SPLANCHNIC HYPOPERFUSION PRIMES NEUTROPHILS AND ENDOTHELIUM

内脏灌注不足引发中性粒细胞和内皮细胞

• 批准号: 6271802
• 负责人: ERNEST EUGENE MOORE
• 金额: $ 16.82万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6271802
• 关键词: antioxidants; biological signal transduction; cell adhesion molecules; clinical research; cytotoxicity; disease /disorder model; enzyme inhibitors; gastrointestinal system; human subject; ischemia; laboratory rat; lung injury; microcirculation; mitogen activated protein kinase; multiple organ failure; neutrophil; platelet activating factor; reperfusion; respiratory circulation; selectins; trauma; vascular endothelium

GLOBAL HYPOTHESIS: Our objective is to decouple obligatory postinjury splanchnic hypoperfusion from provoking systemic hyperinflammation that ultimately culminates in multiple organ failure (MOF). During the first 5 years of this project, we focused on the mechanisms involved in gut ischemia/reperfusion (I/R) induced priming of circulating neutrophils (PMNs). In the next 5 years, we plan to characterize and target intracellular signaling events involved in PMN priming and pathologic PMN- endothelial interaction in distal organs following splanchnic hypoperfusion. WORKING HYPOTHESIS: Splanchnic hypoperfusion renders the injured patient at risk for MOF by a) priming circulating PMNs for cytotoxicity (02 generation, protease release, adhesion molecule CD11b/CD18 expression) and b) stimulating distant microvascular endothelium for primed PMN adherence (E-selectin, ICAM1). While traditional therapy has concentrated on extracellular events; eg, blocking receptors (monoclonal antibodies) or nullifying cellular products (antioxidants), intervention at the level of signal transduction may prove to be more effective clinically. Mitogen- activating protein (MAP) kinase cascades are an integral component of the intracellular signaling for both PMN priming and endothelial adhesion molecule expression. More specifically, the p38 MAPK pathway appears central to both cellular responses. We hypothesize the inhibition of p38 MAPK will attenuate a) gut I/R induced PMN priming for cytodestruction and b) distant organ endothelial expression of counterligands for the primed PMN and, thereby, decouple postinjury splanchnic hypoperfusion from initiating MOF.

全球假设：我们的目标是将强制性的损失造成 从挑衅的全身性高炎症引起的斑点张性灌注不足 最终最终导致多器官故障（MOF）。在前5个 在这个项目的多年中，我们专注于肠道的机制 缺血/再灌注（I/R）诱导的循环中性粒细胞的启动 （PMN）。在接下来的5年中，我们计划表征和定位 PMN启动和病理PMN的细胞内信号传导事件 闪烁后，远端器官的内皮相互作用 灌注不良。 工作假设：诊断性灌注不足会导致受伤的患者 a）启动循环PMN的MOF风险（02） 产生，蛋白酶释放，粘附分子CD11b/CD18表达）和 b）刺激针对PRIMN粘附的远处微血管内皮 （E-选择素，ICAM1）。传统疗法集中于 细胞外事件；例如，阻断受体（单克隆抗体）或 无效的细胞产物（抗氧化剂），干预水平 信号转导可能在临床上更有效。有丝分裂原 激活蛋白（MAP）激酶级联反应是 PMN启动和内皮粘附的细胞内信号传导 分子表达。更具体地说，出现p38 MAPK途径 两个细胞反应的中心。我们假设抑制p38 MAPK将衰减a）肠道I/r引起的PMN启动，用于细胞地位和 b）反物的反物的远处器官内皮表达 PMN，从而使后损伤后的Splanchnic灌注不足。 启动MOF。