Inhibition of leukocyte adherence by anti-CD18 monoclonal antibody attenuates reperfusion injury in the rabbit ear.

Abstract

Tissue injury resulting from ischemia and reperfusion forms the basis of several important disorders including myocardial infarction, stroke, and circulatory shock. To examine the role of neutrophils in this process and to determine the extent to which injury is a consequence of reperfusion, we utilized the monoclonal antibody 60.3, directed to CD18, the human leukocyte adherence glycoprotein, to block intravascular neutrophil aggregation and neutrophil adherence to endothelium in a rabbit model of tissue ischemia and reperfusion. Antibody treatment either before ischemia or after ischemia, but prior to reperfusion, resulted in the same degree of significant protection against endothelial, microvascular, and tissue injury. We conclude that neutrophils and increased neutrophil adhesiveness are important in the development of microvascular and tissue injury after ischemia and reperfusion and that under these circumstances, injury is primarily a consequence of reperfusion.Ischemia-related cellular, tissue, and organ injury form the basis of many important clinical disorders, including myocardial infarction, stroke, vascular disease, organ transplantation, and circulatory shock. Much progress has been made in the area of early restoration or perfusion. However, there is evidence that under certain circumstances, a significant proportion of the injury associated with ischemia may be a consequence of events associated with reperfusion of ischemic tissues, i.e., "reperfusion injury" (1, 2). This concept has clinical implications since specific therapy usually cannot be instituted until after the ischemic event, whereas it may be feasible to administer therapy prior to reperfusion.Oxygen-derived free radicals, generated within the tissues at the time of reperfusion, have been identified as potentially important mediators of this reperfusion injury (3). Another important source of free radicals is the neutrophil. Activated neutrophils can also release proteases and phospholipase products, all of which are capable of causing significant cellular and tissue injury (4, 5). Neutrophil-mediated endothelial injury has been demonstrated to result in loss of vascular integrity, edema, hemorrhage, thrombosis, and tissue necrosis. An important role for neutrophils in ischemiareperfusion injury is suggested by studies that have shown a close association between neutrophil accumulation and tissue injury in this setting (6) and by studies that have demonstrated significant injury reduction by depletion of circulating neutrophils (7,8).Increased neutrophil adhesiveness is a critical early step in the sequence of events leading to neutrophil-mediated injury (4). An alternative approach to the investigation and perhaps to therapy of neutrophil-mediated injury has developed from studies that have identified a human neutrophil membrane glycoprotein heterodimer, designated CD11b/CD18 (Mac-i, Mol), which plays a major role in mediating neutrophil adhesiveness (9). We have shown that specific monoclonal antibodies (mAbs) directed to ...

Characterization of Human Inducible Costimulator Ligand Expression and Function

“…Adhesion of monocytes to endothelial cells or extracellular matrices plays a critical role in triggering monocyte activation in extracellular sites of infection or tissue damage and induces calcium signaling, phosphorylation of signaling and cytoskeletal proteins, and induction of inflammatory cytokines (28 -31). Monocyte adhesion to surfaces is inhibited by mAbs to the leukocyte integrin ␤ 2 -subunit CD18 (32,33). Using CD18 mAb, we could selectively block integrin-mediated up-regulation of ICOSL but not of CTLA4 ligands, suggesting that ICOSL vs CD80/CD86 are differentially regulated after adhesion to the plastic substrate.…”

Milk Fat Globule-EGF Factor VIII in Sepsis and Ischemia-Reperfusion Injury

“…The hallmarks of I/R injury are the formation of reactive oxygen species (74), cytokine release (75), complement activation (6,76), the production of eicosanoids (77,78), recruitment of activated leukocytes (79,80), mitochondrial dysfunction (81) and a combination of cell necrosis and apoptosis (82,83). These I/R injuryinduced events can trigger intense and detrimental inflammatory responses which lead to organ damages.…”

Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation

“…Many documented attempts to directly reduce the I/Rinduced inflammatory response in various models have unmasked inflammation as a significant cause of subsequent tissue injury and dysfunction (1,14). The present studies indicate that early apoptosis is a crucial event in the process that initiates inflammation and subsequent tissue injury.…”