During reperfusion injury following myocardial ischemia, which mechanism BEST explains the paradoxical exacerbation of cell death upon restoration of blood flow?

• A Mitochondrial permeability transition pore (mPTP) opening triggered by Ca²⁺ and ROS overload upon reperfusion ✓
• B Re-acidification triggering lysosomal enzyme release
• C Activation of caspase-8 by death receptor TNFR1
• D Complement C5a-mediated neutrophil influx causing coagulative necrosis

Explanation

Reperfusion injury is mediated primarily by sudden opening of the mitochondrial permeability transition pore (mPTP) driven by the convergence of Ca²⁺ overload, ROS burst from re-oxygenation, and normalization of pH during reperfusion. mPTP opening dissipates the mitochondrial membrane potential, halts ATP synthesis, releases cytochrome c triggering apoptosis, and causes osmotic swelling leading to necrosis. Cyclosporine A (inhibits cyclophilin D, an mPTP regulator) has been investigated as cardioprotective during reperfusion. Neutrophil influx contributes later but is not the initiating mechanism.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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