Cerebral ischemia-reperfusion injury and adhesion.
1997
Prompt reperfusion of ischemic tissue is critical for restoring normal function, but it can precipitate a progressive destruction of reversibly damaged cells, leading to paradoxical tissue dysfunction and necrosis. This reperfusion injury has a multifactorial etiology but it is associated with a fulminating infiltration of leukocytes, with subsequent release of cytotoxic mediators, into the previously ischemic tissue.1,2 An early event in the reperfusion process is the adhesion and accumulation of neutrophils. Although this is expected as part of the healing process, it can be fulminating due to a vascular endothelium that has been activated by inflammatory mediators such as platelet activating factor (PAF) and reactive oxygen metabolites. Accumulation of neutrophils, together with red blood cells and platelets, can lead to capillary plugging3 and a reduction in microvascular blood flow, resulting in focal areas of stasis. Once infiltrated into tissues, neutrophils are capable of releasing various proteases, lipid-derived mediators, and reactive oxygen species that can injure potentially salvageable cells.
The adhesion and migration of neutrophils are orchestrated by several classes of cell surface glycoproteins. These include the leukocyte integrins(CD11/CD18), the immunoglobulin supergene family [intercellular adhesion molecule-1 (ICAM-1); vascular cell adhesion molecule-1 (VCAM-1)], and the selectins (L-, P-, and E-selectin).4 Studies employing monoclonal antibodies (MAbs) directed at specific members of these various pathways have been instrumental in demonstrating the importance of neutrophils in ischemia-reperfusion injury. In the heart, studies by Simpson et al.5 (anti-CD11b) and Seewaldt-Becker et al.6 (anti-CD11a, anti-CD18, anti-ICAM-1) were among the first to demonstrate that MAbs directed against either leukocyte or endothelial cell adhesion glycoproteins were effective in limiting the myocardial necrosis that developed in response to an ischemia-reperfusion protocol. Efficacy has also been demonstrated for MAbs administered just before reperfusion directed against the following molecules: L- …
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