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.

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FREE RADICAL INJURY
I. Basic Principles

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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 (O2), 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)—Fe2+ 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 (O2) → H2O2
ii. Glutathione peroxidase (in mitochondria)—GSH + free radical → GSSH and
H 2O
iii. Catalase (in peroxisomes)—H2O2 → O2 and H2O
3. Metal carrier proteins (e.g., transferrin and ceruloplasmin)

II. 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
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Fundamentals of Pathology aims at providing general principles of pathology and its associated
disciplines and is not intended as a working guide to patient care, drug administration or
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the responsibility of the treating practitioner, relying on independent expertise and knowledge
of the patient, to determine the best treatment and method of application for the patient.
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