Leukocyte-endothelial cell interactions which occur after ischemia-reperfusion are mediated by adhesion molecules ( Fig, 1(b)). Leukocytes can initially roll along the microvascular endothelium through an L-selectin (leukocyte-expressed) interaction with a counter-ligand derived from endothelial cells. In addition, endothelial-derived oxygen radicals can mobilize preformed P-selectin, another rolling factor, to the surface of the endothelial cell. Endothelial-derived radicals can also stimulate production of platelet activating factor, which in turn causes rolling leukocytes to adhere firmly to the endothelial cell. Platelet activating factor promotes firm adherence by facilitating leukocyte integrin binding to integrin ligands expressed by endothelial cells. The leukocyte integrins mediating firm adherence are CD11a/CD18 and CD11b/CD18; these are also known as LFA-1 and MAC-1 respectively. The adherence factors expressed by endothelial cells belong to the immunoglobulin superfamily of proteins and are known as intercellular adhesion molecules (ICAM-1 and ICAM-2).
The firm adhesion of leukocytes to endothelial cells activates leukocytes, causing release of oxygen radicals and proteases. Furthermore, firm adhesion and subsequent migration of leukocytes across the endothelial barrier stimulates active contraction of endothelial cells. When endothelial cells contract, the microvascular barrier becomes very leaky to even large plasma proteins. Interstitial edema will then develop since microvascular permeability to both fluid and protein is greatly increased (layloreial 1994).
The process described above is an oversimplification, but studies in many organs have confirmed that rolling and adherence factors are necessary for the production of acute microvascular injury by ischemia-reperfusion, and that oxygen radicals formed from xanthine oxidase activation initiate this process.
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