NEUTROPHILS IN ISCHEMIA REPERFUSION INJURY IN SHOCK

创伤是1-44岁儿童死亡的主要原因。其中 晚期死亡、多器官系统衰竭(MOSF)是主要因素。 多脏器功能衰竭的分期可在最初受伤时设定为直接 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，可能是 PNMs与内皮细胞(EC)之间的粘附性增加。一大专业 PMN-EC黏附机制是通过白细胞黏附蛋白实现的 CD11/CD18复合体。我们已经研制出一种单抗， 编号为60.3的单抗属于这个复合体。单抗60.3体外预防PMN-PMN PMN-EC依从性。在一种兔模型的初步研究中 失血性休克，单抗60.3，在休克前或休克时给予 复苏显著提高存活率，减少酸中毒和 大体和组织学改变与对照动物相比。 在本申请中，我们建议继续进行这些研究，以解决三个问题 地区： 1)我们将把这些研究扩展到亚人灵长类动物模型 失血性休克，以验证初步观察到的 不是物种特有的。 2)因为对PMN附着的干扰可能会干扰 正常的细菌防御，我们将调查单抗60.3 在细菌症模型中增加对感染的敏感性 腹膜炎模型。 3)为进一步阐明PMN介导的细胞毒作用机制 缺血再灌注损伤我们将采用两种模型：一种是肾阻塞 模型和兔耳游离组织瓣模型。这些将允许 阐明PMN-EC黏附、蛋白水解酶和 氧化剂的功能和组织学检查 改变。 这些研究将提供与以下角色相关的基本信息 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.