CYTOKINES, OXIDANTS, NEUTROPHILS AND LUNG INJURY

细胞因子、氧化剂、中性粒细胞和肺损伤

• 批准号: 2028604
• 负责人: Asrar B. Malik
• 金额: $ 24.43万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2028604
• 关键词: DNA binding protein; biological signal transduction; cell migration; cytokine; gel mobility shift assay; gene expression; genetic promoter element; glutathione; hydrogen peroxide; in situ hybridization; laboratory rabbit; leukocyte adhesion molecules; lung injury; lung ischemia /hypoxia; neutrophil; northern blottings; nuclear factor kappa beta; oxidative stress; oxidizing agents; phosphorylation; protein tyrosine kinase; respiratory oxygenation; transcription factor; tumor necrosis factor alpha; vascular endothelium

The production of the oxidant, H2O2, during the adhesive interaction between the activated neutrophil (PMN) and the vascular endothelium, during reoxygenation of tissues, and following TNFalpha exposure of endothelial cells is a critical event in the pathogenesis of acute lung injury. We have demonstrated that subcytolytic concentrations of H2O2 mediate intercellular adhesion molecule-1 (ICAM-1)-dependent vascular endothelial hyperadhesivity through increasing ICAM-1 mRNA synthesis and cell surface protein, thus providing a basis for PMN-mediated pulmonary vascular endothelial injury. The goal of the proposed studies is to define the mechanisms by which H2O2 signals the expression of endothelial ICAM-1 and adhesivity. Preliminary binding activity of several AP-1-like elements of the ICAM-1 promoter, including sequence repeats similar to the anti-oxidant responsive element (ARE). These studies will provide fundamental information on the mechanisms of oxidative stress-induced regulation of ICAM-1 expression in endothelial cells and the expression of endothelial cell adhesivity and PMN migration. With a better understanding of redox-regulated activation of ICAM-1 it will be possible to design rational strategies for prevention of vascular endothelial cell adhesivity and inappropriate PMN adhesion to the endothelium.

在粘合过程中氧化剂过氧化氢的产生 互动 活化的中性粒细胞(PMN)与血管 内皮细胞， 在组织复氧过程中，以及在肿瘤坏死因子α暴露后 内皮细胞是急性心肌梗死发病机制中的关键事件 肺 受伤。我们已经证明了亚细胞溶解浓度 双氧水 细胞间黏附分子-1(ICAM-1)依赖性 血管 通过增加ICAM-1基因表达实现内皮细胞高粘附性 综合和 细胞表面蛋白，从而为PMN介导的 肺 血管内皮损伤。拟议研究的目标是 至 定义H_2O_2发出信号表达的机制 内皮细胞 ICAM-1与粘附性的关系。几种化合物的初步结合活性 AP-1样蛋白 ICAM-1启动子的元件，包括序列重复相似 至 抗氧化反应元件(ARE)。这些研究将 提供 关于氧化机理的基本信息 应激诱导 细胞间黏附分子-1在血管内皮细胞中的表达调控 表达式 内皮细胞黏附性和中性粒细胞迁移。拥有更好的 对氧化还原调节的ICAM-1激活的理解 可能的 合理设计预防血管疾病的策略 内皮细胞 黏附性和PMN与内皮细胞的不适当黏附。