Reperfusion Injury (5-mark answer)

1. Oxidative stress (ROS burst) - On reoxygenation there is a surge in reactive oxygen and nitrogen species generation. This occurs because damaged mitochondria cannot fully reduce oxygen, cellular antioxidant defenses are depleted after the ischemic period, and infiltrating leukocytes release additional ROS - Robbins, Cotran & Kumar, Pathologic Basis of Disease, p. 67 (Fig. 2.24 region).
2. Intracellular and mitochondrial calcium overload - Calcium influx that begins during ischemia is worsened during reperfusion due to membrane damage and ROS injury to the sarcoplasmic reticulum. This favors opening of the mitochondrial permeability transition pore, causing further ATP depletion and cell death.
3. Inflammation - Ischemic injury releases "danger signals" from dead cells and upregulates adhesion molecules on hypoxic endothelium/parenchymal cells. On reperfusion, this drives increased influx and activation of neutrophils, whose products (proteases, ROS) cause additional tissue damage. Antibody blockade of cytokines/adhesion molecules experimentally reduces this injury.
4. Complement activation - Activation of the complement system on reperfusion also contributes to tissue injury.

• Explains why some infarcted tissue continues to enlarge even after successful reperfusion therapy (e.g., "no-reflow" phenomenon after coronary reperfusion, reperfusion arrhythmias, and reperfusion edema in stroke).
• Important in transplant medicine (donor organ ischemia-reperfusion injury, e.g., renal and lung grafts) and contributes to delayed graft function.
• Despite mechanistic understanding, clinical trials targeting reperfusion injury (antioxidants, anti-complement, anti-adhesion molecule therapies) have largely not translated into effective therapy so far.