"The alveolar epithelium in lung injury and repair"

描述(申请人提供)：急性肺损伤(ALI)在美国每年影响20多万名患者，是住院患者发病率和死亡率的重要原因。我们的工作表明，在ALI患者的肺中，Fas依赖的通路是活跃的，刺激Fas依赖的通路会导致兔和小鼠肺上皮细胞的凋亡和炎症。已发表的数据和我们的初步研究表明，慢性刺激Fas依赖的通路会导致肺纤维化。本研究的主要目的是确定肺内Fas/FasL系统激活与肺损伤发生发展之间的联系机制。主要的假说是Fas/FasL系统在小鼠急性肺损伤的发病机制中发挥了重要作用，其机制既涉及肺泡上皮细胞的凋亡，也涉及肺泡上皮细胞中不依赖于凋亡的转录反应的激活。这一假说将通过以下具体目标进行验证：目的1：确定肺泡上皮细胞凋亡在体内急性肺损伤发生发展中的重要性。目的：研究细胞凋亡抑制如何改变原代肺泡上皮细胞对Fas活化的转录反应。目的3：确定调节肺组织中可溶性Fas配体生物活性的因素。实验方法：将利用小鼠肺损伤模型和肺上皮细胞培养来解决特定的目的，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上皮细胞凋亡与纤维化之间联系的了解的重要空白，并可能导致减少肺功能障碍和改善危重患者预后的新的治疗方法。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，我们还将研究促进肺损伤修复的潜在治疗方法。

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.