NEUTROPHILS IN ISCHEMIA REPERFUSION INJURY IN SHOCK

创伤是1-44岁年龄段死亡的主要原因。 之间 晚期死亡，多器官系统衰竭（MOSF）是主要因素。 MOSF的阶段可以在最初受伤时设定为直接损伤， 缺血再灌注损伤的后果。 中性粒细胞（PNM）是一种 缺血-再灌注损伤的重要介质，据推测， PNM和内皮细胞（EC）之间的粘附增加。 一个主要 PMN-EC粘附的机制是通过白细胞粘附蛋白 CD 11/CD 18复合物。 我们已经开发了一种单克隆抗体（MAb）， 命名为MAb 60.3。 MAb 60.3在体外预防PMN-PMN 和PMN-EC粘附。 在兔子模型的初步研究中， 失血性休克，在休克前或休克时给予MAb 60.3 复苏显着提高了生存率并减轻了酸中毒， 与对照组动物相比的大体和组织学变化。 在本申请中，我们建议继续这些研究，以解决三个问题， 区域： 1)我们将把这些研究扩展到一个亚人类灵长类动物模型， 失血性休克，以证实初步的 观察结果 没有物种特异性。 2)因为干扰PMN粘附可能会干扰 正常的细菌防御，我们将研究是否单克隆抗体 60.3 增加感染的易感性 模型和 腹膜炎模型。 3)为了进一步阐明PMN - 介导 缺血-再灌注损伤我们将使用两种模型： 肾阻塞 模型和兔耳游离皮瓣模型。 这些将允许 说明PMN的相对作用- EC粘附、蛋白酶和 氧化剂的检查 功能和组织学 变化 这些研究将提供与以下方面的作用有关的基本信息： 中性粒细胞在失血性休克缺血再灌注损伤中的作用

Trauma is the leading cause of death between the ages of 1-44 years. Among late deaths, multiple organ system failure (MOSF) is a principal factor. The stage for MOSF may be set at the time of initial injury as a direct consequence of ischemia-reperfusion injury. The neutrophil (PNM) is an important mediator of ischemia-reperfusion injury, presumably as a result of increased adherence between PNMs and endothelial cells (EC). One major mechanisms of PMN-EC adherence is via the leucocyte adhesive protein complex CD11/CD18. We have developed a monoclonal antibody (MAb), designated MAb 60.3 to this complex. MAb 60.3 in vitro prevents PMN-PMN and PMN-EC adherence. In preliminary studies in a rabbit model of hemorrhagic shock, MAb 60.3 administered either pre-shock or at the time of resuscitation significantly increased survival and lessened acidosis and gross and histologic changes compared with control animals. In this application, we propose to continue these studies to address three areas: 1) We will extend these studies to a sub-human primate model of hemorrhagic shock, to verify that the preliminary observations are not species specific. 2) Because interference with PMN adherence may interfere with normal bacterial defense, we will investigate whether MAb 60.3 increases susceptibility to infection in a bactermia model and a peritonitis model. 3) In order to further elucidate the mechanisms of PMN - mediated ischemia-reperfusion injury we will use two models: a renal occlusion model and a rabbit ear free-flap model. These will permit clarification of the relative roles of PMN- EC adherence, proteases, and oxidants by examination of functional as well as histologic changes. These studies will provide essential information related to the role of PMNs in ischemia-reperfusion injury in hemorrhagic shock.