NEUTROPHILS IN ISCHEMIA REPERFUSION INJURY IN SHOCK

休克缺血再灌注损伤中的中性粒细胞

• 批准号: 3301477
• 负责人: ROBERT K WINN
• 金额: $ 15.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3301477
• 关键词: Macaca mulatta; cellular pathology; disease /disorder model; embryo /fetus cell /tissue; hemorrhagic shock; human tissue; laboratory mouse; laboratory rabbit; laboratory rat; monoclonal antibody; neutrophil; peritonitis; renal failure; renal ischemia /hypoxia; reperfusion; vascular endothelium

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.

外伤是 1-44 岁人群死亡的主要原因。 之中 晚期死亡，多器官系统衰竭（MOSF）是一个主要因素。 MOSF 的阶段可以设置在初次受伤时作为直接 缺血再灌注损伤的后果。 中性粒细胞 (PNM) 是 缺血再灌注损伤的重要介质，可能是由于 PNM 和内皮细胞 (EC) 之间的粘附增加。 一个专业 PMN-EC 粘附的机制是通过白细胞粘附蛋白 复杂的 CD11/CD18。 我们开发了单克隆抗体（MAb）， 该复合物被指定为 MAb 60.3。 MAb 60.3 体外预防 PMN-PMN 和 PMN-EC 依从性。 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 与对照动物相比的总体和组织学变化。 在本申请中，我们建议继续这些研究以解决三个问题 领域： 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，以验证初步观察结果是否正确 不特定于物种。 2) 因为干扰 PMN 依从性可能会干扰 正常的细菌防御，我们将研究 MAb 60.3 是否 增加菌血症模型中感染的易感性 腹膜炎模型。 3）为了进一步阐明PMN介导的机制 缺血再灌注损伤我们将使用两种模型：肾闭塞 模型和兔耳自由瓣模型。 这些将允许 澄清 PMN-EC 粘附、蛋白酶和 通过功能和组织学检查来检测氧化剂 变化。 这些研究将提供与作用相关的重要信息 失血性休克缺血再灌注损伤中的 PMN。