Mercer-Jones M A, Heinzelmann M, Peyton J C, Wickel D, Cook M, Cheadle W G
Department of Surgery, University of Louisville School of Medicine, Kentucky 40292, USA.
Shock. 1997 Sep;8(3):193-9. doi: 10.1097/00024382-199709000-00007.
Up-regulation of the leukocyte beta 2 integrin, CD18, is a key event in neutrophil-endothelial adhesion and neutrophil-mediated organ injury. Inhibition of CD18 with monoclonal antibodies reduces lung and liver neutrophil sequestration in animal models of Gram-negative bacteremia or endotoxemia. However, with a persistent septic challenge, interference with host leukocyte phagocytic defense could adversely affect outcome. To assess the effects of inhibiting CD18 on organ neutrophil responses, bacteremia, and organ injury after fecal peritonitis, mice underwent cecal ligation and puncture (CLP). At the time of CLP and 12 h later, mice received intravenous anti-CD18 antibody or control IgG. At 3, 6, and 18 h after CLP, lung and liver tissue neutrophil content were measured by myeloperoxidase (MPO) assay, peritoneal cells and blood leukocytes were differentially counted, blood was cultured, and serum aspartate aminotransferase was measured. There was a significant reduction in peritoneal neutrophil migration and an increase in blood neutrophils after anti-CD18 treatment compared with results from treatment with the control antibody. In the anti-CD18-treated group, liver MPO was increased fivefold at 6 and 18 h, while lung MPO was increased two-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 increased liver injury. This study demonstrates a paradoxical increase in organ neutrophil sequestration using a leukocyte anti-adhesion therapy during sepsis and suggests that anti-adhesion therapies targeted towards neutrophil may worsen outcome if given during an ongoing, localized infection.
白细胞β2整合素CD18的上调是中性粒细胞与内皮细胞黏附以及中性粒细胞介导的器官损伤中的关键事件。在革兰氏阴性菌血症或内毒素血症动物模型中，用单克隆抗体抑制CD18可减少肺和肝中的中性粒细胞滞留。然而，在持续的脓毒症刺激下，干扰宿主白细胞吞噬防御可能会对结果产生不利影响。为了评估抑制CD18对粪便性腹膜炎后器官中性粒细胞反应、菌血症和器官损伤的影响，对小鼠进行盲肠结扎和穿刺（CLP）。在CLP时及12小时后，小鼠接受静脉注射抗CD18抗体或对照IgG。在CLP后3、6和18小时，通过髓过氧化物酶（MPO）测定法测量肺和肝组织中的中性粒细胞含量，对腹腔细胞和血液白细胞进行分类计数，进行血培养，并测量血清天冬氨酸转氨酶。与对照抗体治疗结果相比，抗CD18治疗后腹腔中性粒细胞迁移显著减少，血液中性粒细胞增加。在抗CD18治疗组中，与对照抗体治疗组相比，肝MPO在6和18小时增加了五倍，肺MPO在18小时增加了两倍。抗CD18治疗组在6和18小时血培养细菌也增加，1十八小时血清转氨酶增加。我们的数据表明，对内源性粪便刺激的腹腔中性粒细胞迁移是CD18依赖性的，并且该机制是宿主防御的重要组成部分。抑制CD18会增加肝和肺中的中性粒细胞滞留并加重肝损伤。这项研究表明，在脓毒症期间使用白细胞抗黏附疗法会使器官中性粒细胞滞留出现矛盾性增加，并表明如果在正在进行的局部感染期间给予针对中性粒细胞的抗黏附疗法可能会使结果恶化。
