Mechanisms of alveolar epithelial apoptosis during acute lung injury

患者在暴露于有害刺激后发生急性肺损伤。急性肺损伤是一种临床综合征，其特征是肺内分流导致低氧性呼吸衰竭。肺泡上皮是防止水肿和肺内分流形成的主要屏障。近年来的研究表明，细胞凋亡可能是急性肺损伤的重要发病机制。肺损伤的常用实验室模型是高氧（95%-100%O2）。高氧导致肺泡上皮细胞死亡、水肿、炎症和动物在3天内死亡。凋亡途径由半胱氨酸蛋白酶家族（caspase）执行。肺泡上皮细胞可以通过线粒体或受体依赖性途径活化半胱天冬酶。然而，尚不清楚细胞凋亡途径中的任一个在细胞凋亡中是否重要。 急性肺损伤的发展。此外，还不清楚通过死亡受体或线粒体依赖性途径启动凋亡后的半胱天冬酶抑制是否可以防止细胞死亡并保护肺泡上皮细胞的功能。我们推测，肺泡上皮细胞的损失，由于凋亡是一个起始事件的病理与高氧。本申请的重点是确定线粒体或受体依赖性途径是否调节高氧诱导的肺损伤。此外，我们将研究遗传策略抑制半胱天冬酶激活在防止肺损伤和保护高氧期间上皮功能方面的功效。总的来说，这些研究将为了解急性肺损伤的潜在机制提供重要的见解，并可能导致 为已确诊的ARDS患者和有发展为ARDS风险的患者开发新的治疗策略。

Patients develop acute lung injury upon exposure to an injurious stimulus. Acute lung injury is a clinical syndrome characterized by airspace flooding with the development of an intrapulmonary shunt resulting in hypoxemic respiratory failure. The alveolar epithelium is the primary barrier preventing the formation of edema and intrapulmonary shunt. Recent studies have indicated that apoptosis may be an important mechanism underlying the pathogenesis of acute lung injury. A commonly used laboratory model of lung injury is hyperoxia (95%-100% O2). Hyperoxia causes alveolar epithelial cell death, edema, inflammation and death of the animal within 3 days. The apoptotic pathway is executed by caspases, a family of cysteine proteases. Alveolar epithelial cells can undergo activate caspases through either a mitochondrial or a receptor dependent pathway. However, it is not known whether either apoptotic pathway is important in the development of acute lung injury. Furthermore, it is unclear whether caspase inhibition following the initiation of apoptosis through either a death receptor or mitochondrial dependent pathway can prevent cell death and preserve the function of alveolar epithelial cells. We hypothesize that the loss of alveolar epithelial cells due to apoptosis is an initiating event in the pathology associated with hyperoxia. The focus of this application is to determine whether mitochondrial or receptor dependent pathways regulate hyperoxia induced lung injury. In addition we will examine the efficacy of genetic strategies to inhibit caspase activation in preventing lung injury and preserving epithelial function during hyperoxia. Collectively these studies will provide important insight into the mechanisms underlying acute lung injury and may lead to the development of novel therapeutic strategies both for patients with established ARDS and those at risk for developing ARDS.