INHIBITION OF NEUTROPHIL MIGRATION AT THE SITE OF INFECTION INCREASESREMOTE ORGAN NEUTROPHIL SEQUESTRATION AND INJURY

Up-regulation of the leukocyte beta(2) integrin, CD18, is a key event in neutrophil-endothelial adhesion and neutrophil-mediated organ injur y. Inhibition of CD18 with monoclonal antibodies reduces lung and live r neutrophil sequestration in animal models of Gram-negative bacteremi a or endotoxemia. However, with a persistent septic challenge, interfe rence with host leukocyte phagocytic defense could adversely affect ou tcome. To assess the effects of inhibiting CD18 on organ neutrophil re sponses, bacteremia, and organ injury after fecal peritonitis, mice un derwent cecal ligation and puncture (CLP). At the time of CLP and 12 h later, mice received intravenous anti-CD18 antibody or control IgG. A t 3, 6, and 18 h after CLP, lung and liver tissue neutrophil content w ere measured by myeloperoxidase (MPO) assay, peritoneal cells and bloo d leukocytes were differentially counted, blood was cultured, and seru m aspartate aminotransferase was measured. There was a significant red uction in peritoneal neutrophil migration and an increase in blood neu trophils after anti-CD18 treatment compared with results from treatmen t with the control antibody. In the anti-GD18-treated group, liver MPO was increased fivefold at 6 and 18 h, while lung MPO was increased tw o-fold at 18 h when compared with the control antibody-treated group. The anti-CD18-treated group also had an increase in bacteria cultured from the blood at 6 and 18 h and an increase in serum aminotransferase at 18 h. Our data demonstrate that peritoneal neutrophil migration in response to an endogenous fecal challenge is CD18-dependent, and that this mechanism forms a vital part of host defense. Inhibition of CD18 increased neutrophil sequestration in the liver and lung and increase d liver injury. This study demonstrates a paradoxical increase in orga n neutrophil sequestration using a leukocyte anti-adhesion therapy dur ing sepsis and suggests that anti-adhesion therapies targeted towards neutrophil may worsen outcome if given during an ongoing, localized in fection.