A monoclonal antibody to the adherence-promoting leukocyte glycoprotein, CD18, reduces organ injury and improves survival from hemorrhagic shock and resuscitation in rabbits.

Abstract

Leukocytes have been shown to play an important role in the development of isolated organ injury after experimental ischemia and reperfusion. To examine the role of leukocytes in generalized ischemia-reperfusion injury we used the MAb 603 (directed to the human leukocyte adherence glycoprotein, CD18) to block leukocyte adherence functions in a rabbit model of hemorrhagic shock and resuscitation. In control animals subjected to 1 h of shock (mean blood pressure 45 torr and mean cardiac output 30% of baseline) followed by resuscitation, only 29% survived 5 d. All had gross and histologic evidence of injury to lungs, liver, and gastrointestinal mucosa. In contrast, 100% of the MAb 60.3-treated animals survived 5 d (P < 0.01) and organ injury was absent or markedly attenuated. The control animals also had a persistent acidosis, lost more weight, and had evidence of continued gastrointestinal bleeding in contrast to MAb 60.3-treated animals. We conclude that increased leukocyte adhesiveness plays an important role in the development of multiple organ injury and death after generalized ischemia-reperfusion and that this injury may be significantly reduced by blocking leukocyte adherence functions with the MAb 60.3. IntroductionThe organ injury that results from ischemia and reperfusion determines the outcome of many important clinical disorders including myocardial infarction, stroke, mesenteric and peripheral vascular disease, organ transplantation, and circulatory shock. A number of recent investigations into the mechanisms of ischemia-reperfusion injury have focused on oxygenderived free radicals and their production of microvascular

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

“…mAb 60.3 does not affect other neutrophil functions such as grinule release or oxidant production (25). This specific blocking effect of mAb 60.3 occurs without altering circulating leukocyte counts (14,15).…”

Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen‐induced acute liver injury

“…Thus, these observations implied that HO-1 had a protective role in APAP-induced liver injury and that the reduction in HO-1-expressing macrophages may account for incomplete attenuation in APAP-induced liver injury in CXCR2-KO mice, compared with neutropenic WT mice. [8][9][10][11][12][31][32][33][34][35]. However, our previous observations that liver dysfunction preceded neutrophil infiltration in APAP-induced liver injury [13,14], prompted us to investigate the pathogenic roles of neutrophils, using the anti-granulocyte Ab.…”

Polyomavirus Enhancer-binding Protein 2/Core Binding Factor/Acute Myeloid Leukemia Factors Contribute to the Cell Type-specific Activity of the CD11a Integrin Gene Promoter

“…The importance of CD11a/CD18 for leukocyte extravasation is exemplified by the existence of an inherited disease (leukocyte adhesion deficiency) in which leukocytes exhibit a deficient expression of the three leukocyte integrins and the clinical symptoms of which are secondary to the lack of phagocyte migration into inflammatory sites (6,7). Conversely, under certain circumstances, CD11a/CD18 activity might become detrimental; CD11a/CD18 participates in T cell and lymphoma metastasis (1,8), and ischemia-reperfusion syndromes, myocardial infarction, and allograft rejection have their origin in an excessive and uncontrolled CD11a/CD18-dependent phagocyte extravasation into the tissues (9,10). To understand the mechanisms controlling transcription of each leukocyte integrin subunit, the proximal regulatory region of the CD11a gene has been isolated (11)(12)(13) and shown to confer leukocyte-restricted expression to reporter genes both in vitro and in vivo (11)(12)(13)(14).…”