 to 6 rows of very flat cells
- usually not identifiable in the thin skin
- keratin filaments in the cytoplasm are closely aggregated & more consistent in their orientation parallel to the skin surface
- CM appears thickened by deposition of dense material on its inner surface
5. Stratum Corneum - thickest
- horny cells
- many layers of very flat, heavily keratinized cells containing no nucleus or cytoplasmic organelles
- CM appears thickened
- entire cell is filled with keratin filaments embedded in an amorphous matrix
- desmosomes have been greatly modified
- cells are reduced to tough, inert shells packed with coarse bundles of keratin filaments
- intercellular spaces are filled with secreted lipid-rich compounds that render the epithelium relatively impermeable
6. Stratum Disjunctum - most superficial layer where fully keratinized, lifeless cells loosen & ultimately desquamate
- flakes / squames

Epidermis in General:
- much thinner stratum corneum
- thin stratum spinosum - only 2 to 3 cells thick
- stratum lucidum is seldom found
- dermal papillae are shallower
- the contour of the dermoepidermal junction differs greatly from region to region

Cellular components:
1. Keratinocytes - form the main bulk of epidermis
Keratinization / Cornification - accumulate increasing amounts of keratin filaments in the cytoplasm
- form superficial dead cells found in middle & superficial layers
2. Melanocytes - situated in the basal layer of the epidermis or in the underlying dermis (ratio of melanin = 1:4-10)
- Fxn: synthesis & production of melanin (brown skin pigment)
* melanin occurs in granules called melanosomes in the cytoplasm of melanocytes & keratinocytes
* formed only by epidermal melanocytes because these cells alone possess tyrosinase
* cytocrine secretion - fully formed melanocytes are transformed from melanocyte dendrites to keratinocytes
* epidermal melanin unit - constitute a melanocyte & its satellite epidermal cells
* DOPA  black & highly branched dendritic processes
* few on the arms & thighs; many on the face & neck
* Caucasians - melanosomes are confined to the cells of stratum Germinativum
* negroids - melanosomes are larger, numerous & are found throughout the epidermis
3. Langerhans cells - dominant cell type
- isolated dendritic cells
- usually located in the upper layers of the stratum spinosum
- H & E  dark-staining nucleus & a pale clear cytoplasm
- can be selectively stained with gold chloride  black & stellate
- take up ethylene blue & other survival dyes
- have affinity for catecholamine & 1,3,4-dihydroxyphenylalanine (L-DOPA)  fluorescent on subsequent exposure to formaldehyde vapor
- most numerous in epidermis but occasionally found in epidermis
- occur in: other stratified squamous epithelia (oral cavity, esophagus & vagina)
Thymus, lymph nodes & spleen
- EM: nucleus is highly irregular in outline
Cytoplasm is of low density
Few mitochondria & little ER
Multivesicular bodies, lysosomes & small vesicles
- Birbeck granules or vermiform granules
* unique membrane-limited granules
* discoid in 3D but rod-like in section with a central linear density from which faint striations radiate to the limiting membrane
* occasionally have expanded end  racquet-like appearance
 * no enzymatic activity
- possess surface receptors & immunological markers similar to those of macrophages
- capable of mitosis
- Fxn: important agents in contact allergic responses & other cell-mediated immune rxns of skin

4. Merkel cells - abundant in fingertips; also found in the oral mucosa

- found in the basal layers of the epidermis
- basal lamina is traversed by the naked terminals of myelinated afferent nerves & these end in close apposition to these cells forming merkel
cell-neurite complexes that may have a mechanoreceptor fxn
- occur singly but may be clustered in certain specialized areas
- long axis is usually parallel to the basal lamina
- nucleus is deeply invaginated & may contain a strange inclusion consisting of a bundle of short parallel filaments
- cytoplasm is of low electron density
- cytokeratins K8, K18 & K19
- dense-cored granules located in the perinuclear cytoplasm & in the dendrite-like cell processes
- Fxn: sensory perception

Mucocutaneous junctions - skin is continuous with the mucous membranes lining the ff structures: eyelids, nose, lips, vulva & prepuce

B. Dermis / Corium - underlying tough supporting & nourishing layer of fibroelastic CT

- tough leathery layer of CT that makes up the greater part of thickness of the skin
- thinner on ventral surface of the body & extremities that it is on the dorsum
- thinner in women than in men
Dermal layers:
1. Papillary layer - more superficial
- made up of areolar CT
- contain thin collagen fiber bundles (type-III) & more cellular fibroblast
- also contains loose network of elastic fibers & many capillaries
- possess elevations which project into epidermis to form dermal papillae:
a. nervous - Meissner’s corpuscle
b. vascular
Fxn: responsible for ridges & lines found on skin surface
Interpapillary pegs - down-growths of epidermis
2. Reticular layer - made up of dense CT
- closely packed coarse bundles of thicker collagen fibers (type-I)
- elastic fibers are abundant around the sebaceous & sweat glands
Cell types: fibroblasts, macrophages, lymphocytes, mast cells & occasionally adipose cells in deeper portion of reticular layer
Structures of dermis: loose plexus of smooth muscle cells - penis, scrotum & areola around the nipples
Arrector pili - insert into the body of the hair follicles
Skeletal muscle - muscles of facial expression (face, scalp, base of the ears)
panniculus carnosus -
Sebaceous glands, Sweat glands

Hypodermis - beneath dermis but not part of skin

- made up of loose areolar & adipose CT
panniculus adiposus - layer of fat found in subcutaneous tissue
- loosely attached to underlying deep fascia or to periosteum of bone
Fxn: binds skin to underlying fascia or bone

Skin Appendages
A. Hair - thin keratinizing structure derived from hair follicle (cells lining deep invaginations of epidermis)
* hairless skin areas: vermillion border of the lips, palms, soles, lateral sides of fingers & toes, lateral surface of the feet below the ankle, glans penis, clitoris, inner
surface of the prepuce, labia minora & inner sides of labia majora
Divisions of hair
1. Hair shaft - project above skin surface
2. Hair root - embedded in the skin
Structures of hair follicle
1. Hair bulb - terminal expansion which has a deep recess in its under side
2. Hair papilla - extend into concavity of hair bulb
Fxn: inductive influence in hair formation
3. Hair matrix - covering hair papilla
- darkly pigmented cells (brown / black)
Fxn: where hair formation & growth occur
* cell matrix - mass of cells in the interior of the bulb around the papilla
* medulla - large vacuolated cells situated above the apex of the papilla
- contains relatively little keratin
* cortex - more peripheral matrix
* as the cells are displaced upward  synthesize a great quantity of keratin filaments & many trichohyaline granules
* trichohyaline granules - coalesce into a hard amorphous substance that obscures the keratin filaments
- insoluble proteins have a high content of glutamic acid, glutamate & citrulline
* hair cuticle - cells farther toward the periphery of the bulb
- very heavily keratinized
* soft keratin with filaments embedded in filaggrin - continuously shed at the skin surface
* hard keratin with filaments embedded in trichohyalin - accumulate in concentric layers forming the hair shaft
 Layers of hair follicle
1. Epidermal root sheath - cellular & epithelial portion
a. external root sheath - in the hair bulb, only 1 row of cells corresponding to stratum basale
- nearer the surface of the skin, it becomes several layers thick & exhibits strata typical of thin skin
b. internal root sheath - concentric layers of the follicle
* Henle’s layer - 1 row of elongated cells in close contact with the innermost cells of the external root sheath
* Huxley’s layer - 2 or 3 rows of less flattened cells
* cuticle of the inner root sheath - flat scale-like cells imbricated with their free edges directed downward
2. Dermal root sheath - dense fibrous CT immediately surrounding the epidermal root sheath
3. Glassy membrane - non-cellular vitreous layer which seems to be an exceptionally thick basal lamina of the outer layer of follicular epithelium
- separate epidermal root sheath (epithelium) & dermal root sheath (CT)
- homogeneous & acidophilic
B. Arrector Pili Muscle
- strands of smooth muscle fibers arranged obliquely in relation to hair follicle
- attached to dermal root sheath at 1 end & to dermal papilla at other end
- goose bumps / goose flesh  erection of hair during muscle contraction
C. Nail - closely compacted hard keratin
- fused cornified cells
O: dorsal surfaces of terminal phalanges of toes & fingers
Parts:
1. Nail Plate
a. free edge - distal part of nail bed
- usually worn-out or cut-off
b. body - visible part covering the nail bed
c. root - proximal end of nail plate covered by thin skin fold
d. lunula - opaque white crescent-shaped portion near the root
- quite often, it is obscured by the proximal nail fold & eponychium
2. Nail bed - epidermis loses its stratum corneum & continues beneath the body of the nail plate
a. nail matrix - proximal portion of nail bed
Fxn: formation of nail substances
b. hyponychium - thickened keratinized skin at distal portion of nail bed beneath free edge of the nail
3. Nail wall - skin folds surrounding the nail plate laterally & proximally
a. eponychium /cuticle - proximal fold made up of cells of horny layer of skin
- overhungs the proximal part of nail plate
- covers the root
- stratum corneum of the epidermis on this fold may extend for a short distance onto the upper surface of the nail forming
thin covering on its proximal
4. Nail groove - slit between nail bed & nail wall
D. Sebaceous glands
- simple branched acinar gland; holocrine secretion
- Fxn: production of sebum (greasy secretions)
- contribute to the maintenance of the soft texture of thin skin & the flexibility of the hairs
- ducts open into neck of hair follicle; if hairless, directly into skin surface
- discharge their secretion into the upper 1/3 follicular canal
- found at an angle between arrector pili muscle & hair follicle
- containing abundant fat droplets
- O: lips, areola of the nipples, labia minora & on the inner aspect of the prepuce
- not found in palms, soles & sides of the feet
- uropygeal gland (preen gland) in birds
* Modified Sebaceous Glands
1. Meibomian - eyelids
2. Zeis - eyelids
3. Tyson’s - glans penis
E. Sweat glands
- simple coiled tubular glands
- mode of secretion: merocrine
Kinds Eccrine Apocrine
Occurrence widely distributed areolae of breasts,
EXCEPT: vermillion border of lips, nailbed, glans penis & axilla, mons pubis, circumanal region
clitoris
Duct ascend to open into skin surface opens into the canal of a hair follicle
Secretory cells - secretory portion (thermoregulatory mechanism) cuboidal or low columnar but may be
embedded in dermis squamous
- Secretory cell types: cuboidal or low columnar epithelium
a. dark cells - inverted pyramid
- usually don’t reach the basal lamina
b. light cells - broad apical region & a narrow basal
region that extends down to the basal
lamina
- devoid of secretory granules
embryology Develop from cords of cells that grow downward from the Arise as an epithelial bud growing from the
epithelium of the dermal ridges side of a hair follicle
Secretory activity Become functional soon after birth doesn’t begin until puberty
Summary of Differences - no connection with hair follicles - appendages of hair follicles
- fxn throughout life producing a watery secretion - begin to fxn at puberty producing a slightly
- innervated by cholinergic nerves viscous secretion
- innervated by adrenergic nerves

Modified Apocrine Sweat Glands:

1. Cerumenous glands of auditory canal - produce ear wax
2. Glands of Moll’s - associated with eyelids

BLOOD & LYMPH VESSELS

Rete cutaneum - plexus, parallel to the skin surface at the boundary between the dermis & hypodermis
Rete subpapillare - small ascending arteries at the boundary between reticular & papillary layers of the dermis
Arteriovenous anastomoses - open under certain circumstances, shunting blood directly from arteries to veins without an intervening capillary bed
- fxn: thermoregulation by controlling blood flow to the superficial layers of the skin

NERVE ENDINGS
- sensory nerves
a. free endings - lack morphologically recognizable receptor specializations at their ends
- common in epidermis
- may be pain receptors or thermo receptors
- Merkel endings - myelinated afferent nerves
- have disc-like expansions in contact with its CM near the base of the epidermis
b. encapsulated nerve endings
Occurrence Description
Pacinian corpuscles dermis & hypodermis of skin, - conspicuous ovoid structures
periosteum of bone, - axon & processes are surrounded by concentric lamellae consisting of
CT stroma of some organs very thin flat cells separated by narrow spaces filled with gel-like material
of low viscosity
- the nerve & its surrounding lamellae are enclosed in a thin CT capsule
Meissner’s corpuscles few of the dermal papillae of the - pear-shaped
glabrous skin of palms, soles, - the axon of a myelinated nerve reaching the lower pole of the corpuscle,
nipples, lips & external genitalia pursues a spiral or zigzag course in its interior
- oriented transversely, resulting in a ladder-like striation in H&E
- has moderately thick capsule
- fxn: mechanoreceptors responding to slight deformation of the skin
Kraus’s end bulbs papillary layer of the dermis, small spherical bodies
conjunctiva,
stratified squamous epithelia of
the mouth, tongue & external
genitalia
Ruffini corpuscles Dermis & hypodermis - small fusiform structures with a relatively thin capsule
- abundant beneath the skin on - oriented parallel to the surface of the skin
the plantar surface of the feet - bundles of collagen fibers run through the core of the corpuscle
- fxn: mechanoreceptors responding to tensional forces

UNIT 4
DIGESTIVE SYSTEM

MOUTH-PHARYNX

DIGESTIVE SYSTEM
Fxns:
1. Ingestion - taking the food into the mouth
2. Digestion - processing / breaking down of food into usable forms
3. Absorption - passage of substances through the intestinal lining into the blood or through a cell membrane into the cell
4. Elimination of unusable portion

I. ORAL / BUCCAL CAVITY

- entrance to the digestive tract  food is mechanically fragmented by the teeth & chemically modified & lubricated by saliva before being transported via the pharynx &
esophagus to the stomach for further processing
- has lumen & the walls are arranged in concentric layers
- vestibule -- narrow space between the inner surface of lips & cheeks & the outer aspect of gums & teeth

MUCOUS MEMBRANE
1. Tunica Mucosa - mucous membrane lining the organ
- in the floor of the mouth & on the cheeks -- can be moved or elevated into folds
- on the gums & hard palate -- firmly bound to the periosteum of the underlying bone by dense CT
- on the soft palate -- continues around its posterior margin for some distance onto its nasal surface & there the stratified squamous epithelium gives way to
pseudostratified ciliated columnar epithelium (characteristic of the nasal & respiratory passages)
Lining epithelium - stratified squamous non-keratinizing
- don’t exhibit the zonation found in the epidermis
 - as cells move upward from the basal layer:
> they increase greatly in size
> contain abundant tonofilaments
> But don’t become greatly flattened as they approach the surface
- Desmosomes are less numerous & smaller
- thin on the vestibule & floor of the mouth
- thicker on the cheeks
- the greater thickness, firmer attachment & greater degree of keratinization of the epithelium on the gums & hard palate make these regions more
resistant to attrition during chewing
- more permeable on the floor of the mouth & under side of the tongue
* certain medications (nitroglycerin) diffuse through the epithelium & into the circulation
Lamina propria - loose  permit considerable mobility over the underlying structures
- extends into deep recesses in the under surface of the epithelium as CT papillae
- more delicate with thinner collagen & elastic fibers compared to the dermis of skin
- large #s of lymphocytes in the posterior portion of the oral cavity & many of these migrate into the epithelium
- plexus of larger vessels in the submucosa contributes branches to a plexus of smaller vessels in the lamina propria, from which branches form capillary
networks in the CT papillae beneath the epithelium
- richly innervated by sensory branches from Trigeminal nerve (V) & on that portion covering the tongue
special sensory branches from Facial nerve (VII) to the specific organs of the sense of taste
Muscularis Mucosae - thin layer of smooth muscle which serves as outer limit of tunica mucosa
- absent in oral cavity!
2. Tunica Submucosa - poorly delineated
- loose areolar CT
- in the floor of the mouth & on the cheeks

Structures:
A. Lips / Labia Oris
- made up of the Orbicularis Oris skeletal muscle & dense CT
- at the free edge, gives way to a hairless very thin skin with an epidermis that is sufficiently transparent to permit the blood in the capillaries of the dermis to impart
to it a red color
- on the inner aspect, there is gradual transition from skin to the mucous membrane lining the vestibule & the mouth proper
Divisions:
1. Oral Side / Internal Portion
Lining epithelium - stratified squamous non-keratinizing with tall CT papillae
Tunica submucosa - contain labial glands which are mixed type but predominantly mucous
2. Skin Side / External Portion
- covered by typical thin skin with hair follicles, sebaceous & sweat glands
3. Vermillion Border / Red Free Margin
- Transitional Zone
- numerous & tall CT papillae
- lamina propria - vascular, contains numerous blood vessels  pink
- hairless & no glands

Gingiva - abrupt transition to a pink layer firmly fixed to the underlying bone by rather dense CT
- covers the gums & extends between the teeth
- in the roof of the mouth, it continues from the alveolar process over the entire hard palate
- has thick stratified squamous epithelium with numerous papillae penetrating deep into its lower surface
- stratum layers are distinguishable
Corneum - cells are keratinized but retain condensed nuclei & appear to be viable
- continually exfoliated into the saliva
Granulosum -
Spinosum - contain bundles of tonofilaments that terminate in conspicuous desmosomes that firmly attach neighboring cells
Basale - hemidesmosomes from which anchoring fibers loop around bundles of collagen fibers in the underlying lamina propria

B. Oral Cavity Proper

- Boundaries:
Above - hard & soft palate
Anteriorly - inner aspect of gums & teeth
Posteriorly - 2 palatoglossal folds of the mucous membrane on either side of the communication between the mouth & the pharynx

TONGUE - occupies much of the mouth

- bulk consists of interlacing bundles of skeletal muscles which run in different planes of sectioning
- highly mobile at anterior portion which is involved in mastication, phonation (speech) & swallowing
- posterior portion is less mobile owing to its continuity with the floor of the mouth & its attachment to the hyoid bone

T. mucosa - found at rough dorsal surface

- tightly adherent to the underlying skeletal muscle
Lamina propria - dense & continuous with interstitial CT of underlying muscle
T. submucosa - found at smooth ventral surface

Dorsal Surface of the Tongue:

- covered by a relatively thick epithelium, firmly bound to an underlying layer of dense CT, from which septa extend downward between the
underlying bundles of muscle fibers
- Sulcus Terminalis - shallow V-shaped groove
- boundary between the anterior 2/3 & posterior 1/3
- open part of V is directed forward
 - apex (foramen caecum) is pointed towards back
 there is slight depression that is a vestige of the thyroglossal duct
 evagination of the floor of the mouth that gave rise to the thyroid gland early in
embryonic life
1. Anterior 2/3 of the Tongue
- oral part / body of the tongue
- rough
- covered by a multitude of small excrescences called the LINGUAL PAPILLAE:
a. Filiform papilla
- most abundant
- slender, conical, slightly curved with their tip pointing toward the back
- covers the entire anterior 2/3 of the dorsal portion of the tongue
- arranged in more or less distinct rows coursing to left or right from median sulcus & parallel to the diverging arms of the sulcus
terminalis
- heavily keratinized cells at the tips are continuously exfoliated
* disturbances of gastrointestinal fxn  normal shedding is delayed & accumulate in a layer mixed with bacteria & form a gray film
over the surface of the tongue  coated tongue
b. Fungiform papilla
- few taste buds
- scattered singly among filiform papilla
- more numerous at the tip of the tongue
- narrow base & slightly flattened hemispherical upper portion
- stand slightly higher than the filiform papillae
- primary & secondary CT papillae in their core project into conforming recesses in the under side of their epithelium which is essentially
unkeratinized & has a smooth free surface
- pink color because their core is highly vascular & relatively thin overlying epithelium
- microscopic appearance:
Primary - narrow base with smooth rounded & expanded top surface
Secondary - has blood vessels  red
* Lamina propria forms secondary with blunt ends
c. Circumvallate / Vallate papilla
- largest
- 6 to 14 are confined to the posterior part of the tongue where they are aligned just in front of sulcus terminalis
- 10 to 12 are arranged along the sulcus terminalis
- free surface is smooth
- sunk on surface of mucous membrane
-> surrounded by 2 circular furrow/trench/crypt
-> lamina propria form multiple secondary papillae which is short & found at the upper surface only
-> numerous taste buds are seen on the lateral side of the epithelium
* 250 per single papilla
-> associated with serous glands of Von Ebner
* secretory end pieces of glands are found at the underlying x-sec of skeletal muscle
* excretory ducts of serous gland empty at the bottom of the crypts
* secretion is thought to fxn in rinsing out the furrow around the papillae
d. Foliate papilla
- rudimentary in human
- well-developed in rabbits, monkeys & many other animals
- a group of parallel ridges, separated by deep clefts, is found in a slightly elevated region on the sides of the tongue at the junction
between its anterior & posterior portions
- the epithelium on the sides of the ridges contains many taste buds
- paired & found on dorso-lateral aspect of posterior part of the tongue

2. Posterior 1/3 of the Tongue

- pharyngeal part / root of the tongue
- has large but few irregular bulges known as lingual tonsils
- lacks papillae

Glands of the Tongue:

1. Anterior Lingual Glands
Blundin / Nuhn - mixed type of gland found at the sides of median line near the apex of the tongue
2. Posterior Lingual Glands
Serous gland of Von Ebner
Glands of the root of the tongue - mucous-type

TASTE BUDS
- pale ovoid bodies in the darker staining lingual epithelium
- consist of fusiform cells slightly wider at the base than at the apex
- taste pore -- small opening in the superficial layers of the epithelium where the narrow apices of taste buds converge
- stem-cell precursors of the gustatory cells -- small cells at the base of the taste bud
- types of cells based on the depth of their staining: Light & Dark cells
a. Type-I cells - slender dark cells situated both at the periphery of the taste bud
- its anterior have long microvilli projecting into the taste pore &
small dense secretory granules in their apical cytoplasm
- supporting cells
- largely surround & isolate the other 2 cell types from each other
- secrete a dense amorphous material that surrounds the microvilli in the taste pre
 b. Type-II cells - light cells
- more centrally situated
- also have long microvilli but lack secretory granules in their apical cytoplasm
- abundant smooth ER but little rough ER
c. Type-III - primary gustatory receptor
- long apical process
- extends through the dense material in the pore to the free surface
- cytoplasm contains small dense-cored vesicles that are most abundant near the cell base
d. Type-IV - basal cells

- receptor surface for the sense of taste -- processes projecting into the pore
- when exposed to a substance to which they can respond, the gustatory cells are depolarized & secrete a
neurotransmitter that stimulates the endings of afferent nerves
- average life span of a cell in the mammalian taste bud is 10-12 days

Basic Taste Location Transduction Mechanisms

Sensations
Sweet abundant near Involve a subset of taste cells that have specific membrane receptors that
the tip of the bind sugars, resulting in a change in a membrane conductance,
tongue depolarizing the cell & causing transmitter release
Salty Depends on apical Na+ channels that can be blocked by amiloride
Bitter back of the Involve a bitter-specific receptors
tongue
Sour Depends on the blocking of K+ channels in the apical CM by acid (H+ ions)

NERVES
- depending on the location of the taste buds on the tongue, may be innervated by sensory axons from cranial nerves:
Branch Areas Innervated
Mandibular nerve (V) Lingual branch tongue anterior to the sulcus terminalis
Facial (VII) Chorda tympani branch Gustatory sensation anterior to the sulcus terminalis
which accompanies the
lingual nerve
Glossopharyngeal (IX) Lingual branch Taste buds in the circumvallate papillae & pharyngeal portion of
the tongue
Vagus (X) Superior laryngeal Taste buds on the epiglottis & extreme posterior portion of the
branch tongue

- nerves to the taste buds lose their myelin sheath & branch profusely to form a sub epithelial plexus from which branches enter the epithelium
- intergemmal fibers -- arborize between the taste buds
- perigemmal fibers -- closely surround the taste buds
- viability of cells is dependent on their innervation
- any given nerve fiber appears to receive its sensory input from cells of the same type

SALIVARY GLANDS
- classification:
1. Exocrine - based on discharge of secretion
- secretions are released on the epithelial surface from which the glands originate
2. Merocrine - based on gland cell participation in secretion
- secretory granules leave the cell with no loss of cellular material
3. Compound tubulo-alveolar gland - based on morphology
- derived from Ectoderm
- morphologic & functional unit: Adenomere
- composed of: Acini - secretory end pieces
Intercalated ducts
Secretory ducts - striated ducts
- composition: smaller salivary glands which is a collection of adenomeres
1. Labial glands - vestibule (upper & lower lip)
2. Buccal glands - cheeks
3. Serous glands of Von Ebner - tongue
4. Glossopalatine glands - floor of the mouth
5. Anterior lingual glands
6. Palatine glands
7. Glands of the roof of the tongue
- secretion: Saliva
- always has: desquamated squamous epithelial cells
salivary corpuscles - degenerating lymphocytes & granulocytes
- composed of: H2O
Carbohydrates
Proteins - mucoproteins & immunoglobulin
Inorganic components - Na, Ca, K, Mg, P, Fe, Cl, I
Enzymes - amylase or ptyalin which splits starch into H2O-soluble CHOs
 - fxns: * lubricate the oral cavity
* initiate digestion of food
* promote excretion of certain substances - thiocyanate & urea
* reabsorbs Na & excrete K
- structure:
1. Stroma - framework of the organ
- encircled by a fibrous capsule
From the capsule, the septa would arise & divide the gland into lobes & lobules & would contain blood vessels, lymphatic vessels, nerves, ducts
also pass through the septa
2. Parenchyma

Duct System Description Lining Epithelium Location

Excretory duct Larger lined by tall columnar epithelium but interlobular
the main excretory duct is lined by
pseudostratified columnar epithelium
Secretory duct striated duct simple cuboidal to simple columnar Intralobular
cells which would demonstrate vertical
striations due to parallel rows of
filamentous mitochondria at the basal
portion
Intercalated duct Attached to the acini or Simple cuboidal to simple squamous Intralobular
secretory end pcs
Basket cells - Stellate-shaped ells with Between granular
many cytoplasmic cells & basement
filaments membrane
- myoepithelial cells that
are believed to be
contractile

- types:
* if the gland is predominantly serous:
mucous cells - near the ducts
serous cells - near the end of the terminal secretory portion
* if the gland is predominantly mucous:
Serous cells - displaced to the periphery or terminal portion
- appear as saccular out-pocketings of the acinus
- darkly stained crescents around the ends of the tubules of mucous cells
- demilunes of Giannuzi or Serous demilunes
Parotid Submaxillary Sublingual
Acinar cells Purely serous Mixed - mainly serous Mixed - mainly mucous
5S:1M 30 M : 1 S
Capsule Present Present Not definite
Length of intercalated duct Long Short Absent
Length of secretory duct Long Longest short
Name of main duct Stensen’s duct Wharton’s duct Bartholin’s duct - main
Rivinus - accessory
Opening of duct Vestibule Floor of the mouth Floor of the mouth
- opposite the 2nd upper - adjacent to lingual - adjacent to lingual
molar frenulum frenulum
Occurrence of mumps Infected None None

TONSILS (lymphoid organs!)

1. Palatine tonsils - between the glossopalatine & pharyngopalatine arches
at the boundary between the mouth & oropharynx
a. with tonsillar crypts - stratified squamous epithelium
- 15 or more
- simple or branched
- extend nearly to the condensation of CT that forms a capsule around the tonsile
b. 2 large ovoid accumulations of lymphoid tissue - lymphatic nodules
- immediately beneath the epithelium
along side the crypts
- prominent germ centers
c. capsule of condensed CT
d. thin partitions of CT - extend inward from the capsule
-separate the masses of lymphoid tissue associated with the crypts
* mast cells, plasma cells, PMNs
e. infiltration of lymphocytes - deeper portions of the crypts
- at boundary between the epithelium & lymphoid tissue (capsule)
- displace & distort the epithelial cells such that only a few are recognizable
 f. salivary corpuscles - lymphocytes & neutrophils migrate through the epithelium
- found in the saliva
- vesicular structures: pycnotic nucleus
Granules
show Brownian Movement
g. small glands - outside the capsule
- ducts open into the surface
few / none open into the tonsilar crypts
h. lumen - large accumulations of living & degenerating lymphocytes
exfoliated epithelial cells
bacteria
- cheesy plugs of increased size of accumulations
* ultimately extruded or calcified
2. Pharyngeal tonsils - midline of the roof & posterior wall of the nasopharynx
a. pseudostratified ciliated columnar epithelium - not invaginated
- plicated to form multiple surface folds
b. infiltration of lymphocytes on the crests of the folds
c. lymphoid tissue - thick layer
- diffuse & nodular
- participates in the fold
d. thin CT capsule - surrounds the lymphoid tissue
- partitions into the core of each fold
e. small glands - markedly dilated
- transverse the lymphoid tissue
- open into the surface of the folds / furrows between the folds
Generalities on Tonsils
- don’t have lymphatic sinuses
- lymph is not filtered through them
- only blind-ending lymphatic capillaries surround the outer surface
- reach maximal development in childhood
- involution begins at 15 yrs
- presence of pharyngeal tonsil in an atrophic condition usually found in adults
 ciliated is replaced by stratified squamous
Palatine Pharyngeal
Epithelium Stratified squamous Pseudostratified columnar ciliated &
stratified squamous
Invaginated to form crypts Plicated to form surface folds
Lymphoid tissue Paired unpaired
Glands Non-dilated ducts Dilated ducts

C. TEETH
-
- hard bone-like structures of jaws for mastication
- derivatives of oral mucous membrane
- surfaces:
Lingual - inner surface that faces the tongue
Buccal - toward the cheek
Labial - for the teeth in the anterior portion of the dental arch
Mesial - on the sides of the arch, anterior surface that face toward the midline of the arch
Distal surface - opposite of mesial
- sets:
1. Milk / Deciduous Teeth - temporary
- 20 in #
- begin to emerge about 7 months after birth
- reach full complement at 6-8 yrs of age
- shed between the 6th & 13th yr
2. Succedaneous Teeth - permanent
- adult has 32 teeth: 16 each in the alveolar process of maxilla & in the mandible
Shape Fxn
Incisors Chisel-like Cutting or Shearing
Canines Pointed Puncturing & Holding
Molars Crushing & Grinding

- anatomical parts:
1. Crown - projecting above the gum
- covered by enamel
2. Root - covered by cementum
- fits into the socket or alveolar of the bone
3. Neck - junction between the crown & root
- histologic parts:
1. Hard Portion
a. Dentin - bulk of the tooth
- slightly yellow & semi-transluscent (fresh)
- harder than bone (20 % organic -- 92 % collagen & 80 % inorganic -- hydroxyapatite crystals)
- radially striated appearance under long section due to minute parallel canals called Dentinal Tubules, radiating from pulp cavity toward the
dentino-enamel junction
Odontoblasts - responsible for dentin formation
- columnar cells that form an epithelial layer around the periphery of the pulp cavity
- odontoblast process (formerly dentinal fibers / Tome’s fibers) extends into a dentinal tubule
Predentin - unmineralized zone around the proximal portions of the odontoblast processes
- traversed by a terminal web
Mineralization front - abrupt transition from the predentin to dentin
Dentinal tubules - major component: fibers near the odontoblast process run parallel to its surface
- not straight!
- S-shaped primary curvature & helical secondary curvature
- may penetrate a short distance into the enamel as Enamel Spindles
Interglobular spaces - not totally calcified
- in the crown, persist in the deeper part of the dentin
Granular layer of Tomes - small interglobular spaces in the root of the tooth
- immediate between the junction of the cementum with the dentin
b. Enamel - bluish-white & nearly transparent in thin ground section
- hardest tissue of the body (99 % is hydroxyapatite crystals)
Enamel rods / prisms - stand upright on the dentin with a pronounced inclination toward the incisal or occlusal surface
- poorly calcified
- x-sec: fluted semicircles or keyhole-shaped prisms with their convex surfaces all facing in the same direction, resulting in an appearance
reminiscent of the pattern of scales on reptilian skin
- long section: alternation of light bands with darker bands where directions of curvatures cross
Lines of Schreger - bands traversing the enamel obliquely
Lines/Striae of Retzius - run obliquely inward from the surface toward the pulp
- result from rhythmic deposition & mineralization of enamel during development of the tooth
Angular spaces (interprismatic regions) - between groups of parallel enamel
- occupied by interrod enamel
Enamel sheath / Prismatic rod sheath - thin layer of organic matrix around each rod
- 2 thin superficial layers at the free surface:
Enamel cuticle - inner
- final product of ameloblasts before they disappear
Outer - keratinizrf remanents of the dental sac of the developing tooth
- adherent to the tooth
- not part of the CT of the gingiva
- not present in older individuals
- organic matrix: not keratin nor collagen
¼ are proline
Relatively high conc of bound phosphorus
- Ameloblasts responsible for secretion of protein organic matrix of enamel
Amelogenins - large protein or glycoprotein products that are broken down extracellularly
Enamelins - proteins extracted from mature enamel
- bound to the crystallites of the enamel prisms
- axial section: dentino-enamel junction has a scalloped contour
Enamel tufts - result from local disturbances in enamel formation during tooth development
- optical illusion due to projection of distorted rods & fibers lying in slightly different planes
Enamel lamellae - linear markings extending inward from the surface of the enamel to the dentin
- thin sheets of uncalcified matrix
c. Cementum - mineralized tissue closely resembling bone
- no blood vessels & haversian systems
- grows very slowly but many undergo hyperplasia in response to chronic irritation
- where periodontal ligaments are attached
Acellular cementum - cervical portion & a thin layer adjacent to the dentin
Cellular cementum - within which Cementocyes are enclosed in lacunae in the matrix
cementoblasts - found on a thin layer of universalized matrix at the surface of the root

Pulp chamber - small central cavity that corresponds in its shape to the outer form of the tooth
- continues downward into each root as a narrow Root Canal that communicates with the Periodontal Membrane through an Apical Foramen at the tip
of the root
Apical foramen - where the blood vessels, nerves & lymphatics enter & leave the tooth

2. Soft Portion
a. Pulp - nerve of the tooth
- CT which fills up the pulp cavity
- predominant cells: fibroblasts
- other cells: lymphocytes, macrophages, plasma cells & eosinophils
- core: nerve, blood vessels, Odontoblasts, collagen fibers
Zone of Weil - relatively cell-free area adjacent to the layer of odontoblasts that line the pulp cavity
Korff’s fibers - bundles of fibrils passing across the zone of Weil & between the odontoblasts
Necrosis of the pulp - compression of blood vessels due to leaking of plasma & increased pressure associated with infection
 Gasserian ganglion
b. Periodontal membrane/ligament - binds the cementum-covered surface of the root to the alveolar bone
- bundles of collagen fibers which serve as firm attachment between bone & root of the tooth
- slightly wavy when the tooth is not in use
- straighten when pressure is applied to the crown
- serve as periosteum of alveolar process of bone
- osteoblasts & osteoclasts may be found
- more vascular & more metabolically active than other ligaments & tendons
c. Gingiva / Gum - part of oral mucous membrane surrounding the teeth & overlying the alveolar process
- in young persons, it is attached to the enamel
- with increasing age & old persons, it is attached to the cementum
- lined by stratified squamous keratinizing epithelium with CT papilla
- lacks stratum Granulosum
- superficial layer of flattened cells retain pycnotic nuclei
- perakeratosis
Free / Marginal gingiva - less firmly attached to the underlying periosteum
Gingival crevice / sulcus - shallow furrow separating the free gingiva from the enamel
Junctional epithelium - lining the sulcus
- relatively thin, unkeratinized & lacks CT papillae
- bound by hemidesmosomes
- prevents entry of bacteria into the periodontal tissues
- lamina propria contains many lymphocytes & PMN leukocytes
- if severely damaged, a persistent gingivitis may result
- directly applied to the neck of the tooth
Alveolar bone - cancellous bone between 2 layers of cortical bone
- quite labile
- readily available source of calcium
Outer cortical plate - continuation of the mandible or maxilla
Inner cortical plate / Lamina Dura - adjacent to the periodontal membrane
- surrounds the roots to form their sockets
Cancellous trabeculae - buttressed by the labial & lingual coritical plates
- aid in resisting the pressure on the teeth during mastication

D. Palate
- no T. submucosa
- has sero-mucous glands
- hard -- roof of oral cavity separating it from nasal cavity
Soft -- posterior continuation of hard palate ending in tongue-like structure  uvula
Hard Soft
Oral side lining epithelium Stratified squamous Stratified squamous
Middle layer Maxillary & Palatine bones Skeletal muscle
Nasal side lining epithelium Pseudostratified columnar ciliated Pseudostratified columnar ciliated

II. PHARYNX
- posterior continuation of the oral cavity
- portion where respiratory passages & pathway for food merge/cross
- regions:
Nasopharynx Oropharynx Laryngopharynx
1. T. mucosa
Lining epithelium Pseudostratified columnar ciliated Stratified squamous Stratified squamous
with goblet cells
Lamina propria Fibro-elastic tissue with Fibro-elastic tissue with
Mixed type of glands Mucous glands Mucous glands
Muscularis mucosa Absent Absent Absent
2. T. submucosa Mixed type of glands Absent Mucous glands
3. T. muscularis Skeletal muscle Skeletal muscle Skeletal muscle
4. Location Above the soft palate From the level of the soft palate Upper border of epiglottis
Behind the nose To the upper border of epiglottis To the lower border of the
esophageal opening

ESOPHAGUS-STOMACH

General features of GIT

- the wall of the alimentary tract is made up of 4 layers:
1. Mucosa - innermost
a. Lining epithelium varies in type of different regions of the tract depending whether the fxn is conductive, secretory or absorptive
b. Lamina propria - layer of highly vascular loose CT
- components: fibroblasts, macrophages, wandering lymphocytes
 reticular & elastic fibers
Local aggregation of lymphoid tissue
c. Muscularis mucosae -- 2 tenuous layers of smooth muscle (ICOL)
- permit independent movement of the mucosa to change its surface contour
return it to the resting state after distention of the lumen
2. Submucosa - dense CT
- small blood vessels that supply the mucosa
- Meissner’s plexus (sympathetic nerves) -- control much of the intrinsic motility
3. Tunica muscularis - 2 moderately thick layers of smooth muscle (ICOL)
- Auerbach’s plexus (sympathetic nerves) -- coordinates the peristaltic contractions of the muscle that move the contents along the tract
4. Tunica serosa - outermost
- mesothelium -- simple squamous that lines the abdominal cavity & covers the organs within it
- underlain by a very thin layer of loose CT
- mesentery -- very thin sheet of CT covered on both sides by mesothelium that is continuous with that of the serosa

ESOPHAGUS
- greater part of its 25 cm length is within the thorax
- after passing through the diaphragm to join the stomach, its terminal is 2-4 cm in the abdominal cavity
I. MUCOSA
Lining epithelium - stratified squamous
- 2 to 3 cells thick
- stratum Corneum
Spinosum - superficial cells retain their nucleus & have a few keratohyaline granules
- short microplicae in stratum spinosum
- processes of cells are attached by desmosomes
- contain bundles of intermediate filaments & vesicles
Germinativum - cuboidal & have desmosomes on their interdigitating lateral surfaces
- hemidesmosomes at their base
- Langerhans cells -- occasional stellate cells that are not attached by desmosomes
- fewer filaments
- small #s of rod-like granules with a laminar internal structure
- antigen-presenting cells
- base is quite irregular with closely spaced deep recesses in its under surface, occupied by papillae of lamina propria
- maintains a barrier to the passive diffusion of ions & toxic substances from the lumen to the blood
- doesn’t depend on tight junctions in the epithelium
- reside in the glycoconjugates of stratum corneum & outer layers of stratum spinosum
Muscularis Mucosae - absent in the upper portion of esophagus
- longitudinal smooth muscle fibers in the lower esophagus
II. SUBMUCOSA
- interlacing bundles of collagen fibers
- abundant elastic fibers
- many small blood vessels
II. MUSCULARIS EXTERNA - ICOL
- upper 1/3 -- skeletal muscles
- middle -- skeletal  smooth
- lower 1/3 -- smooth muscles

ESOPHAGEAL GLANDS
Superficial mucosal glands - Cardiac Esophageal Glands
- Islands of Ectopic Gastric Mucosa
- lamina propria
- limited in # in the upper esophagus & near its junction with the stomach
- tortuous tubular glands
- small ducts join a larger duct that usually opens at the tip of a small papilla
Submucosal glands - more widespread
- extend into submucosa
- tubuloacinar
- arranged in small lobules that are drained by a single duct
- mixed type (mucous & serous)
- Lysozyme & Pepsinogen in the cytoplasm (not in the mucous cells)
- Oncocytes -- occasional eosinophilic cells at the transition from acinus to duct
- no obvious secretory granules
- large #s of closely packed mitochondria
HISTOPHYSIOLOGY OF THE ESOPHAGUS
Physiological sphincters - no thickening of the wall
- no change in orientation of the muscle fibers
a. Pharyngoesophageal sphincter - higher muscular tone on the junction of the pharynx with the esophagus
b. gastroesophageal sphincter - maintain an intraluminal pressure slightly higher than enterogastric pressure

Hiatus hernia - esophageal hiatus in the diaphragm fails to close completely around the esophagus during development
- a portion of the stomach may protrude into the thoracic cavity
- interferes with the normal sphincteric fxn of the terminal esophagus permitting reflux of gastric contents
- esophageal epithelium is poorly equipped to resist the acidity of gastric secretions
- inflammatory responses may cause difficulty in swallowing
- may ultimately lead to fibrosis & stricture of the lower esophagus
 Nerve supply - via nerves from the cervical & thoracic sympathetic trunks that form plexuses in the submucosa & between layers of the muscularis

STOMACH
- capable of considerable expansion during meal without significant increase in internal pressure
- storage fxn is quite limited
- multichambered in ruminants: rumen  reticulum  omasum  abomasum
- regions: cardia -- narrow zone around the esophageal orifice
Fundus - dome-shaped bulging to the left above the level of the opening of the esophagus
Corpus - capacious central region
Pyloris - tapering distal portion terminating at the gastroduodenal orifice

I. GASTRIC MUCOSA
Rugae - conspicuous longitudinal folds
- flatten out in the full stomach
Gastric pits or foveolae - funnel-shaped invaginastion of the surface epithelium
Gastric glands - slender, straight
- from the bottom of each foveolae
- occupy the greater portion of the depth of the mucosa
Lining epithelium - simple columnar
Mucous cells - apical surface bears short microvilli
- sparse glycocalyx at the tips
- attached by juxtaluminal tight junctions
- have occasional gap junctions & desmosomes on their lateral surfaces
- narrow lammellipodia extend from the side of the cells
- apical cytoplasm -- filled with secretory granules -- faintly stained in H&E
- intensely colored by PAS rxn for carbohydrates
- homogeneous & electron-dense
- pale with a uniformly stippled texture

CARDIAC GLANDS - slender tubular glands

- arise from shallow foveolae in a narrow zone around the gastroesophageal junction
- tortuous at their lower end & some are branched
- few undifferentiated cells are found near the necks of the glands
- occasionally endocrine cells occur among mucous-secreting cells
- majority secrete Gastrin -- stimulates secretory activity of glands in the corpus
- influences gastric motility

OXYNTIC GLANDS - glands of the fundus & corpus

- make the greatest contribution to the gastric juice
- arise from each foveola
- isthmus -- confluence with the foveola consists mainly of surface mucous cells
- neck: mucous neck cells & oxyntic cells
- base: chief cells, oxyntic cells & mucous neck cells
- 5 cell types:
a. Mucous neck cells - columnar cells
- lodged between oxyntic cells
- either: broad apex & slender mid region
Constricted apical region & a broader base
- polyribosomes are more abundant
- deep pink secretory granules
- larger than surface mucous cells
- dense core & lighter outer core
- mucin in their apical cytoplasm has a stronger affinity for basic dyes at low pH than that of the surface cells
- produce sulfated glycoproteins & small amount of secretin

b. Stem cells - mitotic activity

- large nucleolus
- abundant polyribosome
- continuous renewal of the gastric mucosa depends on their proliferation
- as daughter cells differentiate  migrate upward  replace surface mucous cells
downward  form new oxyntic & chief cells
c. Oxyntic (Parietal) cells - most conspicuous cells of the gastric mucosa
- produce HCl
- have broad rounded bases
- cytoplasm -- stains intensely with eosin or phloxine
- no secretory granules
- smller paranuclear golgi complex
- large mitochondria occupy 40% of the cell volume
- more actin
- not prominent organelles of the biosynthetic pathway for proteins:
Small golgi complex & limited amount of rough ER - Gastric Intrinsic Factor
- Secretory Canaliculus -- meandering invagination of the apical surface
- have a rate of O2 consumption 5x that of the mucous cells
- Tubulovesicular system -- abundance of membrane-bounded structures that don’t appear to be elements of the ER
 - internal organization undergoes striking changes:
nonsecretory cells - secretory canaliculus is small
- short microvilli
- very extensive tubulovesicular system
Stimulated cell - rapid elongation of the canaliculus
- increase in # & length of its microvilli
- 5fold increase in surface area
- H,K-ATPase
- dramatic reduction in the extent of tubulovesicular system
- reorganization of the cytoskeleton
d. Chief (Zymogenic) cells - predominant cells in the lower 1/3 of oxyntic glands in the corpus of the stomach
- absent from the cardiac glands
- sparse in the glands of the fundus
- rare in pyloris
- have strongly basophilic cytoplasm
- numerous apical secretory granules -- selectively stained by Bowie’s Biebrich scarlet method
- contain pepsinogen
- luminal surface bears short microvilli coated with a thin glycocalyx
- numerous lysosomes
- exocytosis of the secretory product can be accelerated by feeding or by Secretin
e. Endocrine cells - found in all segments of the gland

PYLORIC GLANDS - occupy the distal 4-5cm of the stomach

- 1/5 of the surface area of the gastric mucosa
- deeper gastric pits or foveolae
- larger lumen
- more highly branched & tortuous than the oxyntic glands
- seldom seen in continuity in histological sections
- predominant cell type is mucus-secreting cell -- secrete lysozyme
- occasional oxyntic (parietal) cells are also found
- abundant enteroendocrine cells
- lymphoid cells contain Russell’s bodies between the epithelial cells of the gland

ENTEROENDOCRINE CELLS
- small granulated cells scattered individually among the cells of the gland
- stained selectively by silver or chromium salts  argentaffin or enterochromaffin cells
- contain small secretory granules that are concentrated in the cytoplasm at the cell base
- those containing monoamines exhibit fluorescence
- APUD (amine precursor uptake & decarboxylation) cells

Secretion & its Fxn Description of the cells

G cells Gastrin - stimulates gastric motility - abundant in pyloric antrum
- potent stimulator of acid secretion - pyramidal
- stimulates proliferation & differentiation of stem cells into - long microvilli
oxyntic cells in the corpus
- regulator of mucosal growth
EC cells Serotonin - influences gastric motility - pyramid with a narrow apex
- granules have oval or elongated dense
cores
D cells Somatostatin - inhibitory effect on the other enteroendocrine cells - occur in glands near the pyloris
- more numerous in the duodenum
A cells Enteroglucagon - raises blood glucose levels by stimulating hepatic - small granules with a clear halo around a
glycogenolysis dense core
ECL cells Histamine - stimulates gastric secretion - large secretory granules
- mediate or complement the action of gastrin - contain 1 or more eccentrically placed
dense cores

Zolliger-Edison Syndrome - overproduction of gastrin results in excessive acid secretion & mucosal hyperplasia

Lamina propria - loose CT

- reticular & collagen fibers but very few elastic fibers
- component cells: fibroblasts, lymphocytes, eosinophils, mast cells & few plasma cells
- few slender strands of smooth muscle may be found running vertically
- small accumulations of lymphoid tissue

II. SUBMUCOSA - moderately thick layer of dense CT

- coarser bundles of collagen fibers & many elastic fibers
- numerous wandering cells: lymphocytes, eosinophils, sessile mast cells & plasma cells
- few adipose cells may occur
- many arterioles, venous plexus & lymphatics

III. MUSCULARIS EXTERNA - 3 layers of smooth muscle

longitudinal fibers - thickest along greater & lesser curvatures of the stomach
 - don’t continue all the way to pyloris
- incomplete & cannot be found in some areas of the dorsal & ventral sides of the organ
Circular - complete layer over the whole stomach
- thickest in the pyloris where it forms an annular Pyloric Sphincter
Oblique - don’t form a complete layer
- more concentrated at the cardia
- lacking along the lesser curvature of the stomach
- contraction is regulated with great precision by Autonomic nerve plexuses between its layer

CELL RENEWAL & REPAIR

- mitotic activity is largely confined to cells in isthmus & necks of the glands
- chief cells are capable of division
- gastric mucosa also has a remarkable capacity to reestablish epithelial continuity after superficial injury
- repair is due to migration of viable cells from the depths of the foveolae in a process called gastric Mucosal Restitution
- destruction of the basal lamina by very low pH in gastric lumen greatly retards restoration of epithelial continuity
- high rate of blood flow to the mucosa & plasma leakage at a site of injury can maintain a pH of 6-7 even when acid of pH 1 is present in the lumen

HISTOPHYSIOLOGY OF STOMACH
- when empty, its luminal volume is only 50-75 mL but 1.2 L can be swallowed
- volume of secretions produced daily ranges from 0.5-1 L
- gastric juice -- clear, colorless
- contains: mucus, H2O, HCl, pepsin
- secretion of acid maintains an optimal intraluminal environment for proteolysis by pepsin which is most active at pH 2
- gastric mucosa has an ability to produce a secretion having a pH ranging from 2 to as low as 0.9

SMALL INTESTINE

SMALL INTESTINE

Length: 4-7 m
Segments: No distinct boundaries in between
Duodenum - 25 cm in length
- firmly fixed to the dorsal wall of the abdomen & is largely retroperitoneal
- has C-shaped course around the head of the pancreas
Jejunum - freely movable on its mesentery
- proximal 2/5 of the length of SI
- its convolutions occupy the central region of the abdomen
Ileum - 3/5 of the length of SI
- situated in the lower portion of the cavity

Concentric layers:
I. MUCOSA
- efficiency of the absorptive fxn of SI is augmented by a # of structural devices that increase the total area:
a. Plicae circulares (valves of Kirkring) - visible to the naked eye
- crescentic folds that extend for 1/2-2/3 of the distance around the lumen
- permanent
- including both mucosa & submucosa
- absent from the 1st portion of the duodenum
- greatest abundance in the terminal duodenum & 1st portion of the jejunum
- seldom found beyond the middle of the ileum
b. Intestinal villi - finger-like projections
- length depends on the degree of distension of the intestinal wall & the degree of smooth muscle contraction in their interior
- cover the entire surface of the intestine & give it a characteristic velvety appearance
- most numerous in duodenum & proximal jejunum
c. Crypts of Lieberkuhn (intestinal glands) - invaginations between the bases of the villi
- tubular glands

- epithelium: simple columnar -- have a remarkable capacity to close tears in their membrane & survive
Cell types:
a. Absorptive cells (enterocytes) - columnar with central nucleus
- has a prominent brush border (striated border)
- beneath is a clear zone devoid of organelles
- contain a distinct terminal web -- layer of transversely oriented fine filaments that exhibit birefringence under a polarizing
microscope
- selectively stained using Tannic Acid, Phosphomolybdic acid & Amido Black

Surface coat / Glycocalyx - consist of core polypeptide & oligosaccharide side-chains of a glycoprotein
- form a layer that is resistant to mucolytic & proteolytic agents
- protect the striated border
- form a substrate for the digestive process because the pancreatic amylase & other intraluminal enzymes are adsorbed to the large
surface presented by its filaments

Brush border - in the core of microvilli: 20 parallel actin filaments

- anchored in a cap-like subplasmallemal density at the tip of the villus
- extend downward into the apical cytoplasm
- x-linked by Fimbrin & Villin
 - the bundle as a whole is attached to the membrane by a helical array of lateral arms or bridges
- the bridges consist of brush-border myosin-I -- complex of Ca-binding Calmodulin & Myosin
- at the lower end of actin filaments, they are surrounded by tropomyosin & fodrin of the terminal web
- microvilli don’t shorten

- lateral contraction of the terminal web increases the convexity of the cell apex & spreads the tips of the microvilli apart
- smooth ER are abundant in the cytoplasm below the terminal web
- absorption of fat

Juxtaluminal junctional complex - bars access to the intercellular clefts from the lumen
Occluding junction - completely encircling the cell
- ensures that products of digestion must traverse the brush border, apical cytoplasm & lateral CM below the tight junction to gain
access to the intercellular spaces & move on to capillaries of lamina propria

Adluminal membrane - rich in glycolipid

Peptide hydrolases - aminopeptidase
N-dipeptidylpeptidase-IV
p-amino benzoic acid peptide hydrolase
Disaccharidases - sucrase-isomaltase
Lactase-phlorizin hydrolase
Maltase-glucoamylase
Carrier proteins for amino acid & carbohydrate transport
- enzymes are absent from basolateral membrane

b. Goblet cells - mucus-secreting unicellular glands

- scattered among the absorptive cells of the intestinal epithelium
- apex: has an expanded cup-shaped rim of cytoplasm called Theca
Filled with secretion
- narrow base
- secretory material is in the form of large pale granules that more-or-less confluent
- hydrophilic mucin takes up water, resulting in swelling of the apical portion of the cell
- luminal surface: bears a few microvilli around the periphery
Smooth & convex over the secretory granules
- firmly attached to neighboring absorptive cells
- has well-developed cytoskeleton
- intermediate filaments are abundant in the theca

Inner basket-like layer - surrounded by circumferential bundles of filaments arranged like barrel hoops around the mass of secretory granules
- vertically oriented microtubules -- between the inner layer of filaments & mucin granules
- upward movement of newly formed mucin
- contains little or no actin
- no evidence that its contraction is involved in release of the cells secretory product

Mucin - viscid fluid or thin gel

- consists of glycoprotein: 20% peptides & 80% carbohydrates
- synthesized & secreted at a relatively constant basal rate
- normally released by exocytosis of 1 granule at a time
- in accelerated secretion, there may be fusion of granule membranes resulting in chains of intercommunicating granules opening at the cell surface
 compound exocytosis
- within the release, the content of granules undergoes a several-hundred-fold expansion in volume due to its rapid hydration
- forms a layer over the surface that protects the epithelium form abrasion & prevents adherence & invagination by pathogenic bacteria

c. Enteroendocrine cells - enterochromaffin cells

- small cells near the base of the intestinal epithelium
- secretory granules concentrated at the cell base
- release their secretion into the lamina propria (not into the intestinal lumen)
- bind alkaline bichromates (chromaffinity)
- precipitate silver salts in the absence of a reducing agent (argent affinity)  argentaffin cells
- argyrophilic
- highly heterogenous cell population
- highly variable in form: ovoid or pyramidal - in the crypts
Columnar - on the villi
- bulk of the cell body is always in the lower half of the epithelium
- narrow apical region extends to the lumen & as a brush brder
- nucleus is round & poor in heterochromatin
- paler cytoplasm
- longer & thicker microvilli -- chemoreceptor fxn
- substances identified: 5-hyrodroxytryptamine (serotonin) - EC cells throughout the intestinal tract
Glucagon / glicentin - GLI cells in distal ileum, colon & rectum
 Somatostatin - D cells occur throughout the intestine
Gastrin - G cells -- few in # confined to the proximal duodenum
Cholecystokinin - I cells - most numerous in the
Motilin - Mo cells proximal & midportion
Secretin - S cells of intestine
Neurotensin - N cells - very rare in the
Gastric inhibitory polypeptide - K cells colon & rectum
Substance-P
B-endorphin

CRYPTS OF LIEBERKUHN & CELL TURNOVER

- upper ½ is lined with low columnar epithelium
- lower ½, the cells are less differentiated except for paneth cells
- cell turnover -- continuous renewal of the epithelial lining of the intestinal tract by proliferation of cells in the crypts, their migration up onto the villi & exfoliation of
effete or dying cells at the villus tips
- mucosa of the jejunum has the fastest rate of turnover of any tissue in the body
- in the colon, villi are lacking but the pattern of cell renewal is much the same
Proliferate zone in the crypts is more extensive
Cells are extruded when they reach the mucosal surface between the crypts
Slower cell division & migration
- starvation or protein deficiency  atrophy of both muscular & mucosal components of SI
Mitotic cycle in the crypts are prolonged
Slow migration

d. Paneth cells - don’t participate in the upward migration of cells

- pyramidal in form with a round or ovoid nucleus near their base
- basophilic basal cytoplasm
- numerous secretory granules at the apex stain with acid dyes such as eosin & orange-G
- long-lived
- not observed in mitosis
- don’t incorporate tritiated thymidine
- secretory granules: large, homogeneous & electron-dense
- secrete continuously but enhanced by feeding
- increased by pilocarpine
- lysozyme -- highly charged cationic protein that is capable of digesting the wall of certain bacteria
- phagocytize & digest intestinal flagellates & certain spirilliform microorganisms
- may play a role in controlling the microbial flora of the intestinal glands
- contain IgA

- lamina propria: loose CT

- occupies the interstices between the crypts of Lieberkuhn & the cores of the intestinal villi

Lacteals - slender lymphatic vessels

- terminal branches of submucous lymphatic plexus
- pathways for the transport of absorbed lipid & other nutrients

Macrophages - in the SI, located in the lamina propria of the upper half of the villi
- greatest in # in the colon, immediately beneath the surface eptihelium
- contain lysosomal hydrolases: nonspecific esterase
Acid phosphatases
-glucuronidase
N-acetyl--D-glucosamidase
4-6x higher than in the monocytes
- 1st line of defense against any microorganisms

Mast cells: typical - found in CT throughout the body

- predominate in the submucosa
Atypical (mucosal mast cells) - in the lamina propria
- have Fc receptors for the IgE
- secrete histamine, serotonin, & chemotactic agents for neutrophils & eosinophils
- involve in local defenses of intestine against enteric parasites

Lymphocytes - most abundant of the free cells of the lamina propria

IMMUNOLOGICAL SURVEILLANCE OF LUMINAL ANTIGENS

Peyer’s patches - aggregated lymphoid nodules
- larger & more numerous in the ileum
- usually located in the mucosa opposite the line of attachment of the mesentery
- intestinal epithelium covering the dome contain specialized M-cells that are not found elsewhere in the mucosa
M cells - broad cells with a few short microvilli
- invaginated basal surface forming deep recesses or pockets between basal CM & the basal lamina
- continuously sampling antigens in the intestinal lumen
- gram (-) bacteria & viruses adhere to these cells
MHC class II positive dendritic cells, helper T cells - complete the processing & presentation of antigens to antibody producing B lymphocytes
 SECRETORY IMMUNE SYSTEM OF THE INTESTINE
IgG - general immunological defense of the body
IgA - secretory immune system produced by plasma cells
Secretory component (secretory piece) - carrier protein of IgA
Immune exclusion - inhibit bacteria adherence, & neutralize viruses & toxins
IgA proteases - bacterial enzymes that cleave IgA
MUSCULARIS MUCOSAE - smooth muscle with networks of elastic fibers
- its contraction increases the height of folds of the mucosa

II. SUBMUCOSA - moderately dense CT rich in elastic fibers

- contain small clusters of adipose cells
- in the duodenum, largely occupied by the glands of Brunner

Brunner’s glands - initial portion of the duodenum

- few may also be found in the lamina propria of pyloric antrum
- in the submucosa of the plicae circulares
- secretory portions are coiled tubules forming small lobules
- ducts ascend through the muscularis mucosae to open into the crypts of Lieberkuhn or between the villi
- secretion of duodenal glands is clear & has an alkaline pH 8.2-9.3
- protect the duodenal mucosa against the potentially damaging effects of the strongly acidic gastric juice
- synthesize & secrete a low-molecular-wt polypeptide  urogastrone
- (EGF) stimulate cell division & inhibit gastric acid secretion
- regulation of growth, tissue repair & regeneration
- resistant to trypsin, chemotrypsin & pepsin digestion
- modulate the secretion of acid by the oxyntic cell of stomach
- influence rate of cell proliferation in intestinal crypts
- concentrated in urine, gastric juice, saliva, bile & milk
- accelerate healing

III. MUSCULARIS - ICOL layers of smooth muscle

- slow rate of cell replication throughout the external layers
- sympathetic myenteric nerve plexus between the layers
- responsible for peristalsis
- segmental movements -- alternative constriction & relaxation of short segments
- don’t advance the content toward the large intestine
- result in to-&-fro movements that serve to agitate & mix the material in the lumen
- in the ileum, it is somewhat thickened forming the Ileocecal Sphincter -- normally remains partially contacted

IV. SEROSA - mesothelium

- loose CT

Mesentery - suspend the GIT from the dorsal wall of the abdomen
- thin bilaminar sheet of mesothelium through which the blood vessels reach the gut
- along the line of its attachment, the serosa is continuous with the 2 apposed leaves of the mesentery
- at the base, these are in turn continuous with the serous lining of the abdominal cavity

Peritoneum - continuous layer of mesothelium suspending the inner aspect of the abdominal wall & the surface of all organs
Parietal - lining the cavity
Visceral - lining the organs

Transudation of fluid from the underlying capillaries - moistens the smooth serous surfaces of organs
- facilitates frictionless sliding of the loops of the intestine over 1 another during peristalsis
Peritonitis - severe inflammatory process that is often fatal
- result from bacterial contamination of the abdominal cavity due to perforating lessions of the gut wall

LARGE INTESTINE

Cecum - blind-ending pouch at the proximal end of the ascending colon

Ileocecal valve - closes the orifice at the junction of the cecum & ascending colon, where the ileum joins it on its medial side
Appendix - projecting from the cecum posteromedial to the ileocecal valve

APPENDIX
- length: 2-8 cm
Mucosa - thickened by an extensive accumulation of lymphoid tissue which forms a nearly continuous layer of large & small lymphatic nodules
- lymphatic tissue often shows chronic inflammatory changes
- small lumen -- has an angular outline in x-sec
- filled with dead cells & detritus
- villi are usually absent
- crypts of Lieberkuhn -- irregular in shape
- largely embedded in the underlying lymphoid tissue
- glandular epithelium -- contains only a few goblet cells
 - consists mainly of columnar cells having a brush border
- zone of mitotically active cells in the crypts is shorter than in the SI
- enteroendocrine cells & paneth cells are regularly founding the depths of the crypts
- paneth cells are more numerous than in the crypts of the SI
Muscularis mucosae - poorly developed
Submucosa - relatively thick
Muscularis externa - reduced in thickness but its 2 layers are still identifiable
Serosa - same as that covering the rest of the intestines

CECUM & COLON

Mucosa - doesn’t form folds
- no intestinal villi beyond the ileocecal valve
- (colon) has smooth surface with the naked eye but somewhat irregular in outline in histological sections due to agonal contraction of the muscularis
- LPO: innumerable crypts or glands of Lieberkuhn -- straight tubular glands
- longer than those in the SI
- no paneth cells
- greater abundance of goblet cells -- most conspicuous cell type
- columnar absorptive cells -- majority of cells in the middle & upper portions of the crypts
- principal cell type in the epithelium
- enteroendocrine cells are present in small #s
- epithelium is constantly being renewed
- Extrusion Zones -- where cells slough off into the lumen
- situated about midway between the openings of neighboring crypts
- lamina: scattered lymphoid nodules are always present
Muscularis mucosae - well developed
Submucosa - no unusual features
Muscularis externa - longitudinal fibers are aggregated into 3 evenly spaced longitudinal bands  Taenia coli
- between taenia, longitudinal muscle fibers form a very thin often discontinuous layer
- taenia are in a state of partial contraction which causes the intervening portions of the wall to bulge outward forming shallow sacculations 
Haustrae - conspicuous in the ascending, transverse, descending colon & sigmoid flexure
- in rectum, forms a continuous layer of uniform thickness & no haustrae
Serosa - have accumulation of adipose cells beneath the mesothelium that form pendulous protuberances  Appendices Epiploicae

RECTUM
- terminal portion of the intestinal tract
- length: 12 cm
- extending from sigmoid colon to the pelvic diaphragm
- slightly dilated in its lower portion to form the Rectal Ampulla
Mucosa - 2 or 3 transversely oriented folds are found above the rectal ampulla
- crypts are somewhat longer than those of the colon
- narrows rather abruptly at the end of the ampulla & continues as the Anal Canal

ANAL CANAL
- length: 4 cm
Mucosa - exhibits longitudinal folds  Rectal Columns of Morgagni
- crypts of Lieberkuhn suddenly become short & disappear all together along an irregular line about 2 cm above the anal opening
- abrupt transition from simple columnar to stratified squamous epithelium
- at the level of external anal sphincter, lining of the canal has the appearance of skin
- typical sebaceous glands
- large circumanal apocrine glands
- lamina propria contains a plexus of large veins -- often become distended
- may protrude as hemorrhoids
Anal Sphincter - thick circular layer of smooth muscle
External Anal Sphincter - circumferential annulus of striated muscle

HISTOPHYSIOLOGY OF THE INTESTINE

Succus Entericus - intestinal juice

Enzymes secreted are incorporated into the membrane of the brush border of the absorptive cells:
Leucine aminopeptidase
Sucrase - cleaves sucrose to glucose & fructose
Lactase - cleaving lactose to glucose & galactose
Maltase - hydrolyzes maltose derived from starch to glucose

Brush border - increase the surface area for absorption

- site of enzymes involved in the terminal steps in digestion of carbohydrates & proteins
- possesses the carriers necessary for transport of glucose & AA into the cell

Absence of lactase from the intestinal brush border  unable to tolerate milk  feeding milk results in bloating & copious diarrhea

(by pancreatic lipase) Dietary Fat = free fatty acids + monoglycerides  combined with bile salts  micelles  come into contact with the microvilli  FA &
monoglycerides diffuse across the CM  accumulate in the apical cytoplasm  membranes of smooth ER contains enzymes for resynthesis of triglycerides  form
numerous lipid droplets  transported to the golgi complex  converts into Chylomicra (complex glycoprotein)  leave the cells & are transported via the intestinal
lymphatics to the blood stream
 Composition of Feces: dead bacteria
Indigestible fibrous constituents of ingested vegetable mater
Chyme - less than 100 mL

Major contribution of the intestinal flora: production of vit. B12 - hemapoiesis

Vit. K - maintenance of the clotting mechanism of the blood

BLOOD VESSELS OF THE INTESTINAL TRACT

Stomach - arteries arise from 2 arterial arches along the lesser & greater curvatures
- distributed to the ventral & dorsal surfaces
Intestine - reach the organ from the mesentery
- penetrate the muscularis externa to enter the submucosa where they form a large plexus
SI - submucous arterial plexus fives off 2 kinds of branches
- some ramify on the inner surface of the muscularis mucosae
- break up into capillary networks that surround the crypts of Lieberkuhn
- other branches are destined for the villi
- small veins have no valves but their continuations that pass through the muscularis externa with the arteries are provided with valves

LYMPH VESSELS OF THE INTESTINAL TRACT

Stomach & Colon - begin as an extensive system of large lymphatic capillaries in the superficial portion of the mucosa between the glands
- always situated below the blood capillaries
- anastomose extensively around the glands
- take a downward course to the inner surface of the mucosa where they form a plexus of lymphatics that are provided with valves
- from submucosa plexus, larger lymphatics run through the muscularis externa
- receive numerous lymphatics from the lymphatic plexus in the muscular coat
- follow blood vessels into the retroperitoneal tissues
SI - Fxn: absorption of fat
- during digestion, lymphatics become filled with milky white lymph (fine emulsion of neutral fats) Chyle
- Lacteals -- carry the chyle away from the epithelium
- core of the villi

NERVES OF THE INTESTINAL TRACT

- innervated by the autonomic nervous system:

Sympathetic & Parasympathetic - extrinsic nerve supply

- exert influence on digestive fxn through the intrinsic enteric nervous system
- preganglionic fibers from the vagus nerve
- postganglionic sympathetic fibers arise manly in the celiac ganglion
- cutting the extrinsic nerves results in little impairment of digestive fxn
- intestinal movements are determined by local neuromuscular mechanisms that are only modulated by input through the extrinsic nerves
Enteric - most important
- consists of nerve cell bodies & their processes located within the wall of the tract
- consists of ganglia & interconnecting bundles of nerve fibers that form extensive plexuses in various layers of the digestive tract
- can carry out many of its fxns without input from the CNS

Subserous plexus - formed by the most superficial neural elements in the gut wall
- lacks ganglia
- made up of a loose network of fine nerve fibers that connect the extrinsic nerves with the more deeply situated nerve plexuses

Myenteric plexus = Auerbach’s plexus / Plexus Entericus Externa

- most conspicuous enteric plexus found between the longitudinal & circular layers of the muscularis
- consists of ganglia containing 3-50 or more nerve cell bodies & bundles of unmyelinated axons that connect the ganglia to form a continuous network
- 2 cell types:
1st type - multipolar with short dendrites
- associative
2nd cell type - more numerous & more variable in form
- dendrites are diffuse receptor endings related to cells of the 1st type or to the same type, in the same or in other ganglia
- motor

Interstitial cells - 3rd cell type

- has short branching processes that intermingle with those of other cell typ
- doesn’t contain demonstrable neurofibrils
- may be a form of glial cell

Deep Muscular Plexus = Plexus Muscularis Profundus

- situated on the mucosal aspect of the circular muscle layer
- devoid of ganglia
- consists of thin anastomosing nerve bundles with their prevailing orientation parallel to the muscle fibers
- branches penetrate into the muscle layer
- some are connected with the myenteric plexus

Submucous Plexus = Meissner’s Plexus / Plexus Entericus Interna

- network of ganglia & interconnecting nerve bundles within the CT of the submucosa
 - fibers innervate the muscularis mucosae & smooth muscle fibers in the cores of the intestinal villi
- fibers also form a mucosal plexus situated in the lamina propria & sending components between the intestinal glands & into the villi

Cholinergic neurons - only intrinsic nerves for which both the transmitter & the fxns are known
- supply both longitudinal & circular muscle
- prime importance in the peristaltic reflex

Non-cholinergic & non-adrenergic - responsible for relaxation of intestinal smooth muscle

- release adenosine-5-triphosphate  Purinergic neurons
- Vasoactive Intestinal Polypeptide -- more likely transmitter
- responsible for inhibitory reflexes that relax smooth muscle in advance of a wave of peristaltic contraction, thus facilitate passage of
the intestinal contents along the tract

Biologically active peptides in nerve cells of enteric plexus:

Substance P
Somatostatin
Enkephalins
Vocative intestinal polypeptide
Bombesin
Neurotensin

GALL BLADDER-PANCREAS

GALLBLADDER
- pear-shaped hollow organ occupying a shallow fossa on the inferior surface of the liver
- consists of a fundus, body & neck that continues into the cystic duct
- variable in shape
- frequently the site of pathological processes

Fxns: store, concentrate & release into the duodenum the bile secreted by the liver

- all but the hepatic surface is covered by a serosa continuous with that covering the liver
- wall consists of a thin subserosal layer of CT overlying a layer of smooth muscle

I. Mucosa
Epithelium - simple columnar with oval nuclei & faintly eosinophilic cytoplasm
- microvilli are shorter & less regular in their orientation
- tips of microvilli bear minute filiform appendages similar to glycocalyx
- intercellular cleft in the upper ½ is wide & sealed by Zonula Occludens
- width is narrow in inactive condition
- distended when bile is being concentrated by transport of H2O across the epithelium
Lamina propria - highly vascular
- loose organization of collagenous & elastic fibers provides flexibility
- simple tubuloalveolar glands near the neck of the gallbladder extending into the muscular layer (mucus secretion)
- Rockitansky-Aschoff sinuses -- large inpocketings mistaken for glands
- lining continuous with the surface epithelium
- may represent a pathological change that permits evagination of the mucosa
Convoluted folds - variable in height that delimit narrow base or clefts
- in contracted gallbladder -- tall & closely spaced
- parallel course
- when gallbladder is distended -- short & more widely spaced
- reduced to low ridges
- branch & anastomose

II. Muscularis - irregular loose network of longitudinal transverse & oblique bundles of smooth muscle
- spaces between the bundles are occupied by collagenous & elastic fibers
- occasional fibroblasts

III. Serosa - dense CT

- rich in collagen & elastin
- component cells: fibroblasts, macrophages, occasional clusters of adipose cell
- blood vessels, nerves & lymphatics run in this layer & send branches through the muscular layer to the mucosa

Luschka ducts - peculiar duct-like structure

- may be found on the hepatic surface near the neck of the gallbladder
- none open into the lumen
- some connect with the bile ducts
- may be aberrant bile ducts

Cystic duct - continues from the neck of the gallbladder & joins the Common Hepatic Duct (Common Bile Duct) which courses downward behind the head of the pancreas
- the 2 pass together to the through the muscularis of the duodenum

Ampulla of Vater (Hepatopancreatic ampulla) - union of cystic duct & common bile duct in their oblique course through the submucosa
- opens into the lumen of the duodenum
Sphincter of Oddi - band of smooth muscle
- encircles the bile & pancreatic ducts in the wall of duodenum
- parts:
1. Sphincter choledochus - strong circular band of smooth muscle around the terminal portion of the bile duct
- contraction stops the flow of bile
2. Sphincter pancreaticus - around the pancreatic duct
3. Fasciculus longitudinalis - longitudinal bundles of smooth muscle in the space between the ducts
- shorten the intramural portion of the ducts
- facilitate the flow of bile into the duodenum
4. Sphincter ampullae - meshwork of muscle fibers around the ampulla
- undesirable effect of causing reflux of bile into the pancreatic duct  pancreatitis

Blood supply - Cystic artery

Veins - empty into the small veins of the liver with only a few joining the cystic branch of the portal vein

Lymphatic vessels:
Rich supply of lymphatic vessels in 2 plexuses: in the lamina propria & outer CT layer
Lymphatic plexuses  drain into larger lymphatics that pass to the lymph node or nodes at the neck of the gallbladder  accompany the cystic & common bile ducts 
traverse several nodes near the duodenum  empties into the Cisterna Chyli

Nerve supply
Branches of the Splanchnic sympathetic & Vagus nerves - both contain contain excitatory & inhibitory fibers
Sensory nerve endings - over distension of the gallbladder or spasm of the extrahepatic biliary tract  initiate reflex disturbances in the gut

Histophysiology of the gallbladder

- entry of food  enteroendocrine cells in the intestinal mucosa release Cholecystokinin  carried in the blood to the gallbladder  induces rhythmic contractions of the
wall
- as waves of smooth muscle relaxation pass the ampulla of Vater in duodenal peristalsis  sphincter of Oddi relaxes  permit
intermittent outflow of bile
- ion channels present in the apical membrane permit free passage of Na ions
- basolateral membranes contain Na,K-pumps
- increased solute conc. creates a concentration gradient that moves H2O across the epithelium thereby concentrating the bile in the lumen
- functional capacity of the gallbladder is assessed clinically by observing its ability to concentrate halogen salts of phenolphthalein that are radio-opaque
- failure to clearly visualize the gallbladder in x-rays indicates that the organ has lost its concentrating power

PANCREAS
- pinkish-white organ lying retroperitoneally on the posterior wall of the abdominal cavity
- at the level of L2-L3
head - lodged in the concavity of the C-shaped duodenum
body & tail - extend traversely across the posterior wall of the abdomen to the hilus of the spleen

Length: 20-25cm
Weight: 100-150 g

- covered by a thin layer of CT which doesn’t form an opaque capsule

- lobulated & the outlines of the larger lobules can be seen with the naked eye
- 2nd largest gland associated with the alimentary tract
- portions:
Exocrine Endocrine
Secretion secretes daily about 1.2 L of an enzyme-rich fluid Hormones
Function Digestion of dietary fats, carbohydrates & protein Control of carbohydrate metabolism

EXOCRINE

Acinar Tissue - compound acinous gland

- made up of many small lobules bound together by loose CT
- acini -- round or slightly elongated
- consist of 40-50 pyramidal epithelial cells around a narrow lumen
- lumen -- wider during active secretion
- cytoplasm near the base of the acinar cells is strongly basophilic owing to high conc of ribonucleoproteins
- prominent nucleolus & peripheral clumps of heterochromatin
- apical cytoplasm is filled with secretory granules
- Zymogen granules -- more abundant in acinar tissue fixed during fasting
- reduced in # after the copious secretion induced by a meal
- fluid content
- rough ER (20% of cell volume)
- free polyribosome
- occasional lipid droplets & lysosomes
- no granules in the lumen
Duct System
centroacinar cells - cuboidal or squamous cells lining the duct extend a short distance into the acinus
- pale
Intercalated ducts  intralobular ducts  interlobular ducts (columnar w/ goblet cells)  main pancreatic ducts

Duct of Wirsung - larger main pancreatic duct

- begins in the tail & runs through the length of the gland
- in the head of pancreas, it runs parallel to the common bile duct (ductus choledochus) with which it may have a common opening into the
duodenum at the Ampulla of Vater
- sphincter of Oddi controls the opening & closing of the common outlet

Duct of Santorini - always present

- lies cranial to the duct of Wirsung
- length: 6 cm

Blood Supply
Splenic artery
pancreaticoduodenal branches of the hepatic & superior mesenteric arteries
- walls of capillaries have continuous endothelium (fenestrated in endocrine)

Veins - join the portal, splenic & superior mesenteric veins

Lymphatic Vessels
Lymphatic capillaries end blindly among the acini & drain via larger lymphatics that follow the course of the blood vessels to reach Pancreaticosplenic lymph nodes
distributed along the upper border of the gland.

Nerve Supply
Vagus & Splanchnic nerves via the Splenic nerve plexus
 stimulation results in exocytosis & accumulation of secretion in the lumen of the acini & in small ducts
- there is little outflow of secretion from the gland because only very small amount of H2O & electrolytes are added to the secretion

- small clusters of Autonomic ganglion cells

- Axons - occasionally penetrating the basal lamina & ending in intimate contact with the base of an acinar cell
- terminations of branches of the vagus nerve

Histophysiology of the Exocrine Pancreas

- proenzymes & enzymes:
Trypsinogen  trypsin - most abundant
Chymotrypsinogen
Procarboxypeptidase
Ribonuclease
deoxyribonuclease
Lipase
Elastase
Amylase
Trypsin inhibitor - CHON
- acinar cells secrete enzymes for digestion of protein, lipid, carbohydrate & other constituents of the food ingested
- to protect the integrity of the gland, secretions are produced in an inactive form & activated only after they are secreted into the lumen of the intestine
- Acute Pancreatitis -- proteolytic enzymes are activated & pancreas is rapidly digested by its own enzymes often with fatal outcome
- secretory activity has a rhythmical cycle with a low basal rate of continuous secretion which is greatly increased periodically by hormonal stimulation associated with the
ingestion of food

Presence of food in the gastric antrum & passage of acidic products of gastric digestion into the duodenum stimulate release of 2 intestinal hormones:
Secretin - small peptide of 27 AA
- when carried in the bloodstream to the pancreas, it stimulates the secretion of a large volume of fluid containing a high conc. of HCO3
- doesn’t stimulate acinar cells
- copious alkaline fluid -- produced by epithelial lining of the smaller ducts
- little or no enzymatic activity
- neutralize the acidic chyme entering the intestine from the stomach
Cholecystokinin - 33 AA
- secreted by the mucosa of the duodenum & upper jejunum
- when transported in the blood to the pancreas, it binds to specific receptors in the basolateral membranes of the acinar cells & induces their
release of highly concentrated digestive enzymes
- acting alone, doesn’t significantly increase the outflow from pancreatic ducts
- coordinated action with secretin results in secretion of a large volume of enzyme-rich pancreatic juice

LIVER

LIVER
- largest gland in the body
- wt: 1.5 kg in adult
 - situated in the right upper quadrant of the abdominal cavity with its rounded upper surface conforming to the dome of the diaphragm
- Glisson’s capsule -- thin investment of CT covered over most of its surface by peritoneal mesothelium
- on its under side, blood vessels enter, & the right & left Hepatic Ducts leave the organ at its Hilum / Porta Hepatis
- has a dual blood supply: receive well-oxygenated blood from the general circulation via the Hepatic Artery
larger volume of poorly oxygenated blood come from the intestinal tract via the Portal Vein
- blood from the 2 sources mingles in the hepatic sinusoid

Fxns:
- continuously produces bile -- secreted into the duodenum via the Common Bile Duct
- 1 L is produced daily but the greater portion is diverted to the gall bladder
- facilitates digestion by emulsifying dietary fats & reducing them to micelles
- synthesizes plasma proteins & delivers them directly into the blood
- control over the general metabolism of the body through its ability to store carbohydrate in the form of glycogen & to release glucose
- takes up drugs & other potentially harmful substances absorbed by the intestines & degrades them by oxidation or forms harmless conjugates that are excreted back into
the intestines in the bile

Organization
Lobes  lobules  parenchyma is made up of groups of epithelial cells forming acini at the ends of a branching system of ducts

- little CT in its interior

- epithelium presents a remarkably uniform appearance throughout the organ
- structural subunits are not easily identifiable
- repeating pattern of roughly hexagonal areas
- fenestrated plates of parenchyma cells are arranged radially around a central vein
- at 3 corners of the polygonal areas: small triangular area of CT enclosing a small bile duct Portal Triad or
Branch of hepatic artery Portal Area
Branch of portal vein
- lateral braches of the vessels occurring at short intervals along their length are confluent with thin-walled Hepatic sinusoids that occupy the spaces between the radially
arranged trabeculae & drain into the central vein
- bile is continuously secreted into a network of intercellular Bile Canaliculi within the cell plates & flows outward to bile ductules in the portal areas at the periphery
- Hepatic Lobule -- polygonal unit
- classical lobule
- liver lobule consist of the mass of the parenchyma around each portal area
- Portal Lobule -- structural lobule
- roughly triangular
- includes sectors of 3 neighboring classical lobules
- Hepatic Acinus -- structural & functional unit of the liver (since 1950s)
- roughly ovoid mass of parenchymal cells around each terminal arteriole, venule & bile duct that branch laterally from the portal area
- Terminal Hepatic Venule -- central vein in the classic lobule at either end of the acinus
- acinus -- smaller unit including a sector of 2 neighboring classical lobules
- basis for most contemporary considerations of liver fxn

Blood Supply
Portal vein - principal afferent blood supply
- carries poorly oxygenated blood that has circulated through the intestine, pancreas & spleen
- entering the porta hepatic  divides into interlobar veins  conducting veins  interlobular veins
Portal triads / Portal areas - course parallel to the Central Vein at the corners of the classical lobules
Terminal portal venules or Perilobular venules - small lateral branches given off a short intervals along their length
- course along the boundaries between classical lobules
- give off short Inlet Venules that empty into the sinusoids
- on entering the porta hepatis, hepatic artery branches into Interlobar & Interlobular Arteries
- bulk of the flow in these arteries is distributed to capillaries of the CT stroma of the organ
- smaller volume continues into the Hepatic Arterioles of the portal triads
- give off lateral branches emptying into the sinusoids &
numerous small branches to capillaries that surround the bile duct
Peribiliary or periductal plexus - efferent vessels empty into the sinusoids
- much of the arterial blood reaches the sinusoids indirectly via the peribiliary plexus
- rich vascularity of the smallest bile ducts suggests the possibility that some constituents of the bile may be reabsorbed in their passage through the intrahepatic bile ducts
Sinusoids - carry out the primary fxn of the hepatic circulation
- form 3D plexus within the lobules
- area for exchange of metabolites between the blood & hepatic parenchyma
- blood leaves the sinusoids through numerous openings in the thin wall of central vein (terminal branch of the hepatic vein) & continues into Sublobular veins &
then to Collecting veins
- numerous collecting veins converge to give rise to 2 or more large Hepatic veins that emerge from the porta hepatic & join the inferior vena cava

Hepatic sinusoids
- wider than capillaries
- walls: conform to the surface of the plates of hepatocytes
Have discontinuities
transcellular fenestrations -- “sieve plates” - group of fenestrae

Kupffer cells - stellate cells selectively stained with gold chloride

- with processes crossing the lumen
- frequently contained engulfed erythrocytes & deposits of iron-containing pigment
- actively took up Tryptan blue & other particulates injected into the bloodstream
- derived from circulating monocytes & members of the body’s mononuclear phagocyte system
 - situated on the surface of the endothelial cells
- don’t form desmosomes or other specializations for cell-to-cell attachment
- variable form & location may continually change
- slender villi & undulant lammellipodia
- narrow invaginations of the CM extend into the cytoplasm  form Vermiform Bodies
- 2 parallel membranes with a dense line between them & faint transverse striations
- small juxtanuclear golgi complex & numerous mitochondria
- peroxidase (lacking in endothelial cells)
- cytoplasm is crowded with clear vacuoles, phagosomes, lysosomes & lipochrome pigment deposits
- clear the blood of colon bacilli that manage to get into the portal blood during circulation through the intestines

Perisinosoidal space = space of Disse

- narrow space between the sinusoids & parenchymal cells
- endothelium rests lightly on the tips of numerous irregularly oriented hepatocyte microvilli that project into a narrow per sinusoidal space
- slender bundles of collagen fibers in this space form a loose network that corresponds to the argyrophilic reticulum
- occasional unmyelinated nerve axons
- lack gel-like extracellular matrix
- facilitates exchange of metabolites between the blood & the liver cells
- typical fibroblasts
- fat-storing cells = stellate cells, interstitial cells, lipocytes
- occupy shallow recesses between hepatic cells
- have processes that contact the endothelial cells
- selectively stained with gold chloride
- presence of multiple lipid droplets in their cytoplasm
- more common near the center of the classical lobule
- store exogenous vit. A owing to its lipid solubility
- pit cells -- small cells with short pseudopodia
- not phagocytic
- cytoplasm contains small dense granules & vesicles containing a rod-like inclusion
- belong to the immune system & are large granule-containing lymphocytes
- natural killer cells (lung, SI, epididymis & mammary gland)

Zonation within the Liver Lobule

1. Zone of Permanent fxn - periphery
2. Zone of Variable fxn -
3. Zone of Permanent Repose - around the central vein

- activity of the hepatocytes depended on their location with respect to a gradient in O2 conc. along the length of sinusoids
- cells at the periphery would be most favorably situated
- near the central vein would be exposed to blood largely depleted of O2 & other metabolites
- “centrilobular necrosis” occurs in disease states attended by hypoxemia
- 3 zones in the hepatic sinus:
Zone 1 Zone 2 Zone 3
Location ellipsoidal area immediately surrounding near the ends of the acinus
the hepatic arteriole & terminal portal
venule
Enzymes involved in oxidative metabolism & mixed complement of enzymes involved in glycolysis, & lipid &
gluconeogenesis drug metabolism

- blood flow exits the terminal branches of the hepatic vein at either end of the acinus
- administration of drug Phenobarbital induces hypertrophy of smooth ER in zone 3
Cytology of Hepatocytes
- polygonal & arranged in plates or trabeculae between sinusoids

Sinusoidal Domain Lateral Domain Bile Canalicular Domain

Location sides of the cell exposed to the
sinusoids
Contents - receptors for sialoglycoproteins,
mannose-6-PO4 & other substances
taken up by receptor-mediated
endocytosis
- adenylyl cyclase & Na, K-ATPase
sides in contact with
neighboring hepatocytes
adenylyl cyclase &
Na,K-ATPase
portion of the lateral membrane that
forms the wall of the intercellular bile
canaliculi
- thicker cytokeratin & actin filaments
-- helps to maintain the patency
of the bile canaliculus
-aminopeptidases, 3 glycoproteins

- bear sparse microvilli (sinusoidal & bile canalicular domains) but other surfaces are planar
- nucleus: round with peripheral clumps of heterochromatin & 1 or 2 prominent nucleoli
- cytoplasm: contains conspicuous basophilic bodies (rough ER)
abundant free polyribosome
- smooth ER is not well developed in periportal region (zone 1) but abundant in zone 3
- VLDL -- carrier for cholesterol
- Cytochromes P450 -- involved in synthesis of prostaglandins
 - catabolism of drugs & other potentially toxic exogenous compounds
- mitochondria is elongated with lamellar or tubular cristae projecting into their interior which is occupied by a matrix of relatively low density containing a few dense
matrix granules
- golgi complex consists of multiple stacks of 5-9 cisternae slightly expanded at their ends
- lysosomes -- acid hydrolases
- peroxisomes -- catalase & other H2O2 generating oxidase
- nucleoids -- uricase
- eccentrically placed in the peroxisome (lacking in human liver)
- glycogen:  particles - electron dense particles
 particles - smaller subunits
- few lipid droplets not enclosed in a membrane -- increased after alcohol consumption

Hepatic Ducts
Bile canaliculus - located midway along the interface between adjoining hepatic cells
- minute channels form a network within the plates of hepatocytes
- continuous throughout the lobule
- wall is merely a specialization of the surfaces of adjoining cells
- lumen is a local expansion of the intercellular cleft
- lateral membranes of contiguous cells are planar
- near the middle, the membranes diverge to bound a wider intercellular space that constitutes the lumen of a bile canaliculus
- apposed membranes form a tight junction comparable to the zonula occludens of other epithelia
- isolate the lumen of the canaliculus
- prevent escape of bile
- few short microvilli project into its lumen
- at the periphery of the classic hepatic lobule (axis of the acinus), bile canaliculi are confluent with
Terminal Ductules (Canals of Hering) - squamous
that drain into Interlobular Bile Ducts - cuboidal  larger ducts that converge on the porta hepatis - columnar, dense CT
- extrahepatic portion of the duct system consists of Right & Left Hepatic Ducts emerging from corresponding lobes of the liver & the Common Bile Duct
- Cystic Duct from gallbladder joins the common duct, which continues to the duodenum
wall: Mucosa - columnar
Submucosa - lymphocytes
Muscularis - smooth muscles oriented longitudinally & obliquely but don’t form a complete layer
- forms a sphincter
Adventitia

CT STROMA
Glisson’s capsule - dense CT
- thickest at porta hepatis
Interlobular stroma - reticular fibers between sinusoids & plates of parenchyma cells
- collagen fibers in portal areas

LYMPHATICS
Hepatic lymph - large amount of plasma protein
- higher albumin-globulin ratio than in the plasma
- network of lymphatics parallels the branches of the portal vein from the interlobular portal areas to the porta hepatis
- lymphatics have not been demonstrated within the hepatic lobules!

NERVES
Efferent autonomic nerves - regularly found in the CT around the portal triads
- adrenergic endings can be found in the space of Disse in close apposition to hepatocytes
- nerves are found throughout the lobule
Autonomic innervation - plays an important role in the short-term regulation of cell metabolism influencing glucose & lactate output
- there is less evidence that the nerves may be involved in the longer-term induction of enzymes
LIVER REGENERATION
- hepatic parenchyma is a rather stable cell population
- cells in division are seldom seen in the normal liver
- rapid regeneration occurs after destruction of a substantial part of each lobule following administration of chlorinated hydrocarbon
- carbon tetrachloride produces a central necrosis

HISTOPHYSIOLOGY OF THE LIVER

- principal contribution of the liver to the digestive process: secretion of bile
- components of bile: cholesterol, lecithin, fatty acids & bile salts
- bile salts -- synthesized from cholesterol
Cholesterol  conversion to cholic & chenodeoxycholic acids  combine with glycine or taurine in salt linkage
- have an emulsifying action on ingested fat that promotes absorption of fatty acids & monoglycerides
- important excretory fxn of the liver: elimination of bilirubin from the blood
- bilirubin -- greenish pigment
Degradation of hemoglobin of senescent erythrocytes that are removed from the circulation by Kupffer cells & by other phagocytes in the spleen  taken up
by the liver cells  conjugated with glucuronide in the ER 
 Greater part of the conjugate Bilirubin Glucuronide is excreted into the bile
 Some are released into the blood  Jaundice
- occur when bilirubin production exceeds the capacity of the normal liver to excrete it
- conjugation is impaired by liver disease
- determination of the relative amounts of conjugated & unconjugated bilirubin in a blood sample is commonly used as a measure of liver fxn & to determine the probable
cause in a patient with jaundice
 - situated between the portal system & the general circulation, the liver is strategically located to process nutrients absorbed by the intestine
Other Fxns of the liver:
* Maintain the normal concentration of blood glucose
Absorbed glucose is taken up from the portal blood  polymerized by a series of enzymatic rxns  glycogen
Lactic acid, glycerol & pyruvic acid  converted into glucose  glycogen
- glycogen is broken down to glucose by the enzyme phosphorylase -- normally present in an inactive form
- activated by epinephrine & glucagon which induce release of glucose into the blood
- glycogen is usually located in areas of cytoplasm rich in smooth ER
* Metabolism of lipids
* Maintenance of normal lipid levels in the circulating blood
- VLDL -- EM: small dense particles seen in the terminal expansions of cisternae of rough ER, tubular elements of smooth ER, small transport vesicles & space of Disse
- formed in the liver
- released by exocytosis into the space of Disse
- triglycerides are generated from fatty acids in the smooth ER  combined there with protein synthesized in the rough ER  lipoprotein
* Site of synthesis of Plasma Proteins
Rough ER - albumin
Other proteins: Fibrinogen, Thrombin & Factor III
Hepatocytes - accessory fxn in the immune system of the intestine
IgA - synthesized by plasma cells in the lamina propria of the gut
- complexed with Secretory Component in cells of the intestinal epithelium & secreted into the lumen
- a fraction of the antibody produced takes this direct route in the lumen
- remainder is carried in the lymph to the thoracic duct & then to the general circulation
- much in the blood is destined to reach the lumen of the intestine via the hepatobiliary pathway
- secretory component is continuously synthesized by the liver cells & inserted as a transmembrane receptor protein at the surface facing the space of Disse
- taken up by receptor-mediated endocytosis  transported in vesicles to the bile canaliculi where secretory component is cleaved releasing the antibody into the bile
for transport to the intestinal lumen
- present in the bile at 4x its concentration in the blood
* takes up, by receptor-mediated endocytosis, a # of hormones produced by the endocrine glands & excrete them into the bile
- some of the proteins & steroids traverse the cell by a direct pathway in which they are released intact into the bile by fusion of their transport vesicles with the membrane
of the bile canaliculus
- others follow an Indirect Path in which the vesicles fuse with small primary lysosomes that degrade the contents
* Metabolism of barbiturates that are commonly used as sedatives & of many other lipid soluble drugs
- enzymes that degrade these compounds are localized mainly in the smooth ER
- administration of such drugs induces a marked hypertrophy of smooth ER with a concomitant increase in the drug-metabolizing enzymes
- proliferation of smooth membranes is not a toxic effect but an adaptive response that enhances the ability to eliminate inducing drug
- ultrastructural & biochemical changes are the basis of Drug Tolerance -- progessive loss of in the effectiveness of a drug with continued use
* Blood-filtering fxn
Kupffer cells - remove cellular debris & foreign particulate matter including microorganisms that may invade the blood from the intestinal lumen
- have surface receptors for Igs & for complement
- secrete cytokines, interleukin-1 & tumor necrosis factor

UNIT 5
CHAPTER 4 -BLOOD

- composed of RBC, WBC and platelets suspended in fluid blood plasma.

- transports O2 and nutrients to tissues; carries CO2 and other waste products to organs for excretion; carries hormones to target organs.

- only RBC & platelets function within the vascular system. Leukocytes constantly migrate though the walls of the capillaries and venules and carry out their functions, complete
their life span and degenerate in the tissues.

Normal Volume: 5 Liters (7% of BW)

-45% of the volume-RBC, 1% - WBC and platelets and the remainder is blood plasma.

Blood Plasma -the transparent yellow fluid matrix in w/c blood cells are suspended.
-contains physiologically important proteins: albumin, globulin, fibrinogen and complement.
Plasma Proteins (PP):
1. Albumin – synthesized in the liver and is the smallest and most abundant PP.
Fxns: important in maintaining colloid osmotic pressure
transports small molecules in blood. (albumin binds with some molecules to make them soluble in blood)
2. Globulins – 3 main categories: α-globulins, β-globulins, γ-globulins
Fxn: α-globulins, β-globulins – serve as vehicles for transport of various substances. (ex: transferrin & ceruloplasmin)
γ-globulins – immunoglobulins (immune system)
3. Complement System – group of 12 or more serum CHONs that interact in a cascade of reactions whose products contribute to humoral immune responses, to
initiation of inflammation and to lysis of invading microorganisms.
4. Plasma Lipoproteins – involved in the transport of lipid from the intestine to the liver and then to the tissues.
3 categories (based on their size/density):
a. Chylomicra
b. VLDL – rich in triglycerides
c. LDL – transport of cholesterol

RBC
SHAPE
- The biconcave shape – increased surface area. This favors immediate saturation of hemoglobin with oxygen.
- Poikilocytosis – unusual diversity in cell shape.
- Echinocytes – RBC with 10-30 short, conical projections that are usually uniform in size radiating from their surface.
- Crenation – is the change of RBC from the characteristic disc shape to a sphere with projections (echinocytes). This is reversible.
- The maintenance of normal RBC shape is dependent on ATP. Crenation occurs when ATP levels fall below a critical level. Regeneration of normal ATP levels results in the
return of RBC to their normal biconcave shape.
- Rouleaux Formation – the discoid RBC form aggregates that resemble stacks of coins. This happens only in stagnant blood and does not occur when blood is circulating.
NUMBER
- Males 5.4 million/cubic mm; Females 4.8 million/cubic mm
- Anemia – decrease in the number of normal RBC or decrease in hemoglobin content.
- Polycythemia – an increase in absolute quantity of red cells or total RBC volume.
SIZE
- 7.5 um in diameter; 1.9 um in thickness; 140 um2 surface area.
- Anisocytosis – abnormal variations in cell size.
COLOR
- Stained (Wright Stain) – deep pink
 Polychromatophilic Erythrocytes/Reticulocytes – cells with bluish or greenish tint owing to the basophilic staining of residual ribosomes.
- Unstained: pale yellow or tan due to hemoglobin.
- Anisochromia – significant differences among erythrocytes in the amount of central pallor.
- Erythrocyte Ghost – RBC which appears like an empty membrane because it lost it’s hemoglobin.

- Life Span: 120 days

- Hemolysis – disruption or destruction of RBC and subsequent release of their content such as hemoglobin.
Hemoglobin – the pigment that makes up 33% of the mass of an RBC.
– is a protein consisting of 2 identical α-chains and 2 identical β-chains and an iron containing heme group.
 Oxygen in the lungs will combine loosely and reversibly with the heme portions of hemoglobin.

 Human DNA contains the genes necessary for synthesis and incorporation into hemoglobin of 4 different polypeptide chains (α, β, γ, delta δ).
 Normal Adult: 96% of Hgb is Hemoglobin A (HbA) – 2 α and 2 β chains.
- 2% is Fetal hemoglobin (HbF) – 2 α and 2 γ chains.

 A great variety of inherited disorders of hemoglobin synthesis involve relatively minor amino-acid substitutions. (Ex: Hemoglobin S: substitution of Val for
Gln)
ULTRASTRUCTURE
- RBC has no nucleus and other organelles. It has no capability of DNA-directed CHON synthesis.
- Its cytoplasm consists predominantly of hemoglobin molecules.
- The plasma membrane is the typical lipid bilayer with various integral proteins. Immediately beneath the membrane is the membrane skeleton composed of actin, spectrin
and 2 associated CHONs.
- Spectrin – the major component of the network. It is a heterodimer of α and β polypeptide chains bound end to end to form double
stranded tetramers. Near the middle of each spectrin tetramer, there is a binding site for ankyrin, a phosphoprotein that serves to link network to
cytoplasmic domain of a transmembrane protein.
ABNORMAL BODIES IN RBC
1. Howell Jolly - spheric and granular inclusions in the erythrocytes, probably nuclear remnants; ound in various anemias and after splenectomy or reduced splenic function.
2. Erlich Heinz - inclusion bodies resulting from oxidative injury and precipitation of hemoglobin; seen in the presence of certain abnormal hemoglobins and erythrocytes with
enzyme deficiencies.
3. Cabot’s Ring - A ring-shaped or figure-8 structure, found in red blood cells in severe anemias.

WBC
- All WBC have a single nucleus and are colorless in the fresh state.
- Spherical in the bloodstream but pleomorphic in tissues or in vitro.
NORMAL WBC COUNT: 5000-9000 per cubic mm.
NORMAL DIFF COUNT: Neutrophils 55-60%
Lymphocytes 25-33%
Monocytes 3-7%
Eosinophils 1-3%
Basophils 0-0.7%
Classified as granular or nongranular depending on whether they do or do not have specific granules in their cytoplasm.

GRANULAR WBC
NEUTROPHIL
- The most abundant of the granular leukocytes.
- Absolute count: 3000-6000 per mm. (20-30 billion in circulation)
- Stay in circulation for 8 hours before migrating to the tissues.
- SIZE: in blood 7 um in diameter; 10-12 um in diameter in dried blood smears.
- NUCLEUS: consist of 2 or more lobules connected by narrow constrictions. The number of nuclear lobes depends in part on their age.
- BAND FORMS – young cells with a simple ovoid or elongated nucleus. The number of band forms in the diff count is a useful index of the rate of entry of new neutrophils
into the blood.
- NUCLEAR CHROMATIN: deeply staining clumps at the periphery.
- BARR BODY – found in neutrophils of females; represents the condensed X-chromosomes that form an additional minute lobule. It is also referred to as “the drumstick”
because of its shape. The presence or absence of this body in neutrophils can help determine the genetic sex of an individual
- GRANULES
 Specific (Neutrophil) Granules – widely distributed in the cytoplasm; slightly elongated.
 Lack lysosomal hydrolases found in the azurophil granules.
 (+) for ALP, collagenase, lysoyme, lactoferrin and several basic proteins (phagocytins).
 Azurophil Granules – slightly larger and more electron dense.
 (+) for ACP, peroxidase and β-glucuronidase.
- Neutrophils are the body’s first line of defense against bacterial invasion.
- CHEMOTAXIS - the migration of neutrophils up the concentration gradient of the chemoarreactant.
- Opsonins – coat bacteria and increase the efficiency of phagocytosis. (immune phagocytosis) Phagocytosis without the aid of opsonins is called nonspecific phagocytosis.
- LCAM-1 is a membrane protein of neutrophils responsible for it’s adherence to capillary endothelium.
- Leukotrines – are compounds that contribute to the inflammatory process. They are generated by neutrophils from arachidonic acid. LTB 4 promotes adhesion of
neutrophils to endothelium. LTC4, LTD4, and LTE4 increase permeability of postcapillary venules.

EOSINOPHIL
- SIZE: 9 um in diameter in suspension; 12 um in diameter in blood smears.
- They circulate for 6-10 hours before migrating to tissues
- LIFE SPAN: 8-12 days
- NUCLEUS: bilobed, less segmented than that of neutrophils.
- NUCLEAR CHROMATIN: less course than that of neutrophils.
- GRANULES
 Specific Granules – large pink granules that contain single or multiple crystals.
 Contain aryl sulfatase, β-glucuronidase, ACP, histaminase and ribonuclease
 Major Basophilic Protein (MBP), Eosinphil Cationic Protein (ECP) & Eosinophil-derived Neurotoxin – cationic proteins not found in lysosomes of
other cell types.
 MBP & ECP – cytotoxic effects include creation of transmembrane pores on target cells and release of superoxide ions and H 2O2 that damage the
membranes.
 Also contain few small azurophil granules.
- Numerous in the epithelia of the alimentary and respiratory tracts.
- Eosinophils are involved in damage control in allergic reactions and in defense against parasites. They are attracted to sites of histamine release, their enzymes can degrade
this and other allergic reaction mediators.
- Interleukin-5 and other cytokines – stimulate proliferation of precursors and release of eosinophils.
- ACTH and hydrocortisone – decrese in circulating eosinophils.

BASOPHIL
- The least numerous of the granular leukocytes.
- SIZE: 10 um in stained blood smears.
- NUCLEUS: U or J shaped, therefore may appear bilobed.
- Cytoplasm has particles of glycogen and more ER than other WBC.
- Specific Granules
- Few and larger than the eosinophil granules.
- Round or oval (0.5 um in diameter)
- Metachromatic because of histamine and heparin.

- Basophils share a number of properties with mast cells

- They both have metachromatic granules containing histamine and heparin.
- Very similar functions.
- It is speculated that both arise from a common bipotential stem cell.
- Mast cells have larger and round nuclei, more granules, relatively long-lived and relatively sessile.
- Basophils have IgE receptors on their membrane. After formation of IgE, they accumulate on the surface of basophils. Binding of antigen to the IgE on basophils cause rapid
degranulation and release of histamine and other mediators.
- Massive systemic release of these mediators may sometimes result in anaphylactic shock.

NONGRANULAR WBC
LYMPHOCYTE
- The second most numerous WBC class.
- Small round cells 7-12 um in diameter.
- NUCLEUS: deep staining, slightly indented
- Thin rim of clear blue cytoplasm.
- Few small azurophil granules but no specific granules.
- Based on their diameter and amount of cytoplasm, lymphocytes are described as large, medium or small.
- Major categories of small lymphocytes:
- T-Lymphocytes, B-Lymphocytes and Null Cells.
- Lymphocytes are the principal agents of the body’s immune responses, involved in recognizing invading microorganisms and neutralizing their harmful effects.
- B-Lymphocytes
- Arise from stem cells in the bone marrow and have a life span of several months.
- Production of immunoglobulin of the same antigenic specificity.
- Previously exposed lymphocytes retain, for a long period of time, the ability to recognize and respond to the inducing antigen, therefore they are referred to as
“memory cell”.
- Plasma cells are differentiated B-cells that produce large quantities of specific antibodies.
- T-Lymphocytes
- Stem cells from the bone marrow will enter the blood and settle in the thymus where they will proliferate and become T-lymphocytes.
- They constitute 70% or more of the small lymphocytes
- They have a long life span that may extend over several years
- Regulate the activity of the B-lymphocytes by secreting lymphokines.
- Subpopulation of T-Cells:
- Helper T-lymphocytes – provide additional stimulus to B-lymphocytes for Ab production.
- Suppressor T-lymphocytes – depress Ab production.
- Cytotoxic T-lymphocytes – pricnicipal agents of cell mediated immunity.
 Perforin/PFP – synthesized by the organelles of the killer cells to form channels on the target cell’s membrane allowing entry of lytic
toxins.
MONOCYTE
- SIZE: 9-12 um in diameter in suspension; 17 um in diameter in blood smears.
- Spherical, larger and have more cytoplasm than lymphocytes.
- CYTOPLASM: pale blue-gray
- NUCLEUS: eccentric and round or reniform.
- CHROMATIN: stains less intensely than that of lymphocytes.
- Few azurophil granules.
- Originate from the bone marrow, circulate in blood for 1-2 days then migrate to the tissues where they differentiate into tissue macrophages.
- They have no essential fxn in blood but become voracious phagocytes in tissues.
- They also process antigens and present them to lymphocytes.
- Mononuclear phagocyte system are a group of cells with the same surface markers as monocytes and are assumed to originate from them.

PLATELETS (thromboplastids)
- minute, colorless, anucleate corpuscles.
- Thin biconvex discs, 2-3 um in diameter.
- 2 concentric zones:
- Hyalomere – pale-blue peripheral zone
- Granulomere – thicker central region with small azurophilic granules, ribosomes and particles of glycogen.
- Small canaliculi that open at 10 or more sites on the surface can also be seen.
- The granules (alpha) contain:
 Platelet factor-IV – counteracts heparin
 Von Willebrand factor – platelet adhesion to vessel wall
 Platelet-derived growth factor – stimulates fibroblast proliferation.
 Thrombospondin – platelet aggregation
- No organelles but in their hyaloplasm, platelets have a greater concentration of actin and myosin than any cell type other than muscle.
- Maintaining the discoid shape of the platelets is a bundle of microtubules near the plasma membrane.
- Arise by fragmentation of the cytoplasm of Megakaryocytes.
- LIFE SPAN: 9-10 days
- FUNCTION:
- Initiate blood clotting to limit blood loss and begin the process of repair.
- When platelets are activated, they extend numerous slender processes and release their alpha granules. The granules contain substances
that promote platelet adhesion and platelet aggregation.
- Phospholipids released during degranulation reacts w/ plasma components to generate platelet thromboplastin and cyclo-oxygenase
enzymes that converts prostaglandin endoperoxides to thromboxane. Both products accelerate the clotting process.
- Platelets also secrete PDGF that contributes to tissue repair by stimulating cell migration and proliferation
- NORMAL COUNT: 150,000-350,000 per cu. mm.

CHAPTER 9 Blood Cell Formation

Hemopoiesis – formation of blood cells in the body.

PRENATAL HEMOPOIESIS
- Three successive stages of hemopoiesis in prenatal life:
- Mesoblastic Phase
 During the 2nd week of gestation.
 Primitive Erythroblasts (Hemocytoblasts)
- Large, spherical, basophilic cells that aggregate forming “blood islands”.
 Hemocytoblasts proliferate and synthesize hemoglobin and develop into Polychromatophilic Erythroblasts that gradually lose their basophilia to become
Primitive Erythrocytes (differ from postnatal erythrocytes in that they retain their nucleus)
 Hemopoeisis occurs in the mesenchyme of the body stalk and the neighboring areas.
- Hepatic Phase
 About 6 weeks after gestation
 Definitive Erythroblasts
- Round, basophilic cells that closely resembles postnatal erythroblasts.
 Definitive Erythroblasts will develop to anucleate erythrocytes.
 2nd month of gestation
 Small number if granular WBC and megakaryocytes appear.
 Blood formation in this phase occurs in the liver then later the spleen also becomes a site of hemopoiesis.
- Myeloid Phase
 After the establishment of ossification centers in the cartilaginous skeleton.
 The primitive bone marrow becomes the predominant site of hemopoiesis and blood formation in the liver and spleen will decline.
BONE MARROW STRUCTURE
- Most of the marrow occupies the marrow cavity of the long bones and surrounded by the compact osseous tissue of the cortex or the trabeculae of the spongiosa.
- Has no independent blood supply; receives blood that has circulated through the osseous tissue.
- Vascular sinuses of the marrow are 50-75 um in diameter and have a very thin endothelium but no continuous basal lamina. The endothelium is composed of very
flat cells joined by junctional complexes.
- The stroma consists of reticular cells, reticular fibers, macrophages and adipose cells.
- Migration pore is formed when the abluminal and adluminal membrane of the endothelium fuse. This allows passage of mature blood cells into the lumen of the
sinuses.
HEMOPOIETIC STEM CELLS
- Pluripotential Hemapoietic Stem Cells can proliferate and differentiate to all of the blood cell types and blood cell formation depends on their presence in the bone
marrow.
- These cells are capable of undergoing self-renewing divisions to maintain the pool of pluripotential cells and differentiating divisions giving rise to progenitor cells.
- Progenitor cells have limited potential for development along alternative pathways and little or no capacity of self-renewal.
- Stem cells and progenitor cells are morphologically and cytochemically indistinguishable.

ERYTHROPOIESIS
- Formation of erythrocytes.
- 2 categories of progenitors:
  Erythroid burst-forming unit (BFU-E)
- High rate of proliferation when stimulated by burst-promoting activity (BPA)
- Its proliferation produces a large number of CFU-E.
 Erythroid colony-forming unit (CFU-E)
- Larger and more slowly proliferating cell that is responsive to erythropoietin.
- Give rise to the morphologically identifiable proerythroblast.
1. Proerythroblast
- Round cell, up to 16 um in diameter with a rim of moderately basophilic cytoplasm.
- Has a large nucleus and often has 2 nucleoli.
- Cytoplasm becomes more basophilic as they differentiate and the number of polyribosomes also increases.
2. Basophilic Erythroblast
- Smaller cell, has an intensely staining cytoplasm
- Smaller nucleus with more heterochromatin.
- Synthesis of Hemoglobin in the cytoplasm.

3. Polychromatophilic Erythroblast
- Greater degree of chromatin condensation
- Color of cytoplasm ranges from blue-gray to a dull olive green.
- Variations in the color of the cytoplasm reflect progressive changes in the relative abundance of ribosomes and hemoglobin.
- This is the last cell of the erythroid series capable of division.
4. Orthochromatic Erythroblast
- Pinker cytoplasm with only a faint tinge of blue.
- Nucleus is small, eccentric in position and intensely stained. Chromatin condensation has progressed.
- Cytoplasm is filled with hemoglobin, with small clusters of ribosomes and no organelles.
5. Reticulocyte
- Anucleate cell with residual ribosomes.
- In further differentiation, the cell divests itself of organelles and other membrane constituents that serve no purpose in erythrocyte.

GRANULOPOIESIS
- Granulocyte formation
- Neutrophil cell lineages arise from CFU-GM
- Progenitors of eosinophils and basophils arise from the pluripotential stem cell separately.
1. Myeloblasts
- The first morphologically identifiable precursors of the granulocyte series.
- Round cells, 16 um in diameter.
- Have large nucleus with dispersed chromatin and multiple nucleoli.
- Cytoplasm is moderately basophilic and devoid of granules.
2. Promyelocyte
- The largest cells of the granulocyte lineages.
- Nucleus is indented and has more marginated heterochromatin than that of myeloblasts.
- Cytoplasm is deeply basophilic contains mitochondria, small GC and ER.
- Contains electron dense, membrane bound and irregular azurophil granules.
- Late promyelocytes are smaller and the chromatin is more condensed.
3. Myelocyte
- Neutrophilic
- Smaller than promyelocytes, more variable shape of the nucleus and greater condensation of chromatin.
- Specific granules also appear at this stage.
- From progenitor to myelocyte stage, 4-7 mitotic divisions occur. After this, cell division ceases and subsequent differentiation occurs.
- Eosinophilic
- First morphologically recognizable stage of eosinophil development.
- Nucleus has coarse pattern of peripheral clumps of chromatin.
- Cytoplasm is slightly basophilic and the specific granules of eosinophils are distinctly larger than those in neutrophils.
- Basophilic
- Nucleus contains little condensed chromatin and is paler staining than that of other myelocytes.
4. Metamyelocyte
- Neutrophilic
- Distinguished from the myelocyte mainly by the shape of its deeply indented nucleus.
- The 2 types of granules are present, the specific granules make up 80% of the granule population.
- Eosinophilic
- Nucleus is slightly indented and not lobulated.
5. Band Forms
- Neutrophilic band forms have straight or slightly curved elongated nucleus.
- During this stage of maturation, local constrictions appear in the nucleus resulting in it’s division to multiple lobules joined by thin segments.
The entire transit time from stem cell to mature granulocyte is about 10 days.

MONOPOIESIS
The progeny of CFU-GM differentiates to monoblasts.
Monoblasts will undergo division giving rise to promonocytes.
Promonocytes can either proliferate rapidly to monocytes and enter circulation or form reserve of very slowly renewing precursor cells in the marrow.
LYMPHOPOIESIS
- Lymphopoietic stem cells originate in the bone marrow.
- T-lymphocytes – unipotential stem cells destined to form T-lymphocytes keave the marrow and carried to the thymus. There they proliferate and differentiate acquiring
surface markers. Different subsets of T-cells acquire their own distinctive surface markers.
- B-lymphocytes – lymphopoiesis primarily occurs in the bone marrow but may occur in the spleen and possibly the submucosal lymphoid tissue of the intestine.
- Transitional cells - proliferating precursors of small lymphocytes are larger with pale-staining nucleus & very thin rim of cytoplasm. These are actively proliferating. 1/5 of all
marrow lymphocytes.
THROMBOPOIESIS
- The development of platelets.
- Platelets comes from the cytoplasm of Megakaryocytes.
Megakaryocytes
- Are large cells (50-70 um) situated adjacent to the marrow sinuses.
- These cells are roughly spherical but may have few short blunt processes.
- Nucleus is pleiomorphic with multiple lobes interconnected by narrower segments. Coarse chromatin pattern and multiple distinct nucleoli. Nucleus also
contains 8-16 sets of chromosomes and occasionally 64.
- Cytoplasm appears homogeneous.
- Megakaryocytes can produce 4000-8000 platelets.
1. Megakaryoblast
- Earliest morphologically identifiable cell.
- Arise from CFU-Meg
- Large cell with round or indented nucleus, loose chromatin pattern.
- Cytoplasm is basophilic and devoid of specific granules.
2. Promegakaryocyte
- 30-50 um in diameter.
- Has a prominent cytocentrum containing a number of pairs of centrioles.
- In further differentiation, numerous small azurophilic granules appear in the cytoplasm.
3. Reserve Megakaryocyte
- Fully formed but not yet active in platelet formation.
- 50-70 um in diameter
- Has very large multilobular nucleus.
- Azurophil granules are uniformly distributed in the center but usually absent at the periphery.
4. Platelet forming Megakaryocyte
- Azurophil granules are clustered in small groups separated aisles of granule free cytoplasm.
- Pale blue ectoplasmic zone is now less conspicuous.
- Endomitosis – cell division that occurs in megakaryoblast where there is nuclear division but no cytoplasmic division.
REGULATION OF HEMOPOIESIS
I. Hemopoietic Microenvironment
- Environment favorable or capable of sustaining blood cell proliferation
II. Humoral Agents
- Erythropoietin – a glycoprotein that is important in maintaining normal numbers of circulation RBCs. Its synthesis is inversely related to oxygen tension
prevailing in tissues. The monitor for tissue oxygenation and site of synthesis of erythropoietin is in the juxtaglomerular apparatus.
- Colony-stimulating factors (CSFs) – four have been isolated and characterized. These are glycoproteins that are effective even in very low concentrations. They
are synthesized by a variety of cells in or out of the bone marrow.
o Granulocyte-monocyte colony stimulating factor (GM-CFS) & multi-CSF/Interleukin 3
 Stimulate early progenitor cells capable of differentiating into more than one cell type
 GM-CFS – stimulate CFU-GM (neutrophils & monocytes)
 Multi-CSF – stimulate CFU-GEMMe (neutrophils, monocytes, RBCs & megakaryocytes)
o Granulocyte-colony stimulating factor (G-CSF) & monocyte-CSF (M-CSF)
 Stimulate differentiationof more advanced progenitors committed to a single cell lineage
Constitutive Hemopoiesis – production of CSFs by cells in the stroma of the bone marrow to maintain normal levels of circulating blood cells.
Induced Hemopoiesis – stimulating factors are produced by cells remote from the marrow activated by products of invading bacteria.

CHAPTER 13 -The Immune System

 The immune system consists of specific lymphoid organs, masses of lymphoid tissue embedded in other organs, individual lymphoid cells infiltrating connective and
epithelial tissues of the body and lymphocytes circulating in the blood & lymph.
 The collective function of these organs and cells is to protect the body from the potentially harmful effects of exogenous macromolecules.
 Fundamental to the ability to mount an immune response is the ability to distinguish self from non-self possessed by the 2 kinds of lymphocytes
ANTIGEN
 any substance recognized as foreign and capable of binding antibodies.
 Antigenic Determinant is the portion of the antigen that is recognized by the antibody or T-cell receptor.
 Antigenicity is the ability of the molecule to react with an antibody; Immunogenicity is the ability to induce an immune response.
 Haptens are small molecules that can react with antibodies but cannot induce their production.
ANTIBODY
 is an immunoglobulin molecule that binds to the surface of an antigen, initiating their destruction.
 Monoclonal Antibody – antibody of the same specificity produced by all progeny of any given lymphocyte.
 Polyclonal Antibody – produced by multiple lymphocytes of differing specificities. The lymphocytes are activated by a single molecule with multiple determinants.
PRIMARY LYMPHOID ORGANS – Thymus & Bone Marrow
SECONDARY LYMPHOID ORGANS – Spleen, Lymph Nodes and Tonsils

HUMORAL IMMUNE RESPONSE

 Antigen binding to the surface immunoglobulins stimulates proliferation of this kind of lymphocyte and synthesis of antibodies specific for the antigen.
 Structure of Monomeric Immunoglobulins
 Composed of 4 polypeptide chains arranged so that each half is made up of one H-chain and one L-chain bound by disulfide bonds.
 The H-chain has a flexible hinge region near the middle. The upper halves of both H-chains plus the L-chains diverge giving the Ig a Y shape.
 Papain cleaves the Ig to 3 parts: 2 Fab fragments which have binding sites for antigens and 1 Fc fragment with a binding site for complement.
 Constant and Variable Regions can be found w/in the H- and L-chains. The variable regions are bound together to form the antigen binding site.
 Classes of Immunoglobulins:
1. IgG
 The most abundant class in of Ig in blood.
  Has affinity for antigenic determinants making very effective in establishing humoral immunity.
2. IgM
 A large pentamer of radially arranged monomeric immunoglobulins bound by disulfide bonds and J-protein that holds the circle together.
 Makes up 10% of serum Ig.
 Produced in the early stages of an antigenic challenge but is soon replaced by IgG.
 First Ig expressed in the embryo and present in the membrane of resting lymphocytes.
 Effective in activating complement.
3. IgA
 Constitutes about 20% of serum Ig
 Can occur either as a monomer or dimer joined by J-protein
 Found in glandular secretions where it occurs as a dimer with an additional secretory component.
 The most abundant Ig in the body.
4. IgD
 Very low concentration in the serum
 Found on the surface of resting lymphocytes, with IgM.
5. IgE
 Found only in trace amounts in serum
 Involved in some forms of allergic reactions.
 Fc portions binds with mast cells causing the cells to degranulate during subsequent binding with an allergen.
B-LYMPHOCYTES
 Effector cells of the humoral immune response.
 Resting B-cells synthesize IgM and IgD which are incorporated in their membrane serving as antigen receptors.
 During an immune response, B-cell activation and proliferation is stimulated by antigen-binding and the helper T-cells.
 There is also synthesis of IL2 which further stimulates proliferation of activated B-cells and T-cells.
 Activated B-cells synthesize IgM and later, IgG.
 Compared to Plasma Cells, the number of antibodies released is small, but they are released earlier and at the site of antigen invasion.
PLASMA CELLS
 Late stage of differentiation of B-lymphocytes.
 Can be found in the lymph nodes, spleen and scattered through the connective tissue of the body
 They are also numerous in the intestinal mucosa secreting IgA instead of IgG.
 They can also be seen in the lymph and blood during an antigenic challenge.
 Round or ovoid in shape. Spherical nucleus, small nucleus, coarse masses of heterochromatin arranged radially Cytoplasm is more abundant than lymphocytes.
 Russell bodies – accumulations of incomplete antibody molecules.

CELLULAR IMMUNE RESPONSE

 Other lymphocytes that do not produce antibodies but have immunoglobulin like receptors on their membranes can bind directly to foreign cells destroying them by
secreting cytoxic agents.
 INTERLEUKINS- signaling molecules that regulate immune response and activate macrophages and granulocytes.
T-LYMPHOCYTES
 Activated by their interaction with histocompatibility molecules, glycoproteins found on the surface of all cells.
 These molecules are encoded by MHC genes.
 3 classes of MHC genes:
 Class I – encode molecules found in all cells.
 Class II – encode molecules expressed exclusively on cells of the immune system.
 Class III – encode serum proteins and components of complement.
 T-lymphocyte receptor consists of α and β chains containing constant and variable regions.
 This receptor can recognize both antigen and histocompatibility molecules. During their sojourn in the thymus, there is elimination of the self-reactive cells
resulting in a population of mature T-cells that react only with non-self.
 Subclasses of T-Lymphocyte:
1. Suppressor T-cells – depress production of antibody by B-cells.
2. Cytotoxic T-cells – the principal agents of cell-mediated immunity. They are the principal cause of graft rejection. They can also destroy fungi, parasites and virus
infected cells. Bear the CD-8 surface marker.
3. Memory T-cells – arise after antigen reaction. These have life spans of several years in man.
4. Helper T-cells – participate in the activation and proliferation of B-lymphocytes, therefore increasing antibody production. Bear the CD-4 surface marker.
MACROPHAGES
 They are versatile participants in the body’s immunological defences, actively eliminating antigens by phagocytosis and intracellular digestion.
 They also present a processed fragment of antigen bound to class II MHC to T-lymphocytes which results to secretion of lymphokines by the T-cells.
 To carry out their antigen presenting role, the macrophage must first bind, ingest and process antigens.
 Other Antigen-Presenting Cells that are incapable of phagocytosis: dendritic, follicular dendritic, interdigitating, and Langerhan’s cells.
LYMPHOKINES
1. Interleukin-1 – soluble factor released by macrophages to activate T-lymphocytes.
2. Interleukin-2 – secreted by activated T-cells which stimulates Ig production by B-cells.
3. Interleukin-3 – produced by T-cells and stimulates proliferation of neutrophils, macrophages and mast cells.
4. Il-4, Il-5, Il-6 – regulate B-cell growth and differentiation.
5. Il-6 – released by T-cells, monocytes, fibroblasts and endothelial cells acts on the temperature regulating centers, causing fever associated with infections. Induces the liver
to produce proteins that promote phagocytosis.
6. Il-6 & Il-3 – acts on stem cells, increasing the output of WBC and promotes maturation of megakaryocytes, increasing production of platelets.
7. Il-8 – produced by monocytes and endothelial cells at the site of inflammation, enhances chemotaxis of neutrophils.

Surface Properties: B-cells – IgM & IgD molecules

T-cells – antigen-receptors
Antigen Response: B-cells – production of antibodies
T-cells – regulate antibody production and direct cell to cell mechanism of destruction.

NON-SPECIFIC STIMULATION OF LYMPHOCYTES

Mitogens - substances that can interact with whole classes of lymphocytes, having the capacity to bind to chemical groupings on the plasma membrane of lymphocytes.
- They belong to a class of substances, called ligands that share a common affinity for certain chemical groups on the surface of cells.
Lectins – extracts of plants that cause agglutination of RBC and Lymphocytes.
Ex: Phytohemagglutinin & Concanavalin-A – stimulate T-cells
Pokeweed nitrogen – both T- & B-cells
LPS – B-cells
LYMPHOID TISSUE
 Sites in which lymphocytes, with or without associated plasma cells, are the principal cellular component.
DIFFUSE LYMPHOID TISSUE
 Lymphoid tissue of this description can be found in the intermodal, deep cortical and medullary regions of lymph nodes; periarterial lymphoid sheaths of the spleen;
intermodal regions of tonsils; in the Peyer’s patches of the ileum.
 Stroma – composed of reticular fibers and reticular cells.
 The reticular cells, other than those of the thymus are fibroblasts involved in the synthesis and maintenance of the reticular fibers.
 Occasional free macrophages are scattered among the reticular cells.
 Free cells of the diffuse lymphoid tissue: lymphocytes, free macrophages, plasma cells
LYMPHOID NODULES/LYMPHOID FOLLICLES
 Circumscribed closely packed collections of lymphocytes within areas of diffuse lymphoid tissue.
 Found in the cortex of lymph nodes, periphery of the white pulp of the spleen and in the lamina propria of the digestive and respiratory tracts.
 Especially numerous in the tonsils, Peyer’s patches and appendix.
 Primary Nodules – rounded aggregation of closely packed small lymphocytes
 Secondary Nodules – ovoid areas of larger pale-staining cells covered by a cap of small lymphocytes.
 Germinal Centers - highly organized component of lymphoid tissues.
- have darker, densely populated pole; paler, less densely populated pole; and a thin layer of slender
elongated cells, which is invested at one pole by a crescentic cap of small lymphocytes.
- sites where B-cells undergo active proliferation following initial or secondary antigen exposure.
LYMPHOCYTE CIRCULATION
 Efficient immunological surveillance is possible only if lymphocytes are able to move freely throughout the body.
 There is a continuous traffic of lymphocytes between the various lymphoid organs, via blood and lymph.
 Slow Migration – slow movement of lymphocytes to and through the thymus; seeding of lymphocytes from the thymus and bone marrow to the lymphoid organs.
 Fast Migration – “recirculation”; this is the rapid movement of long-lived lymphocytes to the lymphoid organs and tissues and back into the blood for another circuit.

CHAPTER 14 –THYMUS

 An organ situated in the superior mediastinum anterior to the great vessels where they emerge from the heart.
 Extends from the root of the neck, cranially, to the pericardial sac, caudally.
 Consists of 2 lobes arising in the embryo as separate primordial but become closely joined by connective tissue.
 Greatest Relative Weight – achieved at the end of fetal life.
 Absolute Weight – continues to increase, reaching 30-40 g at the time of puberty.
 In adult, it is largely replaced by adipose tissue.
 Is the only primary lymphoid organ that has been clearly identified and is the first organ to become lymphoid.
 No germinal centers
 Removal of the organ before complete development of the immune system results in very serious impairment of immunological defences.
HISTOLOGICAL ORGANIZATION
 Thymic Lobule - invested by a thin loose connective tissue capsule
- primary connective tissue septa give rise to thin connective tissue septa that penetrate the lobule as far as the corticomedullary junction
carrying small blood vessels with them.
- subdivided into a number of parenchymal lobules (polyhedral in shape; 0.5-2mm in diameter)
- connective tissue strands connect one lobule to another.
 Principal Cellular Constituents: Lymphocytes, Reticular Cells and Macrophages
 Thymic stroma – often referred as a cytoreticulum, is composed of heterogenous stellate cells whose embryological origin is from one of the epithelial germ layers and not
from the mesenchyme.
 Each lobule has a dark-staining peripheral portion, the cortex and a lighter staining central portion, the medulla.
CORTEX
 Numerous, densely packed lymphocytes contribute to the intense basophilia of this region.
 The vast majority of cells in the cortex are lymphocytes (small, medium and small)
 Macrophages are scattered throughout the cortex. Plasma cells are present in the interstitial CT of the involuting thymus and in the parenchyma at the extreme periphery
of the cortex. Mast cells may also be found outside the lobules.
 Different Epithelial Cell Types in the Cortex:
 Type-1 epithelial cells/subcapsular-perivascular epithelium – invests the parenchyma beneath the capsule and ensheath the connective tissue septa and the
perivascular spaces of the cortex.
 Irregular nucleus and prominent nucleolus. Cytoplasm shows well developed organelles and granules.
 Stroma is composed of stellate reticular cells with processes adhering to one another by desmosomes. Lymphocytes fill the interstices of the
framework.
 Type-2 cells – found at the outer and midregion of the cytoreticulum.
 Large pale nucleus and a prominent nucleolus.
 Cytoplasm has tonofilaments, ER, GC, coated vesicles and granules and some lysosomes.
 Type-3 cells – found deeper in the cortex.
 Nucleus is irregular in shape, peripheral heterochromatin and expanded perinuclear cisternae.
 Cytoplasm: ER and vacuoles.
 Type 2 & 3 cells make up a greater part of the cytoreticulum and are the in vivo counterparts of thymic nurse cells.
 Thymic nurse cells – have molecules of MHC complex on their surface.
MEDULLA
 Fewer lymphocytes (predominantly small) and prominent epithelial cells.
 Macrophages are rarely found; Eosinophils may be found in small numbers; Plasma cells absent.
 Different Epithelial Cell Types in the Medulla:
 Type-4 epithelial cells – can be found at the deeper part of the cortex but more abundant in the medulla.
 Stain more deeply than other epithelial cells; they form the cytoreticulum of the medulla.
 Type-5 cells – undifferentiated cells found in groups at the corticomedullary junction and singly in the medulla.
 More cytoplasm than other reticular cells and rich in polyribosomes.
 Type-6 cells – Larger cells confined in the medulla. Nucleus is euchromatic w/ a prominent nucleolus. Cytoplasm has ER and dense granules.
 Hassall’s corpuscles – could reach up 100 um in diameter. Formed when round or flattened type-6 cells wrap around one another joined by
desmosomes and containing intermediate filaments.
HISTOGENESIS of the THYMUS
 Bilateral outgrowth from the endoderm lining the third brachial branch.
 Embryos at 8 weeks, the separate primordia fuse at the midline and acquire a common mesenchymal investment.
 Lymphocyte precursors appear at this stage.
 12th week, large, pale staining lymphocytes predominate the outer portion while small lymphocytes are abundant in the interior. Septa of the mesenchyme begin to invade
the organ.
 14th week, differentiation of the cortex and medulla is complete. Septa and blood vessels have advanced to the corticomedullary junction. Perivascular spaces formed.
 As early as the 8th week of gestation, Myoid cells and small Hassall’s corpuscles can be found in the thymic parenchyma.
INVOLUTION of THYMUS
 Begins in early childhood with decline of the relative volume of the parenchyma.
 With advancing age,
 there is a decline in lymphocyte production
 cortex becomes thinner
 parenchyma largely replaced by adipose tissue
 Age involution- normal process of involution of the thymus.
 Accidental involution – the gradual process of involution is accelerated. This may occur in response to disease, severe stress, ionizing radiation, endotoxins and
administration of Adrenocorticotrophic hormone.
VESSELS & NERVES
 The thymus is supplied by the Internal Thoracic Arteries and their Mediastinal & Pericardiacophrenic branches.
 Ultimately drained by the Thymic Vein, a tributary of the left brachiocephalic vein.
 Blood Thymus Barrier – interendothelial cell junction of capillaries and the layer of endothelial cells, a barrier to antigens that protects the lymphoid population in the
cortex.
 Small lymphatics are found in the CT septa of the thymus and drained by Sternal, Tracheobronchial & Mediastinal lymph nodes.
 The thymus receives branches from the vagus and sympathetic nerves.
HISTOPHYSIOLOGY
 Thymotaxin – a chemotactic peptide secreted by the subcapsular reticular cells inducing emigration of stem cells from the yolk sac or embryonic liver to the parenchyma of
the thymus.
Maturation of Thymocytes:
1. Migration of T-cell precursors into the cortex of the thymus.
2. Acquisition of distinctive surface markers and MHC class specificity.
3. Gene segment rearrangement creating diversity in the chains of the receptor.
4. Synthesis of T-cell receptors and incorporation into the membrane.
5. Negative selection involving elimination of self-reactive cells.
6. Positive selection by clonal expansion of cells capable of reacting to non-self.
7. Release of immunocompetent T-cells.
 Cytokines are secreted by epithelial cells and macrophages of the thymus that contribute to the special microenvironment within the thymus needed for the maturation of
T-cells.
 Thymic Hormones:
1. Thynulin – development of different subsets of immature lymphocytes.
2. Thymic humoral factor – differentiation and clonal expansion of T-cells
3. Thymopoietin – differentiation of T-cells. Bind to acetylcholine receptors and is suspected to be involved in the pathogenesis of myasthenia gravis.
4. Thymosin-1 – localized in the subcapsular epithelial cells and cells around Hassall’s corpuscles. Various immunomodulatory effects have been attributed to this
peptide. And may have a role in DNA replication.
 It may occur as a larger molecule, prothymosin, which appears to be a signalling peptide targeted at the nucleus.
 Adrenal and gonadal steroids administered in excess could cause significant diminution in the population of thymocytes.
 Adrenalectomy and gonadectomy – increase in the weight of the thymus.
 Thyroxin administration – hypertrophy of epithelial cells and increased thymulin secretion.
 Somatostatin – influence cells of the immune system.

CHAPTER 15- LYMPH NODE

LYMPH NODES
 Small, ovoid or reniform organs, about 3-25 mm in diameter occurring in a series along the course of lymphatic vessels.
 Hilus is the slight indentation of a lymph node, where blood vessels enter and leave the organ.
 The parenchyma of lymph nodes consists of highly organized accumulation of lymphoid tissue, which recognizes antigens in the lymph and initiates a specific immune
reaction against them.
 Macrophages are also seen in lymph nodes, clearing the lymph of invading microorganisms.
HISTOLOGICAL ORGANIZATION
Framework
 Capsule – invests the lymph node; greatly thickened at the hilus.
 Trabeculae – connective tissue branches that extend inward from the capsule into the parenchyma.
 Between the trabeculae, a tridimensional network of reticular fibers and reticular cells supports the lymphoid tissue.
 The stroma of the lymph nodes is made up of a retinaculum of reticular cells and fibers and the lymphocytes that occupy the spaces.
 Lymph node is composed of an outer, densely staining cortex and an inner, paler medulla. The difference in appearance is due to the differences in the number, diameter,
and arrangement of the sinuses and the difference in the concentration of lymphocytes.
LYMPH SINUSES
 Specialized lymph vessels traversing the lymph nodes.
 Channels lined by a layer of attenuated squamous cells.
 The lumen is bridged by a meshwork of stellate reticular cells connected to each other and to the walls of the sinuses by slender cell processes.
 The supporting framework of the sinuses is a layer of reticular fibers continuous with the parenchymal retinaculum.
 No basal lamina intervenes between the fibers and cells of the sinuses.
 The fibers are invested in intraluminal stellate cells therefore they are not directly exposed to the lymph.
 In the lumen of the sinuses are round macrophages with microvilli and undulant processes. Lymphocytes are also present.
 The wall of the sinuses is freely permeable to the constituents of lymph.
 2 distinct categories of cells lining the sinuses: (1) macrophages and (2) flattened or stellate cells similar to endothelial cells.
Afferent lymphatic vessels approach the hilus and open into the marginal/subcapsular sinus. The marginal sinus communicates with the efferent lymphatic vessels at the hilus.
Arising from the marginal sinus are radially oriented intermediate/cortical sinuses which penetrate the cortical parenchyma and continue into the medulla as medullary sinuses.
The medullary sinus subdivides lymphoid parenchyma into medullary cords. The medullary sinuses are confluent with the marginal sinus at the hilus near where it penetrates
the capsule to join the efferent lymphatics.
 Valves of the afferent lymph vessels – free edge of the cusps points toward the nodes.
 Valves of the efferent vessels – free edge points away from the hilus.
 This arrangement of the valves ensures unidirectional flow through the node.
CORTEX
 The cortical parenchyma – a dense mass of lymphoid cells, traversed in places by the collagenous trabeculae and intermediate sinuses.
 Regions of the Cortical Parenchyma:
 Primary Nodules – spherical or ovoid areas of tightly packed small lymphocytes. B-cells are concentrated in this region.
 Secondary Nodules – have germinal center made up of large lymphocytes and macrophages. The germinal centers are sites of B-cell differentiation and antibody
production and also contain some T-cells.
 Germinal centers occur in variable numbers in the outer cortex, seldom found in the inner cortex and rarely in the medulla.
 Mantle/crescent – zone of smaller lymphocytes surrounding the germinal centers forming a cap on the side toward the capsule.
 The primary and secondary nodules form the bulk of the outer cortex.
 Diffuse Lymphoid Tissues – make up the internodular cortex and the inner/deep cortex which are devoid of germinal centers. Diffuse lymphoid tissues contain
abundant T-lymphocytes.
 Lymphocytes of the recirculatin pool only populate the deep cortex.
 The cells of the deep cortex are more closely packed compared to that of the outer cortex. Small lymphocytes predominate, with few large
lymphocytes, macrophages and plasma cells.
 Interdigitating cells – cells characterized by numerous surface processes that interdigitate among the surrounding lymphocytes. Localized in the deep cortex and contain
granules similar to Birbeck’s granules in Langerhans cells of the epidermis.
 Veil cells – cells with numerous surface ruffles. Isolated from the lumen of afferent lymph and may migrate across the endothelium of the marginal sinus. These cells also
contain Langerhans-type granules.
MEDULLA
 Medullary cords – consist of aggregations of lymphoid tissue organized around small blood vessels.
- made up of small lymphocytes, plasma cells and macrophages occupying the interstices of the network of reticular fibers and cells. The
parenchyma may also contain a small number of granulocytes.
- the cords branch and anastomose with one another, terminating or forming loops near the hilus.
BLOOD VESSELS AND NERVES
 Nearly all blood vessels enter through the hilus, some small ones enter through the capsule.
 Large branches of artery run in the trabeculae supply the capillary networks of the medullary cords and supply the capillary plexuses of the cortex.
 Postcapillary venules – have low cuboidal endothelium, arising from the capillary plexuses. Have taller endothelial cells and no muscular coat. Great numbers of blood
borne small lymphocytes can traverse their walls and enter the parenchyma.
 Nerves enter the hilus of lymph nodes with the blood vessels.
HISTOPHYSIOLOGY
 Highly effective filters that remove bacteria and malignant cells from the lymph before they reach the blood via the thoracic duct.
 The configuration and internal structure of the sinuses favour arrest of particles and facilitates removal of these by macrophages on the walls of the sinuses.
 More than 95% efficient in filtering bacteria but a less efficient barrier to lymph borne cancer cells. Viruses are also not destroyed when they are able to enter the
lymphocytes of lymph nodes.
 Lymph nodes also have a role in the body’s immunological defences: lymphocytes & plasma cells in the lymph nodes produce antibodies.
 The only sites of sustained lymphocyte activity in lymph nodes are in the germinal centers.
HEMAL NODES
 Lymph nodes with exceptionally high content of RBCs.
 They have red color.
 The structure is similar to that of lymph nodes but the sinuses are filled w/ blood and usually lack afferent or efferent lymph vessels.

CHAPTER 16 -SPLEEN

SPLEEN
 Situated between the fundus of the stomach and the diaphragm.
 Elongated, irregular. Weighs about 150 g.
 Invested by the peritoneum. Connected to the stomach, diaphragm and left kidney by the gastolineal, phrenicolineal and lienorenal ligaments.
 Serves as a complex filter, clearing the blood of particulate matters and senescent blood cells.
 The spleen’s blood vessels allow blood to come in contact with macrophages.
 Contains large amount of lymphoid tissue that carries out its immunological functions.
HISTOLOGICAL ORGANIZATION
 The spleen has a collagenous capsule that is thickened at the hilus.
 Hilus: where arteries and nerves enter; where veins and lymphatic vessels leave.
 Trabeculae: inward extensions of the capsule.
WHITE PULP
 Elongated, gray areas scattered throughout the red pulp.
 The white pulp of the splenic parenchyma is organized around arteries.
 Forms the periarterial lymphoid sheaths around the arteries
 The sheaths continue along the vessels where they break up into capillaries.
 Along their course, the sheaths contain germinal centers.
 The sheaths consist of predominantly T-lymphocytes of the recirculating pool while the germinal centers are made up of B-lymphocytes.
 The germinal centers are eccentrically situated and have a light region and a cap of small lymphocytes directed towards the red pulp.
 PALS have an organization similar to the cortex of lymph nodes.
 Marginal zone – an 80-100 um transitional zone between the white and red pulp.
 This zone consists of reticular fibers that form a close network and whose interstices are occupied by large numbers of small lymphocytes and
plasma cells.
 Bridging Channels – attenuated strands of the white pulp and equally thin marginal zone that extend to red pulp.
 Malphigian bodies – the lighter areas of the white pulp that consist of diffuse and nodular lymphoid tissue.
RED PULP
 The soft dark red mass of the spleen.
 The color is due to the abundance of RBC that fill the venous spaces and infiltrate the surrounding splenic cords.
 Consists of an elaborate network of tortuous, branching and anastomosing venous sinuses that drain to the pulp veins.
 The interspaces between the sinuses are occupied by the splenic or pulp cords.
 Splenic Cords (cords of Billroth)
 Consist of a spongy mass of extravasated blood cells supported by a framework of reticular fibers.
 The reticular fibers are invested by stellate reticular cells anchored to the walls of sinuses by foot-like processes.
 The meshes of reticulum in the pulp cords are filled with macrophages, plasma cells and great numbers of RBCs and platelets.
ARTERIES
 Branches of Splenic artery enters the hilus – when reduced to a diameter of 0.2 mm, they leave the trabeculae.
 Central artery – upon leaving the trabeculae, the vessels acquire sheaths of lymphoid tissue. The central artery gives off numerous lateral capillary branches. As it courses
along the white pulp, the thickness of the sheath is reduced.
 When the diameter of the artery is reduced to 40-50 um, it suddenly branches giving rise to penicillar arteries.
 Penicillar arteries – less than 1 mm in length, have a continuous basal lamina and are surrounded by a layer of smooth muscle and thin adventitia.
 Penicillar arteries branches and give rise to sheathed capillaries. The sheath is called the Schweigger-Seidel sheath, a local accumulation of reticular cells and macrophages.
Central Artery
 A small muscular artery with relatively tall endothelium and 1 or 2 layers of smooth muscles.
Sheathed Capillaries
 The endothelium of these capillaries consists of fusiform cells oriented parallel to the long axis of the vessel and resting on a discontinuous basal lamina.
SPLENIC SINUSES AND VEINS
 Splenic Sinuses – thin-walled vessels that permeates the red pulp. These vary in shape and the size of the lumen also varies depending on the volume of blood in the organ.
 The endothelial cells are fusiform, about 100 um in length and oriented parallel to the long axis of the sinus. The central region where the nucleus
is located is thickened but tapers towards the end of the cell.
 Only small number of lateral cell junctions can be seen in the endothelium but there is abundance of cytoplasmic filaments.
 The basal lamina is incomplete and unique in that it is reduced to slender bands deployed circumferentially around the endothelium, with
anastomosing longitudinal or oblique strands connecting the successive hoops.
 Pulp Veins – have a conventional endothelium, a continuous basal lamina and a thin layer of smooth muscle.
 These veins converge to form the veins of the trabeculae drained by the veins at the hilus which are tributaries of the splenic vein.
LYMPHATIC VESSELS AND NERVES
Lymphatics are poorly developed and found only in the capsule and the largest trabeculae.
Nerves – originate from the celiac plexus. Consist almost entirely of unmyelinated fibers that accompany the splenic artery.

HISTOPHYSIOLOGY
Blood Filtering Function
 This function depends on the large population of resident macrophages.
 Endothelial cells of the sinuses and the reticular cells of the splenic cords have no significant function in clearing of blood.
 Macrophages can remove antigens, excess lipids and damaged or abnormal blood cells and platelets from blood.
Recycling of Iron
 Also involved in the recycling of iron in the body.
 After macrophages degrade haemoglobin, iron is freed from heme and stored in the spleen as ferritin or hemosiderin.
Blood Reservoir
 The spleen can store up to 30 ml of RBC. But it is a more important reservoir of platelets estimated to contain 1/3 of the body’s supply. These are available for return
to the circulation when needed.
Immunologic Response
 Large fraction of splenic lymphocyte belongs to the recirculating pool.
MYELOID METAPLASIA
 A condition where hematopoietic tissue reappear in the red pulp of adults.

UNIT 6
URINARY SYSTEM

KIDNEYS

- retroperitoneal
Location: posterior wall of the abdomen on either side of the vertebral column
Shape: bean-shaped
Size: length: 10-12 cm, width: 5-6 cm, thickness: 3-4cm

Hilus - medial border of each kidney

- fissure which leads inward to the renal sinus
Renal sinus - deep recess that contains the renal artery & vein, some adipose tissue & renal pelvis
Renal pelvis - funnel-shaped expansion of the upper end of the ureter
 - divides into 2 long branches Major Calyces  short branches Minor Calyces
Cortex - dark reddish-brown
Medulla - lighter colored
- made up of 6-10 conical sectors
Renal Pyramids - broad base toward the cortex
Renal papilla - apex of renal pyramids
- project into the lumen of minor calyx
Renal columns of Bertin - lateral boundaries of each pyramid
- darker inward extensions from the cortex
Renal loble = 1 renal pyramid + bounding renal columns
Parenchyma - made up of myriad, minute Uriniferous tubules -- functional units
- segments are specialized for different roles in urine formation
- parallel tubules at the same level of the renal medulla
 transverse bands or zones which differ slightly in color or texture
Outer medulla -
Outer stripe - thin light-colored
Inner stripe - slightly thicker & darker
Inner medulla
Fine radial striation - attributable to the convergence of the straight portions of the uriniferous tubules on the papilla
Area cribrosa - end of the papilla
- have 25 pores -- openings of the terminal segments of the uriniferous tubules into the minor calyx
Medullary rays - bundles of straight segments from the base of the medullary pyramids
- extend upward into the cortex forming pale vertical striations

URINIFEROUS TUBULES
Functionally Distinct Portions:
1. Nephron - collects a filtrate of the blood created in a spherical mass of tortuous capillaries at its proximal end
- modifies the composition of the fluid by:
Adding nitrogenous wastes to it
Reabsorbing from it certain components that need to be conserved
2. Collecting tubule - absorbs H2O from the filtrate to concentrate its solute  hypertonic urine which is conveyed to the renal pelvis
* 1 & 2 - arise in the embryo from separate primordial that become connected later in development

NEPHRON
Segments:
1. Proximal convolution
2. Loop of Henle - includes the thick D L of the proximal tubule
DTL & ATL of the intermediate tubule
Thick AL of the distal tubule
- length is not closely correlated with the position of its glomerulus in the cortex
Short-looped nephrons - loop turns back in the outer medulla
Cortical nephrons - have a very short loop that doest extend into the medulla but turns back in the inner cortex
3. Distal convolution
4. Collecting duct

Major Subdivisions of the Uriniferous Tubule:

1. Proximal tubule
Bowman’s capsule = Urinary Space
- closed, thin-walled expansion of the tubule
- deeply invaginated  cup-shaped hollow structure
Glomerulus - occupy the concavity of the blind end of the nephron
- globular tuft of highly convoluted capillaries
Renal corpuscle = mass of capillaries + surrounding chalice-shaped epithelial capsule
- has a vascular pole where the afferent & efferent vessels enter & leave the glomerulus
- has a urinary pole where the slit-like cavity between the layers of bowman’s capsule is continuous with the lumen of the proximal tubule

Segments:
a. Proximal Convoluted Tubule (PCT) = Pars Convoluta
- situated in the cortex
b. Proximal Straight Tubule (PST) = Pars Recta
- extend from the cortex into the outer stripe of the medulla
2. Intermediate tubule - forms a long loop
a. Descending Thin Limb (DTL) = Pars Descendens
- traverse the inner stripe of the outer medulla & extend deep into the inner medulla
b. Ascending Thin Limb (ATL) = Pars Ascendens
- recurrent portion
3. Distal tubule
Distal Straight Tubule (DST) = Thick Ascending Limb (TAL)
- connected with ATL at the junction of the inner & outer medulla
- traverse the outer medulla & continue into the cortex  Distal Convoluted Tubule (DCT)
Connecting Tubule (CT) - join the distal convoluted tubule in the cortex to CD
4. Collecting system
Collecting Duct (CD) - passes downward through the cortex & medulla to the area cribrosa of the renal papilla, where it opens into a minor calyx

RENAL CORPUSCLE
Bowman’s capsule - double-walled cup around a glomerus
 - squamous epithelial cells
Capsular space = Bowman’s space
- narrow cavity between the visceral & parietal layer of epithelium
Visceral layer of epithelium = Glomerular epithelium
- at the vascular pole, it is reflected off of the afferent & efferent vessels
- continuous with the parietal layer of epithelium
Parietal layer of epithelium = Capsular epithelium
- at the urinary pole, its squamous epithelium is continuous with the cuboidal epithelium lining the neck of the proximal convoluted tubule
Podocytes - stellate
- with several radiating primary processes that embrace the underlying capillaries
- secondary processes are closely applied to the basal lamina of the underlying capillary
- cell body are usually separated from the capillary
 permit’s the greater part of the capillary surface to be carpeted by small interdigitating foot-processes
 arrangement maximizing the total area of intercellular clefts available for filtration
- cell body & primary processes of 1 podocyte may arch over processes of neighboring podocytes
- terminal branches appear always to interdigitate with those of another cell rather than with foot-processes
- nucleus is often infolded & irregular in outline
- cytoplasm: small golgi complex
Moderate rough ER
Abundant free polyribosomes
Intermediate filaments & microtubules - in cell body & primary processes
Pedicels / Foot-processes = numerous secondary branches
- interdigitate with corresponding processes of neighboring podocytes but are not closely adherent to them
- x-sec are aligned on the unusually thick basal lamina of the endothelium
- their bases -- somewhat expanded  bell-shaped
- plenty actin filaments & heavy meromyosin
- CM has a prominent glycocalyx -- negatively charged  significant component of the filtration barrier
- stains intensely with ruthenium red
- sialoglycoprotein  Podocalyxin
System of intercellular clefts - formed through which a filtrate of the blood plasma can enter the capsular space
Filtration slits - separate adjacent foot-processes
- largely filled with the filamentous molecules forming the glycocalyx on adjacent foot-processes
Slit-diaphragm - spanned the slits at the level of basal lamina
- have porous substructures with a central linear density connected to the membrane of adjacent foot-processes
- pores between them -- small enough to prevent passage of albumin & larger molecules from the blood into the glomerular filtrate
Layers of the basal lamina between the glomerular epithelium & the endothelium
1. Lamina rara externa - adjacent to the foot-processes
2. Lamina densa - darker central zone
- consists of a meshwork of type-IV collagen & laminin in a matrix rich in heparan sulfate proteolgycan
- negatively charged proteoglycan  electrostatic barrier of the glomerular filter
3. Lamina rara interna - adjacent to the endothelium
Fibronectin - anchor the epithelial & endothelial cells to the lamina densa
Endothelium of the glomerular capillaries - thin & perforated by pores
- abundant & uniform distribution
- don’t have pore diaphragm
- thicker portion of the endothelial cell bodies containing the nucleus is usually located on the side of the capillary away from the
capsular space
Mesangium - occupy the spaces between the glomerular capillaries
- CT consisting of Mesangial Cells in an ECM that is relatively free of fibrous elements other than fibronectin
Mesangial cells - specialized type of pericyte providing structural support for the capillary loops
- phagocytic
- participate in continuous turn-over of the basal lamina by removing its outer portion containing residues of filtration while the lamina is renewed on its
inner surface by the endothelial cells
- contractile
- respond to angiotensin-II & other vasoconstrictors that are known to reduce the area of the intraglomerular filtration barrier by reducing the blood flow
through some of the capillary loops
- those near the vascular pole of the glomerulus are most favorably situated to regulate the # of the open loops
- have specific receptors for atriopeptides
- may serve to unclog & recondition the filter by disposing the filtration residues that may accumulate within it
Atriopeptides - hormones secreted by certain cells of the myocardium
- 1 of principal effects: vasodilatation increasing the filtration rate
- mediate the effects of mesangial cells on flow through the glomeruli
Filtration of the blood plasma in the renal glomeruli is essential for:
- elimination of nitrogenous waste
- control of the ECF composition & of blood volume
Structural components of the filter
1. Fenestrated endothelium
2. Basal lamina - main filter
3. Filtration slits between the foot-processes of the podocytes
Endothelial pores - coarse sieve holding back the formed elements of the blood

PROXIMAL TUBULE
Cuboidal epithelium - at the urinary pole, it is continuous with the squamous parietal epithelium of bowman’s capsule
- after a few short convolutions near the glomerulus, it forms a longer loop directed toward the surface of the kidney
Recurrent limb of the loop - returns to the vicinity of the renal corpuscle
 - enters the nearest medullary ray  Pars recta - course inward toward the medulla
- longest segment of the nephron
- greatest part of the renal cortex
Lumen: often appears occluded
Wide
Cells: - single spherical nucleus
- cytoplasm: eosinophilic
Golgi complex forms a crown around the upper pole of the nucleus
Mitochondria - numerous & long
- in the basal half of the cells
- oriented parallel to the axis  faint vertical striation of the basal cytoplasm
Short spiny projections - resembling those seen on the clathrin-coated vesicles of other cell types engaged in receptor-mediated endocytosis
Numerous small vesicles & larger vacuoles - around the ends of the canaliculi
- lateral boundaries are not resolved with LM due to their extensive interdigitation
- very complex shape
- a # of alternating ridges & grooves extend the full length of the cell
 become increasingly prominent from apex to base
 near the basal lamina, they become elongated into branching processes that extend beneath the bodies of neighboring cells
CM: - has prominent brush border & glycocalyx
- paired membranes run from the basal lamina up into the cell, compartmentalizing the basal cytoplasm
- contains the transport systems for glucose & AA
- peptidases -- involved in the regulation of circulating levels of small peptide hormones
Apical Canaliculi - tubular invaginations of the CM
- opening into the clefts between the microvilli
Basal compartments -- not open to the cytoplasm
- not part of the overlying cell
- x-sec of undermining processes of neighboring cells
Interdigitation of the basal portions of the cells  greatly amplifies the area of the cell surface exposed to the fluid in a labyrinthine system of intercellular clefts
Basolateral membrane - Na,K-ATPase

Fxns: - reabsorbs nearly all of the glucose & AA in the glomerular filtrate
- allow other substances of no nutritional value to be excreted in the urine
- reabsorbs H2O & Na ions in the glomerular filtrate
- pumping of sodium accompanied by chloride into the interstitial fluid  creates an electrochemical gradient  moves H2O from the tubule lumen to the
peritubular capillaries

ultrastructurally distinct segments:

S1 to S2 - gradual transition
S2 to S3 - abrupt transition

Segments Cells Interdigitation Mitochondria Fxns

S1 initial end & midportion of taller very extensive - large - active in endocytosis
the pars convoluta basolateral - numerous - highest sodium transport
S2 - distal portion of the pars lower less basolateral shorter
convoluta interdigitation
- beginning of the pars recta
S3 remainder of the pars recta cuboidal few interdigitating - small - longer microvilli
lateral processes - randomly oriented

INTERMEDIATE TUBULE (THIN SEGMENT)

- squamous epithelium bearing few microvilli
- central portion of the cells containing the nucleus bulges slightly into the lumen

Long-looped nephrons Short-looped nephrons

- boundary between the outer & inner zones of the medulla is the site of the - numerous
transition of the thin limb to the ascending thick limb - thin segment: length varies & rarely lacking

DISTAL TUBULE
- begins in the inner stripe of the outer medulla at an abrupt transition from the thin limb of the loop of Henle (pars recta & TAL)
Medullary Thick Ascending Limb (MTAL) - initial portion
Cortical Thick Ascending Limb (CTAL) - contact the vascular pole of the renal corpuscle of the same nephron
- epithelium contains a plaque of specialized cells  Macula Densa
Epithelium: cuboidal
Lumen: wider
Brush border: lacking
Cells - Short microvilli on some
- others have smooth surface -- predominate in the medullary portion of the TAL
- pair of centrioles -- beneath the apical CM
 - 1 serve as the basal body of a short flagellum that projects into the lumen
- vesicles are present in moderate #s in the apical cytoplasm
- NO clathrin-coated vesicles & canaliculi
- long mitochondria
Nucleus: - round & ovoid
- displaced toward the lumen by deep infoldings of the basal CM that bound narrow compartments

TAL - nearly impenetrable to H2O

Inner stripe of the outer medulla - greatest: Na,K-ATPase activity
Resorptive capacity
Surface area of the basolateral membrane
Volume of the mitochondria
Fxn: reabsorption of Na & Cl from the glomerular filtrate

Distal Convoluted Tubules (DCT) - turtuous course

- cells are slightly taller
- membrane invaginations & interdigitation of the lateral cell processes near the cell base are somewhat more extensive  greater total
area of basolateral membrane
- higher Na,K-ATPase activity than any other segment of the nephron
- delivery of an excess of Na & Cl to this segment  induces an increase in its basolateral membrane area & in its Na,K-ATPase activity
Fxn: capable of reabsorbing nearly all of the remaining Na if this is necessary to maintain the normal electrolyte composition of the body fluids

Tamm-Horsfall Proteins - associated with ATL of the loop of Henle

- contributes to the formation of intratubular casts that occlude the tubules in some diseases of the kidney

COLLECTING TUBULES
Connecting tubule - short transitional segment joining the DCT to the Collecting Duct
Cellular heterogeneity - characteristic of the epithelium of the connecting tubule
- diminishes in the CCD & OMCD where only P-cells & I-cells are found
Cell types:
1. DCT cells
2. Connecting tubule cells (CTC) - have round or ovoid nucleus
- small paranuclear golgi complex
- numerous small mitochondria
- luminal surface is relatively smooth
- few vesicles in the apical cytoplasm
- less lateral interdigitation of cells
3. Principal cells (P-cells) - simpler ultrastructure
- short, stubby microvilli
- centrally located single flagellum
- ovoid nucleus is centrally located
- mitochondria are quite small & randomly oriented
- at the cell base, there are many folds of the basal membrane that are closely compacted in varying orientation
- less space between these peculiar basal folds
4. Intercalated cells (I-cells) - microplicae on their free surface
- extraordinary abundance of vesicles in the apical cytoplasm
- short plump mitochondria are distributed throughout the cytoplasm
- no basal compartmentalization
- many slender villi or folds of the CM may be interposed between the cell body & the basal lamina in varying orientation
- involved in the control of acid-base balance by resorption of HCO3
- have a high carbonic anhydrase activity
- basolateral membranes contain the anion-channel protein Band-3 -- linked to the membrane skeletal proteins Ankyrin & Spectrin

Collecting ducts - participate in secretion of K & acidification of the urine

- course inward in the medullary rays
- when they reach the inner medulla, pairs of them approach at an acute angle & become confluent
- about 7 convergences in the inner medulla  formation of larger straight ducts
Papillary ducts (ducts of Bellins) - open into a minor calyx on the area cribrosa of each renal papilla

Segments of the CD based on their location in the zonation of the renal pyramids:
1. Cortical CD
2. Outer Medullary CD
3. Inner Medullary CD

RENAL INTERSTITIUM
- constitute the contents of the spaces external to the basal laminae of the tubules
- in the cortex, its volume is relatively small but it increases in the medulla
- includes:
a. Fibroblast-like cells
Fibroblasts - in the cortex, they have long tapering processes that are in contact with processes of like cells
Nucleus - elongate
- often indented
- small clumps of chromatin are evenly spaced along the nuclear envelope
Cytoplasm - actin filaments are abundant in the peripheral cytoplasm & subplasmalemmal densities, resembling those of smooth muscle
- occasional small lipid droplets
 - dilated cisternae of rough ER
- produce the fibrous & amorphous components of the ECM
Medullary Interstitial Cells - fibroblast-like cells
- highly pleomorphic
- oriented perpendicular to the axis of the tubules  rungs of a ladder appearance
- long processes are more slender
- tips are closely apposed to the tubules & to the walls of blood vessels
Cytoplasm - multiple lipid droplets -- size & # vary in different states of salt & H2O balance
- prostaglandins can be extracted from the renal medulla but are not secreted by the cells
- triglycerides rich in arachidonic acid & PUFA
- contain substrate for synthesis of Medullipin-I
- smooth ER
- few expanded cisternae of rough ER
- have endocrine fxn -- low BP in hypertension
b. Mononuclear cells - more-or-less spherical
- large heterochromatic nucleus
Cytoplasm - relatively thin rim
- few mitochondria
- abundant free ribosomes
- little or no ER
- often located in close proximity to the fibroblasts
- early stages of the monocyte-macrophage lineage
- few are present in the outer zone of the medulla
- rare or absent in the inner zone & papilla
c. Small bundles of collagen fibers in a highly hydrated proteoglycan matrix

Medullipin-I - has been extracted from the renal papilla

- causes vasodilatation of major vascular beds & lowering of BP of hypertensive
- secretion by the interstitial cells is influenced by renal artery perfusion pressure
- must traverse the liver  Medullipin II -- active vasodilator
Medullipin - secreted in the medulla  hypertensive
Renin - secreted by the juxtaglomerular cells in the cortex  hypotensive

JUXTAGLOMERULAR COMPLEX
- made up of tubular & vascular elements of the nephron that have interactive fxns influencing systemic BP & the rate of glomerular filtration
DCT - located at the vascular pole of the glomerulus between the afferent & efferent arterioles
- on 1 side of the tubule nearest to the afferent arteriole, epithelial cells are slender & more crowded than elsewhere

1. Macula densa - sector of the wall of the tubule is conspicuous owing to close packing & intense staining of its nuclei
Cells - have numerous microvilli on their luminal surface
- centrally located cilium
Cytoplasm - mitochondria are short & randomly oriented
- golgi complex is usually located between the nucleus & the cell base
- polarity is opposite
- basal lamina is thin & discontinuous
- blunt cell processes extend through the basal lamina toward the juxtaglomerular cells in the afferent arteriole
- has sensory fxn that influences the activity of juxtaglomerular cells
- in the tubuloglomerular feedback mechanism, it detect changes in the conc. or flow rate through the renal tubule & transmit signals to other elements of
the juxtaglomerular complex that alter glomerular filtration rate
2. Juxtaglomerular cells - contained by the afferent arteriole adjacent the macula densa
- modified smooth muscles
- have round nuclei
- cytoplasm contains secretory granules
- vary in abundance from nephron to nephron & may be absent from some
- located in the terminal segment of the afferent arteriole near the glomerulus
- rarely found in efferent arteriole
- vary in their fine structure
- some have few secretory granules & retain features typical of smooth muscle
- bundles of myofilaments & dense bodies at their sites of attachment to the CM
- others have more numerous granules, well-developed ER, prominent golgi complex & few/no myofilaments
Secretory granules - when 1st formed -- small & fusiform or rhomboid in shape
- have a paracrystalline interior
- later coalesce into irregularly shaped conglomerates
- mature granules -- spheroidal
- have a homogeneous content devoid of crystalline order
- contain Renin -- acid protease that catalyzes the cleavage of plasma angiotensinogen to angiotensin-I
converting enzyme in the lung cleaves angiotensin-I  angiotensin-II
angiotensin-II - potent vasoconstrictor that raises BP & indirectly influences renal blood flow
- local release may influence filtration rate by causing constriction of glomerular vessels
- local action in the kidney regulating the rate of glomerular filtration
- contain acid phosphatases, cathepsin B & D, & -glucosidase
Cathepsin B - may be involved in activation of renin in the course of granulopoiesis prior to its release by exocytosis
3. Extraglomerular Mesangial Cells = Lacis cells or Goormaghtigh cells
- irregularly shaped cells with pale-staining nuclei
- occupy the angular interspace between the glomerulus & the diverging afferent & efferent arterioles
 - in the angle between the afferent & efferent arterioles, they are in communication with each other & with glomerular mesangial cells
via gap junctions

Glomerular mesangial cells - contractile & have receptors for angiotensin-II & other vasoconstrictors & for atriopeptide vasodilators
- contraction & relaxation induced by vasoactive agents may modulate flow through the glomerular capillaries

BLOOD SUPPLY - very large blood flow averaging about 1.2 L/min
Renal artery - enters the hilus
- divides in the adipose tissue of the renal sinus into anterior & posterior divisions
Segmental arteries
Lobar arteries - each renal pyramid
2 Interlobular arteries - before entering the substance of the kidney
- course toward the cortex in the renal columns on either side of a pyramid
Arcuate arteries - at the level of the corticomedullary boundary
- run parallel to the surface of the kidney
Small cortical radial arteries - arise at regular intervals
- course radially in the cortex
Afferent arterioles - juxtamedullary, midcortical & superficial glomeruli
Efferent arterioles - where blood leaves the glomeruli
- small caliber in superficial glomeruli -- ramify to form the cortical Intertubular Capillary Network
Peritubular capillaries - renal cortex
- endothelium is fenestrated
- pore diaphragms have a complex hub-&-spoke pattern with openings between the radial spokes
- larger in juxtamedullary glomeruli -- course into the medulla & branch into many vessels
Vasa recta - larger than capillaries
- continuing deeper into the medulla, they will form hairpin loops at various levels in the medulla
- turning back & coursing parallel & close to the descending limb of the loop of Henle
Vascular bundle or rete - countercurrent system of vessels formed by the descending & ascending limbs of numerous loops
Descending limbs - smaller & have a continuous endothelium
Ascending limbs - larger & have thin walls & fenestrated endothelium
- proximity of the vessels & large surface area facilitate diffusion of ions & small molecules between blood in the ascending &
descending limbs
- serve as efficient countercurrent exchangers for diffusible substances

Superficial cortical veins - radially arranged branches

- drain the capillaries of the outermost zones of the cortex toward the surface
Stellate veins - surface of the kidney
- have a characteristic radial pattern
Interlobular veins - relatively small #
- confluent at their inner end
Arcuate veins - accompany corresponding arteries

Deep cortical veins - radially oriented

- drain the deeper portion of the cortex
- run parallel to a corresponding # of interlobular arteries
 arcuate veins  interlobar veins  renal vein

LYMPHATICS
Lymphatic capillaries - among the tubular elements making up the parenchyma of the renal lobules
- tributaries of larger interlobar lymphatics
Renal cortex - have lymphatics
- drain mainly into the interlobular lymphatics  lymphatic plexuses in the hilus of the kidney
- some in the outer cortex drain to a plexus in the renal capsule
Volume of lymph in the cortex - 1 % of blood volume in peritubular capillaries

NERVES
Sympathetic celiac plexus
Nerve fibers - myelinated & unmyelinated
- provide sensory endings to the adventitia of the vessels
- motor endings in the muscular coat
- some terminate in the afferent arterioles of the renal corpuscles
Renal tubules - have nerve supply

RENAL PELVIS & URETER

- transitional epithelium
Calyces - 2 to 3 cells thick
Ureters - 4 to 5
Lamina propria - abundant CT & rich in elastic fibers
- may contain small lymphoid nodules
- deeper portion has a loose arrangement  permit the mucosa of the empty ureter to be thrown up into several longitudinal folds
 give the lumen a highly irregular outline
- no distinct submucosa
Walls of the renal calyces, pelvis & ureter - provided with a well-developed layer of smooth muscle
- muscular coat is not arranged in clearly defined longitudinal & circular layers
 - made up of anastomosing bundles of muscle fibers of varying orientation
- thickness gradually increases along the urinary tract
- beginning in the lower 1/3 of the ureter, additional layer of predominantly longitudinal fibers is added
In small calyces capping the papillae of the renal pyramids
- bundles of inner longitudinal smooth muscle terminate at the attachment of the calyx to the papilla
- outer bundles predominantly circumferential in orientation extend farther up & form a muscular ring around the papilla
- exhibit periodic contractions
- muscular activity may assist in expelling urine from the papillary ducts into the calyces
In the pelvis & ureter - muscular coat creates a slow peristalsis with waves of contraction proceeding from the renal pelvis toward the bladder

URINARY BLADDER
Transitional epithelium - 6 to 8 cells thick
- rounded or club-shaped at the lumenal surface
- effective permeability barrier against H2O loss -- reside in the occluding junctions between the superficial cells & in special properties of the thick
lumenal membrane
in distended bladder - epithelium is much thinner & flattened
- lumenal surface has a scalloped appearance
CM: - thicker
- asymmetrical (outer dense line is thicker than the inner dense line)
- made up of plaques of thick membrane connected by thinner interplaque regions
- plaques appear as segments of fairly uniform length that are straight or slightly concave & seemingly stiff
- neighboring plaques are so oriented  produce angular surface contours
Cytoplasm - beneath the CM, there is a conspicuous ectoplasmic layer of microfilaments with some filament bundles extending deeper into the cell
- in the apical cytoplasm:
- numerous discoidal vesicles
- lenticular or ellipsoidal
- bounded by thick membrane identical to that at the luminal surface of the cell
- formed by interiorization of adjoining plaques of the surface membrane
- reinserted into the membrane to provide for rapid expansion of its surface area during bladder distention
- dense network of filaments is attached to the plaques in the lumenal membrane & to the discoid vesicles in the cytoplasm
- x-linking of adjacent plaques by filaments  orderly infolding of membrane & pinching off of discoid vesicles during bladder
contraction
Tonicity of bladder urine - 2 to 4 times higher than that of the plasma in the capillaries of the lamina propria
Thick muscular coat - composed of sizable strands of smooth muscle cells that form 3 layers
- intermingle at their interface so that layers cannot be clearly separated from 1 another
Outer longitudinal layer - most prominent
- compact on the dorsal & ventral surface
Middle circular or spiral layer - thickest
Inner layer - consists of relatively sparse longitudinal & oblique muscle strands
Internal sphincter - at the region of the trigone at the base of the bladder, dense bundles of smooth muscle encircle the transmural portion of the urethra

BLOOD VESSELS, LYMPHATICS & NERVES

Blood vessels - provide capillaries to the muscle coat as they pass through it
- form a plexus in the outer portion of the lamina propria
- small arteries pass inward to form richer plexus immediately beneath the epithelium
Lymphatics - well-developed network of lymphatic capillaries
Renal pelvis & ureters - lamina propria & muscularis
Bladder - only in the muscularis
Nerve plexus & small ganglia - present in the adventitial & muscular layers of the ureter
Plexus vesicalis - sympathetic nerve plexus in the adventitial coat of the bladder
- arise from the hypogastric plexus
Parasympathetic efferent fibers Sympathetic efferent fibers
arise from sacral segments of the spinal cord lower thoracic & upper lumbar segments of the cord
synapse with nerve cells in the wall of the bladder on cells in the hypogastric plexuses & in the wall of the bladder
send Motor fibers to the muscle Sphincter
send Inhibitory fibers to internal sphincter muscle coats
the

MALE URETHRA
Length: 18 cm
- serves as terminal portion of both the urinary tract & the reproductive tract
Segments:
1. Prostatic urethra = Pars Prostatica
- length: 3 cm
- runs through the prostate from its base to its apex
Urethral crest - medial longitudinal ridge on the posterior wall of urethra
Colliculus seminalis (verumonatnum) - slight elevation in urethral crest
- on either side, there are numerous minute openings of the ducts of the prostate gland
Prostatic utricle (utricles prostaticus) - opening is in the midline of the colliculus
- blind pouch extending upward & backward into the substance of the prostate
- rudimentary homologue of the uterus
2 Ejaculatory ducts (ductus ejaculatorius) - slit-like openings are on the either side of the orifice of prostatic utricles
 Lining epithelium:
Transitional epithelium - proximal to the ejaculatory ducts
Pseudostratified or Stratified columnar epithelium - distal to the ejaculatory ducts
- contains occasional mucus-secreting goblet cells
Lumenal surface
a. most of the cells are polygonal in outline & have abundant short microvilli
b. others - have convex apex bulging into the lumen
- microvilli are few & largely confined to the periphery leaving the central area smooth
c. other cells - nearly 2x as large
- have a surface exhibiting a labyrinthine pattern of microplicae
d. rare cells bear numerous cilia
2. Membranous urethra = Pars Membranacea
- no significant change in the character of the epithelium
- length: 1-2 cm
- passes through the urogenital diaphragm (perineal membrane) postero-inferior to the pubic symphysis
External sphincter urethrae - striated muscle surrounding the urethra in the urogenital diaphragm
- supplied by the peroneal branch of the pudendal nerve
3. Spongiosae or Penile urethra = Pars Spongiosa
- length: 12-14 cm
- courses through the corpus spongiosum from the urogenital diaphragm to the external opening of the urethra on the glans penis
- lined by stratified columnar epithelium up to the fossa navicularis
Fossa navicularis - slightly expanded terminal of the urethra
- lined by stratified squamous like that covering the glans penis

Bulbourethral glands - lie on the urogenital diaphragm on either side of the membranous urethra
- long ducts penetrate the diaphragm
- below it, ducts penetrate into the floor of the penile urethra
Lacunae of Morgagni - many shallow recesses in the mucous membrane along the entire length of the urethra
Glands of Littre - opening into the out-pockets of lacunae of Morgagni
- run obliquely in the lamina propria
- blind ends directed toward the base of the penis
- largest of them are on the dorsal aspect of the pars spongiosa
- few may penetrate into the corpus spongiosum
- lining epithelium is similar to that on the surface of the mucous membrane but contains nests of pale cells that have staining rxns for mucus
- in old age, some of the recesses in the urethral mucosa may contain concretions similar to those found in the prostate (longer)

FEMALE URETHRA
Length: 25-30 mm
Mucosa - stratified squamous epithelium
- plicated to form longitudinal folds
- numerous shallow invaginations of the epithelium -- may accumulate colloidal material in their lumen
- may contain more solid concretions
- walls lined in many places with mucous cells like those of the glands of Littre in the male urethra
Lamina propria - loose CT containing abundant elastic fibers
- includes a complex system of venous plexuses  give an architecture resembling that of the corpus cavernosum of the male
Muscularis - ILOC smooth muscle
Sphincter of striated muscle - distal to the smooth muscle