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7Growth Adaptations, Cellular Injury, and Cell Death
Extrinsic receptor-ligand pathway2. 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 CD83. + T cell-mediated pathwayPerforins secreted by CD8i. + T cell create pores in membrane of target cell.Granzyme from CD8ii. + T cell enters pores and activates caspases.CD8iii. + T-cell killing of virally infected cells is an example.
free raDical inJuryBasic PrinciPlesI.
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 O2. 2 yields superoxide (O2
.–), hydrogen peroxide (H2O2), and hydroxyl radicals (.OH).
Pathologic generation of free radicals arises with C. Ionizing radiation—water hydrolyzed to hydroxyl1. free radicalInflammation—NADPH oxidase generates superoxide ions during oxygen-2. dependent killing by neutrophils.Metals (e.g., copper and iron)—Fe3. 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. Enzymes2.
Superoxide dismutase (in mitochondria)—Superoxide (Oi. 2.–) → H2O2
Glutathione peroxidase (in mitochondria)—GSH + free radical ii. → GSSH and H2OCatalase (in peroxisomes)—Hiii. 2O2 → O2 and H2O
Metal carrier proteins (e.g., transferrin and ceruloplasmin)3.
free radical injuryII. Carbon tetrachloride (CClA. 4)
Organic solvent used in the dry cleaning industry1. Converted to CCl2. 3 free radical by P450 system of hepatocytesResults in cell injury with swelling of RER; consequently, ribosomes detach, 3. impairing protein synthesis.Decreased apolipoproteins lead to fatty change in the liver (Fig4. . 1.12).
Reperfusion injuryB. Return of blood to ischemic tissue results in production of O1. 2-derived free radicals, which further damage tissue.Leads to a continued rise in cardiac enzymes (e.g., troponin) after reperfusion of 2. infarcted myocardial tissue
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PATHOMA.COMFundamentals of Pathology: Medical Course and Step 1 Review, First Edition
ISBN 978-0-9832246-0-0
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