The alveolar epithelium in lung injury and repair

肺泡上皮在肺损伤和修复中的作用

• 批准号: 7145363
• 负责人: GUSTAVO MATUTE-BELLO
• 金额: $ 41.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145363
• 关键词: CD95 molecule; adult respiratory distress syndrome; apoptosis; cysteine endopeptidases; enzyme activity; fibrosis; inflammation; laboratory mouse; laboratory rabbit; lung alveolus; lung injury; oxidative stress; pathologic process; polymerization; respiratory epithelium; tissue /cell culture

DESCRIPTION (provided by applicant): Acute lung injury (ALI) affects more than 200,000 patients in the U.S. each year and is an important cause of morbidity and mortality in hospitalized patients. Our work has shown that Fas-dependent pathways are active in the lungs of patients with ALI, and that stimulation of Fas-dependent pathways causes epithelial apoptosis and inflammation in the lungs of rabbits and mice. Published data and our preliminary studies show that chronic stimulation of Fas-dependent pathways leads to lung fibrosis. The major goal of this proposal is to determine the mechanisms linking activation of the Fas/FasL system in the lungs with the development of lung injury. The main hypothesis is that the Fas/FasL system plays an essential role in the pathogenesis of acute lung injury in mice, by a mechanism involving both apoptosis of alveolar epithelial cells, and activation of an apoptosis-independent transcriptional response in the alveolar epithelium. This hypothesis will be tested with the following specific aims: Aim 1: Determine the importance of apoptosis of alveolar epithelial cells in the development of acute lung injury in vivo. Aim 2: Determine how inhibition of apoptosis alters the transcriptional response to Fas activation in primary alveolar epithelial cells. Aim 3: Determine the factors that modulate the bioactivity of soluble Fas ligand in the lungs. Experimental approach: Murine models of lung injury and culture of lung epithelial cells will be used to address the specific aims, taking advantage of transgenic mice with specific gene deficiencies. Importance of the Results. The results of these studies will fill important gaps in our understanding of the link between epithelial apoptosis and fibrosis in the lungs of patients with acute lung injury, and could lead to novel new treatments to reduce pulmonary dysfunction and improve outcome for critically ill patients. Relevance for public Health: This study will help us understand the mechanisms that result in respiratory failure in patients who are critically ill. In addition, we will investigate the potential treatments that will facilitate the repair of injured lungs.

描述（由申请人提供）：在美国，急性肺损伤 (ALI) 每年影响超过 200,000 名患者，是住院患者发病和死亡的重要原因。我们的工作表明，Fas 依赖性途径在 ALI 患者的肺部活跃，并且 Fas 依赖性途径的刺激会导致兔子和小鼠肺部上皮细胞凋亡和炎症。已发表的数据和我们的初步研究表明，长期刺激 Fas 依赖性途径会导致肺纤维化。该提案的主要目标是确定肺部 Fas/FasL 系统激活与肺损伤发生之间的联系机制。主要假设是 Fas/FasL 系统在小鼠急性肺损伤的发病机制中发挥着重要作用，其机制涉及肺泡上皮细胞的凋亡和肺泡上皮细胞中不依赖于凋亡的转录反应的激活。该假设将通过以下具体目标进行检验： 目标 1：确定肺泡上皮细胞凋亡在体内急性肺损伤发展中的重要性。目标 2：确定细胞凋亡的抑制如何改变原代肺泡上皮细胞对 Fas 激活的转录反应。目标 3：确定调节肺部可溶性 Fas 配体生物活性的因素。实验方法：利用具有特定基因缺陷的转基因小鼠，采用肺损伤小鼠模型和肺上皮细胞培养来实现特定目标。结果的重要性。这些研究的结果将填补我们对急性肺损伤患者肺部上皮细胞凋亡和纤维化之间联系的理解的重要空白，并可能带来新的治疗方法来减少肺功能障碍并改善危重患者的预后。与公共卫生的相关性：这项研究将帮助我们了解导致危重患者呼吸衰竭的机制。此外，我们将研究有助于修复受损肺部的潜在治疗方法。