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.

创伤是1-44岁之间死亡的主要原因。 之中 晚期死亡，多器官系统故障（MOSF）是主要因素。 MOSF的阶段可以在初次受伤时设定为直接 缺血再灌注损伤的结果。 中性粒细胞（PNM）是 缺血再灌注损伤的重要介质，结果可能 PNM和内皮细胞之间的依从性增加（EC）。 一个主要 PMN-EC依从性的机制是通过白细胞粘附蛋白 复杂的CD11/CD18。 我们已经开发了一种单克隆抗体（MAB）， 指定为MAB 60.3到这个复合物。 MAB 60.3体外阻止PMN-PMN 和PMN-EC依从性。 在兔子模型的初步研究中 出血性休克，mab 60.3进行预击或在 复苏显着提高了生存率，酸中毒和降低 与对照动物相比，总体和组织学变化。 在此应用中，我们建议继续这些研究以解决三个 区域： 1）我们将将这些研究扩展到一个亚人类灵长类动物模型 出血性休克，以验证初步观察是 不是特定于物种的。 2）因为干扰PMN的依从性可能会干扰 正常细菌防御，我们将调查MAB 60.3是否 在Bactermia模型和A中增加了感染的敏感性 腹膜炎模型。 3）为了进一步阐明PMN介导的机制 缺血 - 重新灌注损伤我们将使用两种型号：肾脏闭塞 模型和兔耳朵自由式flap型。 这些将允许 阐明PMNEC依从性，蛋白酶和 通过检查功能和组织学的氧化剂 更改。 这些研究将提供与 出血性休克中缺血 - 重新灌注损伤的PMN。