Ischemia-reperfusion injury paradoxically causes more cellular damage than sustained ischemia alone. Which sequence of events BEST explains why reperfusion augments injury?
- A Reperfusion restores lysosomal membrane integrity, releasing cathepsins that were inactivated during ischemia, causing abrupt autolysis
- B Reperfusion causes acute calcium washout from cells, triggering calcineurin-mediated dephosphorylation events that activate death pathways
- C Reperfusion restores ATP production, which ironically activates kinase-driven programmed necrosis (necroptosis) that was suppressed during ischemia
- D During ischemia, xanthine dehydrogenase is converted to xanthine oxidase; upon reperfusion, molecular oxygen is used as an electron acceptor, generating superoxide and hydrogen peroxide; simultaneously, calcium overload triggers mitochondrial permeability transition pore (mPTP) opening, releasing cytochrome c and causing apoptotic and necrotic cell death ✓
Explanation
Ischemia-reperfusion injury is a two-hit phenomenon. During ischemia: energy failure, cytoplasmic acidosis, Na+/Ca2+ overload, and conversion of xanthine dehydrogenase to xanthine oxidase accumulate. Upon reperfusion: (1) restored oxygen is consumed by xanthine oxidase to generate superoxide and H2O2, overwhelming antioxidant defenses and causing oxidative damage to membranes, proteins, and DNA; (2) calcium overload in mitochondria triggers the mitochondrial permeability transition pore (mPTP), dissipating the proton gradient, releasing cytochrome c, and committing cells to death; (3) neutrophil influx amplifies injury via further reactive oxygen species and proteases. Lysosomal pathway and calcineurin-mediated washout are not the primary mechanisms.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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