Pathoma 2023 PDF- Cellular Injury and Cell Death

Www.Medicalstudyzone.com Growth Adaptations, Cellular Injury, and Cell Death 5 CELL DEATH I. BASIC PRINCIPLES...

Www.Medicalstudyzone.com Growth Adaptations, Cellular Injury, and Cell Death 5 CELL DEATH I. BASIC PRINCIPLES A. The morphologic hallmark of cell death is loss of the nucleus, which occurs via nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis). B. The two mechanisms of cell death are necrosis and apoptosis. II. NECROSIS A. Death of large groups of cells followed by acute inflammation B. Due to some underlying pathologic process; never physiologic C. Divided into several types based on gross features III. GROSS PATTERNS OF NECROSIS A. Coagulative necrosis 1. Necrotic tissue that remains firm (Fig. 1.5A); cell shape and organ structure are preserved by coagulation of proteins, but the nucleus disappears (Fig. 1.5B). 2. Characteristic of ischemic infarction of any organ except the brain 3. Area of infarcted tissue is often wedge-shaped (pointing to focus of vascular occlusion) and pale. 4. Red infarction arises if blood re-enters a loosely organized tissue (e.g., pulmonary or testicular infarction, Fig. 1.6). B. Liquefactive necrosis 1. Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction. 2. Characteristic of i. Brain infarction - Proteolytic enzymes from microglial cells liquefy the brain. ii. Abscess - Proteolytic enzymes from neutrophils liquefy tissue. iii. Pancreatitis - Proteolytic enzymes from pancreas liquefy parenchyma. C. Gangrenous necrosis 1. Coagulative necrosis that resembles mummified tissue (dry gangrene, Fig. 1.7) 2. Characteristic of ischemia of lower limb and GI tract 3. If superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene). D. Caseous necrosis 1. Soft and friable necrotic tissue with "cottage cheese-like" appearance (Fig. 1.8) 2. Combination of coagulative and liquefactive necrosis 3. Characteristic of granulomatous inflammation due to tuberculous or fungal infection Fig. 1.6 Hemorrhagic infarction of testicle. Fig. 1.7 Dry gangrene. Fig. 1.8 Caseous necrosis of lung. (Courtesy ofYale (Courtesy of humpath.com) Rosen, MD)  Www.Medicalstudyzone.com 6 FUNDAMENTALS OF PATHOLOGY E. Fat necrosis 1. Necrotic adipose tissue with chalky-white appearance due to deposition of calcium (Fig. 1.9) 2. Characteristic of trauma to fat (e.g., breast) and pancreatitis-mediated damage of peripancreatic fat 3. Fatty acids released by trauma (e.g., to breast) or lipase (e.g., pancreatitis) join with calcium via a process called saponification. i. Saponification is an example of dystrophic calcification in which calcium deposits on dead tissues. In dystrophic calcification, the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate. ii. Metastatic calcification, as opposed to dystrophic calcification, occurs when high serum calcium or phosphate levels lead to calcium deposition in normal tissues (e.g., hyperparathyroidism leading to nephrocalcinosis). F. Fibrinoid necrosis 1. Necrotic damage to blood vessel wall 2. Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically (Fig. 1.10). 3. Characteristic of malignant hypertension and vasculitis IV.APOPTOSIS A. Energy (ATP)-dependent, genetically programmed cell death involving single cells or small groups of cells. Examples include 1. Endometrial shedding during menstrual cycle 2. Removal of cells during embryogenesis 3. CD8 + T cell-mediated killing of virally infected cells B. Morphology 1. Dying cell shrinks, leading cytoplasm to become more eosinophilic (pink, Fig. l.ll). 2. Nucleus condenses and fragments in an organized manner. 3. Apoptotic bodies fall from the cell and are removed by macrophages; apoptosis is not followed by inflammation. C. Apoptosis is mediated by caspases that activate proteases and endonucleases. 1. Proteases break down the cytoskeleton. 2. Endonucleases break down DNA. D. Caspases are activated by multiple pathways. 1. Intrinsic mitochondrial pathway i. Cellular injury, DNA damage, or decreased hormonal stimulation leads to inactivation of Bcl2. ii. Lack of Bcl2 allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases. Fig. 1.9 Fat necrosis of peri-pancreatic adipose Fig. 1.10 Fibrinoid necrosis of vessel. Fig.1.11 Apoptosis. tissue. (Courtesy of humpath.com)  Www.Medicalstudyzone.com Growth Adaptations, Cellular Injury, and Cell Death 7 2. Extrinsic receptor-ligand pathway i. FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases (e.g., negative selection of thymocytes in thymus). ii. Tumor necrosis factor (TNF) binds TNF receptor on the target cell, activating caspases. 3. Cytotoxic CD8+ T cell-mediated pathway i. Perforins secreted by CD8 + T cell create pores in membrane of target cell. ii. Granzyme from CD8 + T cell enters pores and activates caspases. iii. CD8 + T-cell killing of virally infected cells is an example. FREE RADICAL INJURY I. BASIC PRINCIPLES A. Free radicals are chemical species with an unpaired electron in their outer orbit. B. Physiologic generation of free radicals occurs during oxidative phosphorylation. 1. Cytochrome c oxidase (complex IV) transfers electrons to oxygen. 2. Partial reduction of O2 yields superoxide (O2ꜙ), hydrogen peroxide (H2O2 ), and hydroxyl radicals (˙OH ). C. Pathologic generation of free radicals arises with 1. Ionizing radiation - water hydrolyzed to hydroxyl free radical 2. Inflammation - NADPH oxidase generates superoxide ions during oxygen- dependent killing by neutrophils. 3. Metals (e.g., copper and iron)-Fe 2+ generates hydroxyl free radicals (Fenton reaction). 4. Drugs and chemicals - P450 system of liver metabolizes drugs (e.g., acetaminophen), generating free radicals. D. Free radicals cause cellular injury via peroxidation of lipids and oxidation of DNA and proteins; DNA damage is implicated in aging and oncogenesis. E. Elimination of free radicals occurs via multiple mechanisms. 1. Antioxidants (e.g., glutathione and vitamins A , C, and E) 2. Enzymes I) Superoxide dismutase (in mitochondria) - Superoxide (O2ꜙ) → H2O2 II) Glutathione peroxidase (in mitochondria) - 2GSH + free radical → GS-SG and H2O III) Catalase (in peroxisomes) - H 2O2 → O2ꜙ and H2O 3. Metal carrier proteins (e.g., transferrin and ceruloplasmin) II. EXAMPLES OF FREE RADICAL INJURY A. Carbon tetrachloride (CCl4) 1. Organic solvent used in the dry cleaning industry 2. Converted to CCl3 free radical by P450 system of hepatocytes 3. Results in cell injury with swelling of RER; consequently, ribosomes detach, impairing protein synthesis. 4. Decreased apolipoproteins lead to fatty change in the liver (Fig. 1.12). B. Reperfusion injury 1. Return of blood to ischemic tissue results in production of O2 -derived free radicals, which further damage tissue. 2. Leads to a continued rise in cardiac enzymes (e.g., troponin) after reperfusion of infarcted myocardial tissue