Complement, neutrophils and free radicals: mediators of reperfusion injury

Myocardial ischemia of sufficient duration produces irreversible myocardial injury and cell death. Associated with the direct ischemic insult, there is the indirect attack on the jeopardized tissue through activation of the complement system. The latter, occurring in response to ischemia, facilitates neutrophil-endothelial cell interactions, neutrophil migration into and across the vascular wall, along with the formation of cytotoxic oxygen metabolites and release of proteolytic enzymes. The neutrophil dependent actions participate in extending the tissue injury beyond that due to ischemia alone. The invading neutrophils injure the myocardial vasculature and sarcolemma through the generation of oxygen free radicals. Components of the complement system can damage tissue indirectly through formation of neutrophil chemoattractants as well as directly through assembly of the "membrane attack complex." Pharmacologic interventions that prevent complement activation, modulate neutrophil function or scavenge oxygen radicals, can reduce the extent of myocardial injury associated with ischemia reperfusion. The inflammatory reaction of cell injury mediated by neutrophil invasion of the affected tissue is an important site for pharmacologic intervention. Specific adhesive glycoprotein receptors are expressed on the neutrophil in conjunction with corresponding endothelial cell ligands. Recognition of these events has led to the development of specific antibodies having the potential to prevent cell-cell interactions essential for promoting and maintaining the inflammatory response. Therefore, neutrophil-independent extension of irreversible cell death that occurs upon reperfusion, is additive to the component of cell death attributed to the ischemic interval. As is the situation with any organ, function and cellular viability are dependent upon a blood supply, which if interrupted for a sufficiently long period, will lead to irreversible cellular changes and necrosis. Reperfusion is essential for arresting the otherwise progressive injury due to ischemia. The accelerated inflammatory response upon reperfusion contributes to an extension of the injury, a phenomenon known as "reperfusion" or "reoxygenation" injury.