Microvascular Aspects of Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion (I/R) has been implicated in the pathogenesis of a number of diseases that affect a variety of organ systems. Research on this problem has led to the recognition that the microcirculation is particularly vulnerable to the deleterious effects of I/R. The microvascular dysfunction caused by I/R is manifested as impaired endothelium-dependent dilation in arterioles, enhanced fluid filtration and leukocyte plugging in capillaries, and the trafficking of leukocytes and platelets, as well as extravasation of plasma proteins in postcapillary venules. Activated endothelial cells in all segments of the microcirculation produce more oxygen radicals, and the bioavailability of nitric oxide diminishes after reperfusion. The resulting imbalance between superoxide and nitric oxide in endothelial cells leads to the production and release of inflammatory mediators and an enhanced biosynthesis of and increased cell surface expression of adhesion molecules that mediate the recruitment of both leukocytes and platelets. More recent evidence indicates that I/R reveals a link between inflammation and hemostasis, such that the accumulation of leukocytes coincides with the recruitment of platelets. Our work on intestinal venules indicates that approximately 40% of the adherent leukocytes are platelet bearing, and that platelets utilize P-selection to bind to the P-selectin glycoprotein ligand-1 that is constitutively expressed on the surface of leukocytes. A fraction of the platelets that accumulate in postischemic venules bind directly to activated endothelial cells. Some of the known risk factors for cardiovascular disease, including hypercholesterolemia, hypertension, and diabetes appear to exaggerate many of the microvascular alterations elicited by I/R. Finally, the inflammatory mediators released as a consequence of reperfusion also appear to activate endothelial cells in remote organs that are not directly exposed to the initial ischemic insult. This distant response to I/R can result in leukocyte-dependent microvascular injury that is characteristic of the multiple organ dysfunction syndrome.