ROLE OF ENDOTHELIN IN ACUTE LUNG INJURY

目的：这个正在进行的项目的总体目标是调查 内皮素-1（ET-1）在人肺损伤中的作用 假设：1.在失调的炎症事件中，我们假设 炎症介质、O/2张力的变化以及 第二信使导致ET-1产生和ET受体增加 在人肺细胞中表达。 2.我们推测ET-1通过增加内皮细胞的增殖而引起肺损伤。 细胞对氧化损伤的敏感性，并通过增强PMN介导的 损伤 3.我们假设ET-1水平的增加和表达的增加 ET受体的表达促进肺泡炎症和肺动脉高压 在ARDS患者中。 研究：该项目将研究分子，生物化学和 ET系统（ET-1和ET受体）的生理机制 影响肺损伤。第一个目标是研究分子和 人肺ET-1合成及其受体的细胞调节 内皮细胞、上皮细胞和巨噬细胞响应于 炎症调节剂和生理条件（缺氧和高氧） 存在于ARDS患者中。选择这些细胞是因为， 与非ARDS肺相比，这些细胞在 ET-1免疫染色。第二个目标将确定ET对 肺内皮细胞，血管组织，离体肺损伤 整个动物。这些实验将检验ET 通过增加内皮细胞对氧化剂的敏感性而产生损伤 损伤和促进嗜中性粒细胞介导的损伤。这些实验将 扩展我们的初步发现，这表明ET促进损伤， 并将重点调查潜在的机制。第三个目标将 比较在不同的时间点， 肺的ARDS和危险患者，并评估 血浆和支气管肺泡灌洗ET-1水平和肺动脉高压， 肺泡炎症和临床病程的标志物。这一目标将 研究ET参与肺泡炎症的假说 和肺动脉高压。 意义：拟议的研究将大大提高我们的 ET-1在人肺损伤中的作用及其机制的研究进展 ET-1通过其促进血管损伤和炎症。

OBJECTIVE: The overall goal of this ongoing project is to investigate the role of endothelin-1 (ET-1) in human lung injury. HYPOTHESES: 1. During dysregulated inflammatory events, we hypothesize that inflammatory mediators, changes in O/2 tension, and alterations in second messengers lead to an increase in ET-1 production and ET receptor expression in human lung cells. 2. We hypothesize that ET-1 produces lung injury by increasing endothelial cell susceptibility to oxidant damage and by enhancing PMN-mediated injury. 3. We hypothesize that increased levels of ET-1 and increased expression of ET receptors promote alveolar inflammation and pulmonary hypertension in patients with ARDS. RESEARCH PLAN: The project will investigate molecular, biochemical and physiologic mechanisms by which the ET system (ET-1 and ET receptors) influences lung injury. The first aim will investigate the molecular and cellular regulation of ET-1 synthesis and ET receptors in human lung endothelial cells, epithelial cells and macrophages in response to inflammatory modulators and physiologic conditions (hypoxia and hyperoxia) present in ARDS patients. These cells have been selected because, in ARDS lungs compared to non-ARDS lungs, these cells have a marked increased in ET-1 immunostaining. The second aim will determine the effect of ET on injury in pulmonary endothelial cells, vascular tissue, the isolated lung and the whole animal. These experiments will test the hypothesis that ET produces injury by increasing endothelial cell susceptibility to oxidant injury and by promoting neutrophil-mediated damage. These experiments will extend our preliminary findings, which indicate that ET promotes injury, and will focus on investigating potential mechanisms. The third aim will compare the level of ET-1 production and ET receptor expression in the lungs of ARDS and at risk patients and assess the relationship between plasma and bronchoalveolar lavage ET-1 levels and pulmonary hypertension, markers of alveolar inflammation and clinical course. This aim will investigate the hypothesis that ET contributes to alveolar inflammation and pulmonary hypertension in ARDS patients. SIGNIFICANCE: The proposed research will substantially improve our understanding of the role of ET-1 in human lung injury and the mechanism by which ET-1 promotes vascular injury and inflammation.