"The alveolar epithelium in lung injury and repair"

描述（由申请人提供）：急性肺损伤（ALI）每年影响美国超过200，000例患者，是住院患者发病率和死亡率的重要原因。我们的工作表明，Fas依赖性途径在ALI患者的肺中是活跃的，并且Fas依赖性途径的刺激导致兔和小鼠肺中的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，Fas依赖性通路的慢性刺激导致肺纤维化。该提案的主要目标是确定连接肺中Fas/FasL系统的激活与肺损伤的发展的机制。主要假设是Fas/FasL系统在小鼠急性肺损伤的发病机制中起重要作用，其机制涉及肺泡上皮细胞的凋亡和肺泡上皮细胞中的非凋亡依赖性转录应答的激活。这一假设将与以下具体目标进行测试：目的1：确定肺泡上皮细胞凋亡在体内急性肺损伤的发展中的重要性。目的2：确定细胞凋亡的抑制如何改变原代肺泡上皮细胞Fas激活的转录反应。目的3：探讨肺组织可溶性Fas配体活性的调节因素。实验方法：肺损伤的小鼠模型和肺上皮细胞的培养将用于解决特定的目标，利用具有特定基因缺陷的转基因小鼠。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，并可能导致新的治疗方法，以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。

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.