Cellular Injury, Cell adaptation & Cell death Pathology Study of structural & functional changes in cells, tissues,

, & organs Uses molecular, microbiologic, immunologic & morphologic techniques Foundation for rational clinical care & therapy Types of pathology: o GENERAL reactions of cells to abnormal stimuli o SYSTEMIC reactions of organs/ tissues to stimuli/ diseases 4 ASPECTS OF DISEASE PROCESS (form the core of pathology) Etiology or cause o Can be: Genetic (ex. Trisomy 21) Acquired (ex. HIV) Multifactorial (both genetic & acquired) Ex. Atherosclerosis Pathogenesis o Time frame (from exposure to developed s/sx) o Sequence of events from the initial stimulus to the clinical manifestations of the disease Morphology o How the disease produces changes in the cell o Alteration in the structures of the cells Clinical significance o Refers to the clinical manifestations & prognosis of disease CELLULAR RESPOSES TO STRESS & NOXIOUS STIMULI Cell is in a state of homeostasis Physiologic stresses & some pathologic stimuli will bring about cellular ADAPTATIONS such as: o Hyperplasia both physiologic & pathologic o Hypertrophy both o Atrophy both o Metaplasia always pathologic Depends upon NATURE & SEVERITY of injurious stimuli o I. Cellular adaptations o II. Cell injury (reduced O2, chemical injury, microbial infection o III. Intracellular accumulations & calcifications o IV. Cellular aging

I. CELLULAR ADAPTATIONS:
1. HYPERPLASIA Def: Increase in the number of cells Some cell types are unable to exhibit hyperplasia (nerve, cardiac, skeletal muscle cells) Is mediated by: o Growth factors, cytokines o Growth promoting genes proto-oncogenes o Increased DNA synthesis & cell division PHYSIOLOGIC hyperplasia o Hormonal Breast development at puberty/preg. Uterus development at pregnancy Proliferation of endometrium o Compensatory After hepatectomy PATHOLOGIC o Excess hormones Edometrium (if estrogen = can lead to atypical hyperplasia cancerous) BPH (d/t adrogens) o Excess growth hormones Keloid Papilloma virus Hyperplasia can be malignant 2. HYPERTROPHY Def: Increase un cell size d/t synthesis of structural components Occurs in dividing and non-dividing cells like HEART and SKELETAL muscle cells Causes of hypertrophy: o Increased functional demand PHYSIOLOGIC striated muscles of wt. lifters PATHOLOGIC cardiac muscle in BP o Increased endocrine stimulation Puberty (GH, androgens/testosterone) Gravid uterus (d/t estrogen) Lactating breast (prolactin & estrogen) Main downstream signaling of G-protein coupled receptor is induced by GROWTH FACTOR & VASOACTIVE agents Normal ventricular thickness: o Right 0.3-0.5 o Left 1.3-1.5 *Mechanisms *Hypertrophy & Hyperplasia often occur together

3. ATROPHY Def: Shrinkage in size of cells. Decrease cellular components. Decrease size of organ. Reduce metabolic activity. Causes of Atrophy o Disuse o Denervation atrophy o Diminished blood supply o Inadequate nutrition o Loss of endocrine stimulation (opposite of hypertrophy) o Aging o Pressure Mechanisms of Atrophy o CHON degradation uses Ubiquitin-Proteasome pathway o Microscopic characteristics: small shrunken cells with LIPOFUSCIN granules o Lipofuscin aging pigment golden color Notes: o Senile atrophy wear & tear pigments 4. METAPLASIA Def: One differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. Usually in response to IRRITATION Prone to cancerous transformation (same as hyperplasia) TYPES: o Columnar to Squamous Bronchial epith.undergoes bronchial squamous metaplasia in response to tobacco smoking o Squamous to Columnar AKA: adenocarcinoma Ex: Barretts Esophagus d/t reflux of gastric content a benign disease form of adaptation o Connective tissue metaplasia formation of cartilage, bone, or adipose tissue (mesenchymal tissues) Ex: Myositis Ossificans Example of metaplasia o Columnar squamous = endocervix o Squamous columnar = esophagus Mechanism: Reprogramming of stem cells o The reserve cells (or stem cells) of the irritated tissue differentiate into a more protective cell

type d/t the influence of growth factors, cytokines, & matrix components

II. CELLULAR INJURY

Stages of cell injury o Acute & self-limited acute reversible injury o Progressive & severe irreversible injury cell death necrosis & apoptosis o Mild chronic injury subcellular alterations in various organelles REVERSIBLE cell injury functional & morphological changes that are reversible IRREVERSIBLE cell injury point of no return NOTE: Any of the reversible changes can become irreversible when taken to the extreme

CAUSES OF CELL INJURY 1. O2 deprivation 2. Physical agents 3. Chem.agents & drugs 4. Nutritional imbalance (anorexia nervosa) (2) MORPHOLOGIC PATTERNS OF REVERSIBLE CELL INJURY 1. Cellular swelling - *1st manifestation o Incapable to maintain ionic & fluid homeostasis o Loss of function of plasma membrane 2. Fatty change o Ex. Liver cirrhosis o There is vacuoles ULTRASTRUCTURAL CHANGES of REVERSIBLE CELL INJURY 1. Plasma membrane alterations o Blebbing, blunting, & distortion of microvilli o Creation of myelin figures o Loosening of intercellular attachments 2. Mitochondrial changes o Swelling o Rarefaction o Appearance of small phospholipid rich amorphous densities 3. Dilatation of ER o With detachment & disaggregation of polysomes 4. Nuclear alterations o With disaggregation of granular & fibrillar elements NECROSIS Result of denaturation of intracellular proteins & enzymatic digestion of lethally injured cells Follow cell death d/t: Degradative action of enzymes MORPHOLOGIC APPEARANCE o 1. eosinophilia o 2. Glassy homogeneous appearance o 3. Moth-eaten cytoplasm o 4. Calcification & replacement by myelin figures o 5. Nuclear changes Karyolysis nuclear fading/disolution Karyorrhexis nuclear fragmentation Pyknosis degeneration/shringkage of nuclear chromatin o 6. Morphologic patterns 1. Coagulative necrosis 2. Liquefaction 3. Caseous

HALLMARKS OF REVERSIBLE INJURY 1. Reduced oxidative ATP phosphorylation 2. ATP depletion 3. Cellular swelling (2) MORPHOLOGIC PATTERNS OF CELL DEATH NECROSIS o Pathogenesis: when damage to membranes is severe, lysosomal enzymes enter the cytoplasm & digest the cell, & cellular contents leaks out. APOPTOSIS o Nuclear dissolution w/o complete loss of membrane integrity NOTES o Necrosis always a pathologic process o Apoptosis serves many normal function & is not necessarily associated w/ cell injury FEATURES OF NECROSIS & APOPTOSIS Feature NECROSIS Cell size Enlarged Nucleus Karyopyknosis, rrhexis, lysis Plasma Disrupted membrane Cellular Enzymatic digestion contents Inflammation Frequent Physio/Patho Pathologic role

APOPTOSIS Reduced Karyorrhexis or fragmentation Intact Intact No Physiologic

4. Fat necrosis COAGULATIVE NECROSIS o Denaturation of CHON = is the primary pattern o Basic cellular outline is preserved for a span o *most common form of necrosis o Characterized by hypoxic death of cells on ALL tissues EXCEPT the BRAIN (occurs in liquefaction necrosis) o Microscopic: (-) nucleus but preserved of cell shape o Common: heart, liver & kidney LIQUEFACTION NECROSIS o Hypoxic death of cells w/in the CNS o Digestion of the dead cells o End result is the transformation of the tissue into liquid viscous mass (pus) = *complete dissolution o *gangrenous necrosis (dead tissue) Is the combination of coagulation + liq. Common sites: Lower limbs Testes Gallbladder GI tract Dry gangrene: pattern is coagulative n. Wet gangrene: patter is liquefactive n. o Cellular destruction by hydrolytic enzyme o d/t: autolysis + heterolysis o Common: Abscess, Brain infarcts, pancreatic nec. CASEOUS/CASEATION NECROSIS o Form of coagulative necrosis o Foci of tuberculosis Usually appears in the apex of the lungs*? o Gross: soft, friable, & cottage-cheese-like appearance o (2) types of GIANT CELLS (histiocytes) Langhans nucleus are peripherally arranged Foreign type nucleus are haphazardly arranged FAT NECROSIS o Caused by the action of activated pancreatic LIPASES (w/c liquefy cell membranes) o TGs lipases FA + Ca++ = forming saponified fats o Gross: chalky-white appearance o Micro: foci of shadowy outlines of necrotic fat cells + basophilic Ca++ deposits FIBRINOID NECROSIS o Additional type o Common in vascular wall o Histologically resembles fibrin o Micro: eosinophilic (pink) homogenous appearance

MECHANISMS OF CELLULAR INJURY 1. ATP depletion (hypoxic & toxic injury) o NORMALLY, ATP is produced by: Oxidative phosphorylation of ADP Anaerobic glycolysis ATP is required for: Membrane transport CHON synthesis Lipogenesis Deacylation-reacylation reactions for phospholipid turnover o Effects of ATP depletion to <5% - 10% of normal lev. 1. Dec. activity of Na pump (ouabainsensitive Na+, K+-ATPase - causing swelling) 2. Altered cellular energy metabolism 3. Failure of Ca++ pump 4. Structural disruption of CHON synthetic apparatus 5. CHON may become misfolded unfolded protein response o Na+ K+ ATPase pump Causes: Na+ influx ; K+ efflux Further causing: Cellular swelling Endoplasmic reticulum swelling Loss of microvilli Membrane blebs 2. Mitochondrial Damage (all types) o Dec. oxidative phosphorylation causing formation of mitochondrial permeability transition (MPT) channels. o Thus, there is release of CYTOCHROME C. Cytochrome C = trigger for APOPTOSIS o Mitochondria can be damaged by: * cytosolic Ca++ Reactive oxygen specie Oxygen deprivation o (2) major consequences of mitochondrial damage Formation of high conductance channel called mitochondrial permeability transition pore (MPT) Cyclophilin D one of the structural components of the

mitochondrial permeability transition pore Capable of activating apoptotic pathways (such as cytochrome C) 3. Influx of Ca++ and loss of Ca++ homeostasis 2+ o Increased intracellular Ca causes cell injury by several mechanisms. Opening of the mitochondrial permeability transition pore, w/c leads in failure for ATP generation Activates a number of enzymes:
phospholipases (cause membrane damage), proteases (break down both membrane and cytoskeletal proteins), endonucleases (responsible for DNA and chromatin fragmentation), and ATPases (hastening ATP depletion).

Induction of apoptosis by: activation of caspases increasing mitochondrial permeability 4. Accumulation of O2 derived free radicals (oxidative stress) o Cell injury induced by free radicals, particularly reactive oxygen species (chemical and radiation injury, ischemia-reperfusion injury, cellular aging, and microbial killing by phagocytes) o Reactive oxygen species (ROS) are a type of oxygenderived free radical. are produced normally in cells during mitochondrial respiration and energy generation excess of these free radicals, leading to a condition called oxidative stress (Alzheimer) are also produced in large amounts by leukocytes, particularly neutrophils and macrophages o Mechanisms to reduce free radicals Antioxidants (A,C,E) Binding proteins (transferrin, ferritin, lactoferrin, and ceruloplasmin) Some enzymes Catalase Superoxide dismutase Glutathione peroxidase o Pathologic effects of free radicals Lipid peroxidation in membranes

Oxidative modification of proteins Lesions in DNA Free radicals are capable of causing single- and doublestrand breaks in DNA, crosslinking of DNA strands, and formation of adducts 5. Defects in membrane permeability o membrane damage is a consistent feature of most forms of cell injury (except apoptosis) Mechanisms of Membrane Damage o In ischemic cells membrane defects may be the result of ATP depletion and calcium-mediated activation of phospholipases. o The plasma membrane can also be damaged directly by various bacterial toxins, viral proteins, lytic complement components, and a variety of physical and chemical agents. o Several biochemical mechanisms may contribute to membrane damage: Reactive oxygen species Decreased phospholipid synthesis Increased phospholipid breakdown Cytoskeletal abnormalities

Mechanisms of Cell Injury (SUMMARY) ATP depletion: failure of energy-dependent functions reversible injury necrosis Mitochondrial damage: ATP depletion failure of energydependent cellular functions ultimately, necrosis; under some conditions, leakage of proteins that cause apoptosis Influx of calcium: activation of enzymes that damage cellular components and may also trigger apoptosis Accumulation of reactive oxygen species: covalent modification of cellular proteins, lipids, nucleic acids Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis Accumulation of damaged DNA and misfolded proteins: triggers apoptosis

End of part 1