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: 2685374
• 负责人: Asrar B. Malik
• 金额: $ 25.17万
• 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/2685374
• 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.

粘合过程中氧化剂H2 O2的产生 相互作用 活化中性粒细胞（PMN）和血管内皮细胞之间 内皮， 在组织的再氧合期间，以及在TNF α暴露之后， 内皮细胞是急性脑梗死发病机制中的关键事件 肺 损伤 我们已经证明，亚细胞溶解浓度的 H2o2 介导细胞间粘附分子-1（ICAM-1）依赖性 血管 ICAM-1 mRNA表达增加导致内皮细胞粘附性增强 合成与 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 到 定义H2 O2信号表达的机制 内皮 ICAM-1和粘附性。 几种的初步结合活性 AP-1样 ICAM-1启动子的元件，包括类似于 到 抗氧化反应元件（antioxidant responsive element，ARE） 这些研究将 提供 关于氧化机制的基本信息 应力诱发 内皮细胞ICAM-1表达的调控及细胞凋亡的研究 表达 内皮细胞粘附性和中性粒细胞迁移。 以更好的 了解ICAM-1的氧化还原调节活化， 可能 设计合理的预防血管性并发症的策略， 内皮细胞 粘附性和不适当的中性粒细胞粘附到内皮。