7 Growth Adaptations, Cellular Injury, and Cell Death Extrinsic receptor-ligand pathway 2. FAS ligand binds FAS death receptor (CD95) on the target cell, activating i. caspases (e.g., negative selection of thymocytes in thymus). Tumor necrosis factor (TNF) binds TNF receptor on the target cell, ii. activating caspases. Cytotoxic CD8 3. + T cell-mediated pathway Perforins secreted by CD8 i. + T cell create pores in membrane of target cell. Granzyme from CD8 ii. + T cell enters pores and activates caspases. CD8 iii. + T-cell killing of virally infected cells is an example. FREE RADICAL INJURY BASIC PRINCIPLES I. Free radicals are chemical species with an unpaired electron in their outer orbit. A. Physiologic generation of free radicals occurs during oxidative phosphorylation. B. Cytochrome 1. c oxidase (complex IV) transfers electrons to oxygen. Partial reduction of O 2. 2 yields superoxide (O 2 . – ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals ( . OH). Pathologic generation of free radicals arises with C. Ionizing radiation—water hydrolyzed to hydroxyl 1. free radical Inflammation—NADPH oxidase generates superoxide ions during oxygen- 2. dependent killing by neutrophils. Metals (e.g., copper and iron)—Fe 3. 2+ generates hydroxyl free radicals (Fenton reaction). Drugs and chemicals—P450 system of liver metabolizes drugs (e.g., 4. acetaminophen), generating free radicals. Free radicals cause cellular injury via peroxidation of lipids and oxidation of DNA D. and proteins; DNA damage is implicated in aging and oncogenesis. Elimination of free radicals occurs via multiple mechanisms. E. Antioxidants (e.g., glutathione and vitamins A , C, and E) 1. Enzymes 2. Superoxide dismutase (in mitochondria)—Superoxide (O i. 2 . – ) → H 2 O 2 Glutathione peroxidase (in mitochondria)—GSH + free radical ii. → GSSH and H 2 O Catalase (in peroxisomes)—H iii. 2 O 2 → O 2 and H 2 O Metal carrier proteins (e.g., transferrin and ceruloplasmin) 3. FREE RADICAL INJURY II. Carbon tetrachloride (CCl A. 4 ) Organic solvent used in the dry cleaning industry 1. Converted to CCl 2. 3 free radical by P450 system of hepatocytes Results in cell injury with swelling of RER; consequently, ribosomes detach, 3. impairing protein synthesis. Decreased apolipoproteins lead to fatty change in the liver (Fig 4. . 1.12). Reperfusion injury B. Return of blood to ischemic tissue results in production of O 1. 2 -derived free radicals, which further damage tissue. Leads to a continued rise in cardiac enzymes (e.g., troponin) aſter reperfusion of 2. infarcted myocardial tissue Copyright Pathoma LLC. All Rights Reserved. Purchase online at www.pathoma.com