GROWTH ADAPTATIONS = ↑, ↓ or ∆ in stress

HYPERTROPY • ↑ stress = ↑ cell size • hypertrophy +

• involves gene activation + protein synthesis + production of hyperplasia
organelles generally occur
• *PERMANENT TISSUES = HYPERTROPHY ONLY together
(cannot make new cells):
(1) Cardiac Muscle (LV Hypertrophy due to systemic HTN) • Ex: uterus during
(2) Skeletal Muscle pregnancy
LV Hypertrophy
(3) Nerve • 1st = hyperplasia
• ↑ stress = ↑ # of cells of smooth muscle
• involves production of new cells from stem cells • 2nd = hypertrophy
Physiologic Hyperplasia = does NOT ↑ risk of cancer of smooth muscle
HYPERPLASIA Pathologic Hyperplasia = ↑ risk of cancer
• Pathologic Hyperplasia → Dysplasia → Cancer
• ex: Endometrial Hyperplasia
• *EXCEPTION: Benign Prostatic Hyperplasia = no ↑ risk of cancer
• ↓ stress = ↓ cell size + ↓ # of cells
• ex: ↓ hormonal stimulation, disuse or ↓ nutrients/blood supply
ATROPHY • Apoptosis = ↓ # of cells
• Ubiquitin-proteosome degradation (intermediate filaments of cytoskeleton destroyed) +
Autophagy (autophagic vacuoles fuse w/ lysosomes) = ↓ cell size
METAPLASIA • ∆ stress = ∆ cell type
• involves surface epithelium:
• Squamous (keratinizing or non-keratinizing)
squamous
• Columnar (gut)
columnar
• Urothelial (transitional)
• occurs via reprogramming of stem cells which then produce new cell type
• *REVERSIBLE (ex: tx of GERD)
Barrett Esophagus • persistent stress → Metaplasia → Dysplasia → Cancer
(ex: Barrett Esophagus → Adenocarcinoma of Esophagus)
• *EXCEPTION: Apocrine Metaplasia of Breast = no ↑ risk of cancer
Barrett esophagus
• non-keratinizing squamous epithelium → non-ciliated, mucin-producing columnar cells =
contains goblet cells
Keratomalacia • due to GERD
Keratomalacia = Vitamin A deficiency → Metaplasia (or night blindness, PML)
Myositis Ossificans • Vit A = necessary for differentiation of conjunctiva
• thin squamous lining of conjunctiva → thick stratified keratinizing squamous epithelium
Myositis Ossificans = Mesenchymal (connective) tissue → Metaplasia
• trauma to skeletal muscle → inflammation → metaplasia → bone
• NOT Osteosarcoma because bony growth is in muscle NOT coming off of bone
• disordered cellular growth = proliferation of precancerous cells
Cervical Intraepithelial Neoplasia (CIN) = dysplasia = precursor to cervical cancer
DYSPLASIA • arise from longstanding pathologic hyperplasia (Endometrial Hyperplasia) or metaplasia
(Barrett Esophagus)
• *REVERSIBLE
• persistent stress → Dysplasia → Cancer (= IRREVERSIBLE)
APLASIA • failure of cell production during embryogenesis
Unilateral Renal Agenesis = failure to produce 1 kidney during embryogenesis
HYPOPLASIA • ↓ cell production during embryogenesis = small organ
Streak Ovary during Turner Syndrome
 CELLULAR INJURY = stress > ability to adapt
depends on:
(1) type of stress
• inflammation → growth adaptation NOT injury
(2) severity
• Slowly developing ischemia of kidney (ex: Renal Artery Atherosclerosis or Fibromuscular Dysplasia of
renal artery) → atrophy of kidney
• Acute ischemia of renal artery (ex: Renal artery embolus) → injury (infarction/death of kidney
parenchyma)
(3) type of cell affected
• Neuron → highly susceptible to hypoxia = ischemic injury
• Skeletal muscle → more resistant to hypoxia
common causes:
• Inflammation (infection = pneumonia, autoimmune diseases), Nutritional deficiency or excess, Hypoxia =
(MI’s, ischemic stroke), Trauma (gun shot wound to tissue), Genetic mutations
HYPOXIA • Low O2 delivery to tissue
• O2 = final e- acceptor in ETC of ox phos
• Low O2 → impairs ox phos → ↓ ATP → cellular injury
(A) Na+/K+ pump fails = cell swelling = ↑ [Ca2+] + ↑ [H2O] in cytosol
(B) Ca2+ pump fails = ↑ [Ca2+] in cytosol = dangerous → activates enzymes
(C) aerobic glycolysis → anaerobic glycolysis = poor production of ATP +
production of lactic acid (↓ pH) → denatures protein + precipitates DNA
• Causes = (1) ischemia, (2) hypoxemia, (3)↓ O2 carrying capacity
• ↓ blood flow through organ
Due to:
(A) ↓ arterial perfusion (ex: atherosclerosis of coronary artery = angina)
(B) ↓ venous drainage
(1) ISCHEMIA • ex: Budd-Chiari Syndrome = infarction of liver due to:
• Thrombosis = blockage of hepatic vein
• Polycythemia = ↑ RBC’s = ↑ thickness of blood → Thrombosis
• Lupus
(C) ↓ tissue perfusion = Shock → hypotension (ex’s: cardiogenic, hypovolemic,
neurogenic, anaphylactic shock)
• ↓ PaO2 of blood
• FiO2 (environment) → PAO2 (alveolus) → PaO2 (artery) → SaO2 (RBC)
(A) high altitude = ↓ FiO2 = ↓ PaO2
(B) hypoventilation = ↑ PACO2 = ↓ PAO2 = ↓ PaO2 (ex: COPD)
(2) HYPOXEMIA (C) diffusion defect = ↑ thickness of diffusion barrier = normal PAO2 but
↓ PaO2 (ex: interstitial fibrosis of the lung)
(D) VQ mismatch:
• blood bypasses lung (ex: circulation problem, R → L shunt)
• O2 cannot reach blood (ex: ventilation problem, atelectasis)
• Hb loss or dysfunction
(A) Anemia = ↓ RBC mass (PAO2 + SaO2 = normal)
(B) CO poisoning (↓ SAO2, PaO2 = normal)
• CO binds Hb 100x more avidly than O2
• Exposures = smoke from fires, exhaust from car or gas-heater
• *CHERRY RED appearance of skin (↓ O2 delivery to tissues)
(3) ↓O2 CARRYING CAPACITY • Early sign of exposure = headache
• Significant exposure = coma + death
(C) Methemoglobinemia (↓ SAO2, PaO2 = normal)
• Fe in heme oxidized = Fe2+ → Fe3+ (cannot bind O2)
• Due to oxidant stress = sulfa/nitrate drugs
• Newborns = highly susceptible
• *CHOCOLATE coloured blood + cyanosis
• Tx = IV Methylene Blue reduces Fe3+ back to Fe2+
 REVERSIBLE INJURY IRREVERSIBLE INJURY
• initial phase of injury • due to persistent injury
• *HALLMARK = CELLULAR SWELLING • *HALLMARK = MEMBRANE DAMAGE
(1) loss of microvilli = effaced (1) plasma membrane damage
(2) membrane blebbing = due to ↑ [H2O] • cytosolic enzymes leak into serum (ex: troponin)
(3) swelling of RER = ribosome dissociation + • ↑ [Ca2+] entering cell
↓ protein synthesis (2) mitochondrial membrane damage
• loss of ETC (= inner mitochondrial membrane)
• cytochrome C leaks into cytosol (activates
apoptosis)
(3) lysosome membrane
• hydrolytic enzymes leak into cytosol = activated
by ↑ [Ca2+] intracellularly
• end result = death

CELL DEATH = NECROSIS + APOPTOSIS

*HALLMARK = LOSS OF NUCLEUS
(1) pyknosis = nuclear condensation
(2) karyorrhexis = nuclear fragmentation
(3) karyolysis = nuclear dissolution

APOPTOSIS = “cellular suicide”

• death of single cells or small groups of cells
• ATP dependent + genetically programmed cell death
Ex’s:
(1) endometrial shedding during menstruation
(2) removal of cell during embryogenesis
(3) CD8+ T cells mediated killing of virally infected cells

Morphology
(1) cell shrinks → cytoplasm = eosinophilic = concentrated cytoplasm
(2) nucleus condenses (pyknosis) + fragments (karyorrhexis)
(3) apoptotic bodies = fall from cell + removed by macrophages
(4) *NO INFLAMMATION

CASPASES = mediate apoptosis → activated by multiple pathways

(1) activate proteases = breakdown cytoskeleton
(2) activate endonuclease = breakdown DNA
• inactivation of BCl2 → cellular injury, DNA damage or loss of hormonal
(A) INTRINSIC MITOCHONDRIAL stimulation
PATHWAY • lack of BCl2 → cytochrome C leaks from inner mitochondrial matrix into
cytoplasm → ACTIVATES CASPASES
• FAS ligand binds FAS receptor (CD95) on target cell
• Negative selection of thymocytes in thymus (T cells produced in
(B) EXTRINSIC RECEPTOR- bone marrow + modified in thymus)
LIGAND PATHWAY • Positive selection = bind self antigen? yes, T cell survives
• Negative selection = bind self antigen strongly? yes, death of T cell
via apoptosis (eliminates autoimmune disorders)
• Tumor Necrosis Factor (TNF) binds TNF receptor on target cell
• CD8+ T cells recognize antigen on MHCI + kill cell which expresses antigen
(C) CYTOTOXIC CD8+ T CELL via apoptosis
PATHWAY • CD8+ T cells secrete perforin = creates pores in target cell membrane →
granzyme enters pore + ACTIVATES CASPASES
 NECROSIS = “murder”
• death of large group of cells followed by ACUTE INFLAMMATION
• due to underlying pathologic process

necrotic tissue nuclei normal Red

COAGULATIVE NECROSIS = firm disappear tissue Infarction
•
cell shape + organ structure = preserved by coagulation of proteins
•
*ISCHEMIC INFARCTION OF ANY ORGAN EXCEPT BRAIN
•
infarcted tissue = wedge-shaped (points to area of vascular occlusion) + pale
•
Red Infarction (hemorrhagic) = blood re-enters loosely organized tissue (ex:
pulmonary or testicular infarction cord twists: vein collapses, artery = fine →
blood cannot exit)
• necrotic tissue = liquefied due to enzymatic lysis of cells + proteins
• Brain infarction = proteolytic enzymes from microglial cells (= macrophages of
brain) liquefy brain
LIQUEFACTIVE NECROSIS • Abscess (walled area of dead tissue) = proteolytic enzymes from neutrophils
liquefy tissue
• Pancreatitis (liquefactive + fat necrosis) = proteolytic enzymes from pancreas
liquefy parenchyma
• Dry Gangrene = coagulative necrosis ~ mummified tissue
• ischemia of lower limb + GI tract
GANGRENOUS NECROSIS • ex: atherosclerosis in diabetics
• Wet Gangrene = liquefactive necrosis
Dry Gangrene
• superimposed infection of dead tissue
• necrotic tissue = soft + friable ~ cottage cheese-like
CASEOUS NECROSIS • coagulative + liquefactive necrosis
• ex: granulomatous inflammation due to TB Caseous Necrosis
• or fungal infection of lung
• necrotic tissue = adipose tissue w/ Ca2+ deposition ~ chalky-white
due to:
• Trauma to fat (ex: breast) → FA’s released by trauma + join w/ Ca2+ via
FAT NECROSIS Saponification = dystrophic calcification
• Pancreatitis-merited damage of peripancreatic fat
• → FA’s released by lipases + join w/ Ca2+ via
Fat Necrosis
• Saponification = dystrophic calcification
• necrotic damage to blood vessel
• leaking of proteins (fibrin) into vessel wall = bright pink staining of wall
• ex: Malignant HTN = ↑ BP, headache, renal failure, papilledema = MEDICAL
FIBRINOID NECROSIS EMERGENCY → necrosis of BV wall due to ↑ BP
• (Benign HTN = long-term progressive damage)
• ex: Pre-eclampsia = fibrinoid necrosis of placenta Fibrinoid Necrosis
of vessel
• ex: Vasculitis = fibrinoid necrosis of vessel

DYSTROPHIC CALCIFICATION METASTATIC CALCIFICATION

• NORMAL serum [Ca2+] + [PO4]
• calcification occurs in necrotic tissue = nidus
• ex: psammoma bodies in:
• Papillary Thyroid Carcinoma
• Meningioma
• Papillary Serous Carcinoma of Ovary
• HIGH serum [Ca2+] or [PO4]
• calcification occurs in normal tissue
• ex: Hyperparathyroidism = nephrocalcinosis
• ex: Bone Metastatic Cancer = metastatic calcification
 FREE RADICAL INJURY
• free radicals = unpaired e- in outer orbit = induces injury
• O2 (oxygen) → O2• (superoxide) → H2O2 (hydrogen peroxide) → OH• (hydroxyl radical) → H2O (water)
• physiologic generation of free radicals during ox pos
• cyt C oxidase (complex IV) transfers e-’s to O2
• partial reduction of O2 (does not receive 4e-’s) yields: superoxide + hydrogen peroxide + hydroxyl radicals
• pathologic generation of free radicals
(1) ionizing radiation = H2O hydrolyzed → OH• = *MOST DAMAGING
(2) inflammation → neutrophils kill microbe via O2 dependent mechanism:
• NADPH oxidase: O2 → O2• = oxidative burst
• (Superoxide Dismutase: O2• → H2O2)
• (Myeloperoxidase: H2O2 → HOCl• = bleach)
• O2 independent mechanism
(3) metals (Cu + Fe) → Fenton Rxn = OH• generated
• Hemachromatosis = build up of Fe generates free radicals
• Wilson’s Disease = build up of Cu generates free radicals
(4) drugs + chemicals
• ex: Acetaminophen → free radicals generated via P450 = tissue damage in liver
• free radical damage via:
• PEROXIDATION of lipids (damages lipid membranes)
• OXIDATION of DNA (oncogenesis) + proteins (= cellular damage)
• elimination of free radicals via:
• ANTIOXIDANTS = Vitamin A, C, E + glutathione
• METAL CARRIER PROTEINS = transferrin tightly binds Fe in blood to deliver to liver + macrophages
where Fe is bound to ferritin
• ENZYMES
• SOD = Superoxide Dismutase (in mitochondria) → removes O2•
• Catalase (in peroxisomes) → removes H2O2
• Glutathione Peroxidase (in mitochondria) → removes OH•
• organic solvent used in dry cleaning industry
• converted to CCl3 = free radical via P450 system of hepatocytes:
• damages hepatocytes = reversible injury
(A) Carbon Tetrachloride (CCl4) • cellular swelling
• RER swells
• ribosomes pop off
• ↓ protein synthesis
• lack of apolipoproteins = fatty ∆ of liver
• return of blood to ischemic tissue = production of O2 derived free radicals
(B) Reperfusion Injury • leads to continued ↑ cardiac enzymes (ex: troponin) in infarcted myocardial
tissue
 AMYLOIDOSIS
• amyloid = misfolded protein deposits in extracellular space = tissue damage
• common characteristics:
• β pleated sheet
• congo red stain
• apple-green bifringence
• amyloid deposits in multiple body systems
• Primary Amyloidosis
• systemic deposition of AL amyloid = derived from Ig light chain
• ex: Multiple Myeloma = plasma cell dyscrasias = abnormalities of plasma
cell = over production of Ig light chain → leaks out into blood → misfolds
→ deposits into tissues
• Secondary Amyloidosis
• systemic deposition of AA amyloid = derived from SAA = serum
associated amyloid
• ↑ SAA in:
• chronic inflammatory states
• malignancy
• Familial Mediterranean Fever (FMF) = dysfunction of neutrophils
SYSTEMIC AMYLOIDOSIS • neutrophils activate + create attack = acute inflammation
• fever + acute serosal inflammation
• can mimic MI = serosal surface of heart or acute
appendicitis = serosal surface of abdomen
• acute inflammation = ↑SAA = ↑AA = secondary amyloidosis
• Classical findings:
• *KIDNEY = most common organ
• Nephrotic Syndrome
• Restrictive Cardiomyopathy or arrhythmia = ↓ compliance → no filling =
cardiac failure
• tongue enlargement, bowel-wall thickening (malabsorption)
• Hepatosplenomegaly
• Diagnosis:
• biopsy of abdominal fat pad + rectum mucosa = easy targets
• *AMYLOID CANNOT BE REMOVED = damaged organ must be transplanted
• amyloid deposits localized to single organ system
• Senile Cardiac Amyloidosis
• amyloid = serum transthyretin deposits in heart
• asymptomatic → 25% of people > 80 yo
• Familial Amyloid Cardiomyopathy
• amyloid = mutated serum transthyretin deposits in heart
• leads to restrictive cardiomyopathy → heart = ↓ compliance → no filling =
cardiac failure
• 5% african americans carry mutated gene
• Type II Diabetes Mellitus (insulin resistance = ↑ insulin production)
LOCALIZED AMYLOIDOSIS • amyloid = amylin (derived from insulin) deposits in islets of pancreas
• Alzheimer Disease
• amyloid = Aβ amyloid = deposits in brain
• plaque in brain (derived from β amyloid precursor on protein = gene on
chromosome 21 → pts w/ Down Syndrome develop early onset alzheimer)
• Dialysis-associated Amyloidosis
• amyloid = β2-microglobulin = deposits in joints
• Medullary Carcinoma of Thyroid
• amyloid = calcitonin = deposits in tumour = tumour cells in amyloid
background
• tumor of thyroid derived from c-cells = produce calcitonin
 INFLAMMATION
• inflammatory cells + plasma cells + fluid exit BV + enter interstitial space
• *NEUTROPHILS = ACUTE INFLAMMATION
• *LYMPHOCYTES = CHRONIC INFLAMMATION

chronic inflammation
acute inflammation w/ lymphocyte +
w/ neutrophils plasma cells

(1) ACUTE INFLAMMATION

• EDEMA + NEUTROPHILS
• edema = fluid from BV → tissue
• neutrophils = key inflammatory cell in BV → tissue
• In response to:
• INFECTION = eliminates pathogen
• TISSUE NECROSIS = clears necrotic debris
• immediate response (w/i 24 hrs) w/ limited specificity (generalized response) = INNATE IMMUNITY
(eosinophils, neutrophils, macrophages, mast cells, complement system, mucous, epithelium)
• mediators = (A) TLRs, (B) arachidonic acid, (C) mast cells, (D) complement, (E) Hageman factor
• present on cells of innate immunity = macrophage + dendritic cells
• recognize PAMPs (pathogen associated molecular patterns) on microbes
• ex: CD14 (TLR) on macrophages recognizes LPS (PAMP) = on outer membrane
(A) TLRs of Gram negative cells
• TLR activation → ↑ NF-KB = nuclear transcription factor → activates immune response
genes → production of multiple immune mediators
• also present on adaptive immunity cells = lymphocytes → therefore important role
in mediating chronic inflammation
• released from phospholipid cell membrane via PLA2
• acted on via:
• CYCLOOXYGENASE
• produces prostaglandins = PGI2 + PGD2 + PGE2 (mediate fever + pain)
• mediate:
• vasodilation of arterioles
• ↑ vascular permeability of post-capillary venule
(B) Arachidonic Acid • 5-LIPOXYGENASE
• produces leukotrienes = LTC4 + LTD4 + LTE4 = slow reacting
substances of anaphylaxis
• mediate:
• vasoconstriction (contraction of smooth muscle)
• bronchospasm
• ↑ vascular permeability (pericytes contract)
• LTB4 = attracts + activates neutrophils
* LTB4 + C5a + IL8 + bacterial products = attract + activate neutrophils
• throughout connective tissue
• activated by:
(1) tissue trauma
(C) Mast Cells (2) complement proteins = C3a + C5a
(3) cross-linking of cell surface IgE by antigen
• Immediate response via release of preformed histamine granules = mediate:
• vasodilation of arterioles
• ↑ vascular permeability of post-capillary venule
• Delayed response via ↑ leukotrienes = arachidonic acid metabolites
 • help inflammation = proinflammatory serum proteins
(D) Complement • circulate as inactive precursors
• activated by:
(1) Classical pathway = C1 + IgG or IgM bound Ag
(2) Alternative pathway = microbial products activate complement
(3) Mannose-binding lectin pathway = MBL + mannose on microbe
• result:
• C3 convertase: C3 → C3a + C3b
• C3b → C5 convertase: C5 → C5a + C5b
• Membrane Attack Complex (lyses microbe = creates holes in cell membrane):
C5b → C6-9
• C3a + C5a = mast cell degranulation
• C5a = chemotactic for neutrophils
• C3b = opsonin for phagocytosis
• inactive proinflammatory protein
(E) Hageman Factor • produced in liver
• activated upon exposure to subendothelial tissue or collagen
• activates:
(1) coagulation + fibrinolytic systems = DIC
(2) complement
(3) kinin system → cleaves HMWK (high molecular weight kininogen) to bradykinin
+ mediates: vasodilation, ↑ vascular permeability (~ histamine), mediates pain
(PGE2 + bradykinin)
 (2) ACUTE INFLAMMATION
STEP 1 (1) vasodilation slows blood flow in post capillary venule
Margination (2) cells marginate from center of flow to periphery
(1) selectins (= speed bumps) upregulated on endothelial cells
STEP 2 • P-selectin = release from Weibel-Palade bodies mediated by histamine
Rolling • E-selectin = induced by IL-1 + TNF
(2) selectins bind sialyl lewis X on leukocytes
(3) interaction = rolling of leukocytes along vessel wall
(1) cellular adhesion molecules = ICAM + VCAM are upregulated on endothelium by IL-1
+ TNF
(2) integrins are upregulated on leukocytes by C5a + LTB
STEP 3 (3) CAMs + integrins = firm adhesion of leukocytes to vessel wall
Adhesion (4) Leukocyte Adhesion Deficiency = most commonly due to autosomal recessive
defect of integrins (CD18 subunit)
• clinical features = separation of umbilical cord + ↑ circulating neutrophils (due
to impaired adhesion of marginated pool of leukocytes) + recurrent bacterial
infections that lack pus formation
STEP 4 (1) Leukocytes transmigrate across endothelium of post capillary venule + move toward
Transmigration + chemical attractants = chemotaxis
Chemotaxis (2) Neutrophils are attracted by = bacterial products + IL-8 + C5a + LTB4
(1) consumption of pathogens or necrotic tissue = enhanced by opsonins = IgG +
C3a
(2) pseudopods extends from leukocytes to form phagosomes = internalized + merge w/
lysosomes to produce phagolysosomes
STEP 5 (3) Chediak-Higashi syndrome = protein trafficking defect (autosomal recessive) =
Phagocytosis impaired phagolysosome formation, clinical features:
• ↑ risk of pyogenic infections
• neutropenia = due to intramedullary of neutrophils
• giant granules in leukocytes = due to fusion of granules arising from golgi
• defective primary hemostasis = due t abnormal dense granules in platelets
• albinism
• peripheral neuropathy
(1) O2-dependent killing = most effective mechanism
(2) HOCl• generated by oxidative burst in phagolysosomes
(3) Chronic-granulomatous disease (CGD) = poor O2-dependent killing
• due to NADPH oxidase defect = x-linked or AR
• leads to recurrent infection + granuloma formation w/ catalase positive
STEP 6 organisms = S. aureus + Pseudomonas + Serratia + Nocardia + Aspergillus
Destruction of • nitroblue tetrazolum test = used to screen for CGD
Phagocytosed Material • normal leukocytes = turn blue, defective leukocytes = colourless
(4) Myeloperoxidase deficiency = defective conversion: H2O2 → HOCl•
• ↑ risk of Candida infections (most pts = asymptomatic)
• nitroblue tetrazolum test = normal because respiratory burst = intact
(5) O2-independent killing (less effective than O2-dependent killing) = occurs via
enzymes in leukocyte secondary granules (ex: lysozyme in macrophages)
STEP 7: Resolution (1) neutrophils undergo apoptosis/disappear w/i 24 hrs after resolution of inflam.
stimulus
 (3) CARDINAL SIGNS OF ACUTE INFLAMMATION
REDNESS (RUBOR) • due to vasodilation = ↑ blood flow
+ • via relaxation of arteriolar smooth muscle
WARMTH (CALOR) • key mediators = HISTAMINE + PROSTAGLANDINS + BRADYKININ
• due to leakage of fluid from post-capillary venues into interstitial space = EXUDATE
SWELLING • key mediators:
(TUMOR) (1) HISTAMINE = causes endothelial cell contraction
(2) TISSUE DAMAGE = results in endothelial cell disruption
PAIN (DOLOR) • due to BRADYKININ + PGE2 = sensitize nerve endings
• PYOGENES (ex: LPS from bacteria) cause macrophages to release IL-1 + TNF =
FEVER ↑ cyclooxygenase activity in perivascular cell of hypothalamus = ↑ PGE2 = ↑ temp
set point

(4) MACROPHAGES
• predominate after neutrophils
• peak 2-3 days after inflammation begins
• derived from monocytes in blood
• arrive in tissue via margination + rolling adhesion + transmigration sequence
• ingest organisms via phagocytosis (augmented by opsonins) + destroy phagocytosed material using
enzymes (Ex: lysozymes) in secondary granules (O2-independent killing)
• manage next step of inflammation process
• outcomes include:
• resolution + healing = anti-inflammatory cytokines produced by macrophages = IL-10 + TGF-β
• continued acute inflammation = persistent pus formation (IL-8 from macrophages recruits additional
neutrophils)
• abscess = acute inflammation surrounded by fibrosis (macrophages mediate fibrosis via fibrogenic
growth factors + cytokines)
• chronic inflammation = macrophage present antigen to active CD4+ helper T cells = secrete cytokines
that promote chronic inflammation
 CHRONIC INFLAMMATION
• LYMPHOCYTES + PLASMA CELLS
• delayed response + more specific (ADAPTIVE IMMUNITY) than acute inflammation
• Stimuli:
• persistent infection = MOST COMMON CAUSE
• infection w/ viruses + mycobacteria + parasites + fungi
• autoimmune diseases
• foreign material
• some cancers
• produced in bone marrow as progenitor T cells
• develop in thymus where T-cell receptor (TCR) undergoes rearrangement + progenitor
cells become CD4+ helper T cells OR CD8+ cytotoxic T cells
(1) T cells use TCR complex = TCR + CD3 for antigen surveillance
(2) TCR complex recognizes antigen presented on MHC molecules
• CD4+ cells → MHC class II, CD8+ cells → MHC class I
(3) activation of T cells requires: binding of antigen/MHC complex + additional 2nd signal
• CD4+ helper T cell activation:
(1) extracellular antigen (ex: foreign protein) phagocytosed + processed +
presented on MHC II = expressed by antigen presenting cells (APCs)
(2) B7 on APC binds CD28 on CD4+ helper T cells providing 2nd activation signal
(3) Activated CD4+ helper T cells secrete cytokines = help inflammation + divided
into 2 subsets:
(A) T LYMPHOCYTES (1) TH1 subset secretes IL-2 (T cell growth factor + CD8+ T cell activator)
+ TFN-γ (macrophage activator)
(2) TH2 subset secretes IL-4 (facilitates B-cell class switching to IgG + IgE)
+ IL-5 (eosinophil chemotaxis +
• CD8+ cytotoxic T cell activation:
(1) intracellular antigen (derived from proteins in cytoplasm) processed +
presented on MHC I = expressed by all nucleated cells + platelets
(2) IL-2 from CD4+ TH1 cells provides 2nd activation signal
(3) Cytotoxic T cells are activated for killing
(4) Killing occurs via:
• secretion of perforin + granzyme → apoptosis
• expression of FasL which binds Fas on target cells → apoptosis
• immature B cells produced in bone marrow + undergo Ig rearrangements to
become naive B cells that express surface IgM + IgD
• B-cell activation occurs via:
(1) Antigen binding by surface IgM or IgD = maturation to IgM- or IdD-secreting
(B) B LYMPHOCYTES plasma cells
(2) B-cell antigen presentation to CD4+ helper T cells via MHC II
• CD40 receptor on B cell binds CD40L on helper T cells via MHC II
providing 2nd activation signal
• Helper T cell secretes IL-4 + IL-5 (mediates B-cell isotype switching +
hypermutation + maturation to plasma cells)
(C) GRANULOMATOUS • subtype of chronic inflammation
INFLAMMATION • characterized by granuloma = collection of epithelioid histiocytes (macrophages w/
abundant pink cytoplasm) = surrounded by giant cells + rim of lymphocytes
• divided into noncaseating + caseating subtypes:
(A) NONCASEATING GRANULOMAS = lack central necrosis + etiologies = rxn to
foreign material + sarcoidosis + beryllium exposure + Crohn disease + cat scratch
disease
(B) CASEATING GRANULOMAS = exhibit central necrosis + characteristic of
tuberculosis + fungal infections
• steps involved in granuloma formation:
(1) macrophages process + present antigen via MHC II to CD4+ helper T cells
(2) macrophages secrete IL-12 inducing CD4+ helper T cells to differentiate into TH1 cells
(3) TH1 cells secrete TFN-γ = converts macrophages to epithelioid histiocytes + giant cells