Mechanisms of alveolar epithelial apoptosis during acute lung injury

急性肺损伤时肺泡上皮细胞凋亡的机制

• 批准号: 7435397
• 负责人: NAVDEEP S CHANDEL
• 金额: $ 33.86万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7435397
• 关键词: Acids; Acute Lung Injury; Adenoviruses; Adult Respiratory Distress Syndrome; Alveolar; Animal Model; Animals; Apoptosis; Apoptotic; Aspiration Pneumonia; Caspase; Cell Death; Cells; Cessation of life; Clinical; Cysteine Protease; Development; Edema; Electroporation; Epithelial; Epithelial Cells; Event; Exposure to; Family; Fibrin; Floods; Genes; Genetic; Hour; Hyperoxia; Hypoxemia; Inflammation; Inflammatory; Laboratories; Lead; Ligand Binding; Liquid substance; Mitochondria; Modeling; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Rattus; Respiratory Failure; Risk; Sepsis; Shunt Device; Stimulus; Syndrome; Trauma; alveolar epithelium; caspase-3; caspase-8; caspase-9; cytochrome c; day; insight; lung injury; novel therapeutics; prevent; receptor

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.

患者暴露在损害性刺激下会发生急性肺损伤。急性肺损伤是一种临床综合征，其特征是空域泛滥，并发展为肺内分流，导致低氧性呼吸衰竭。肺泡上皮是防止肺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发病的重要机制之一。常用的肺损伤实验室模型是高氧血症(95%-100%O2)。高氧可引起动物3天内肺泡上皮细胞死亡、水肿、炎症和死亡。凋亡途径是由半胱氨酸蛋白酶家族半胱氨酸酶执行的。肺泡上皮细胞可通过线粒体途径或受体依赖途径激活caspase。然而，目前尚不清楚这两种凋亡途径是否在 发生急性肺损伤。此外，通过死亡受体或线粒体依赖途径启动细胞凋亡后抑制caspase是否可以防止细胞死亡和保护肺泡上皮细胞的功能尚不清楚。我们推测，细胞凋亡导致的肺泡上皮细胞的丧失是与高氧相关的病理过程中的始动事件。这一应用的重点是确定线粒体或受体依赖的途径是否调节高氧诱导的肺损伤。此外，我们还将研究抑制caspase激活的基因策略在高氧期间预防肺损伤和保护上皮功能方面的有效性。总的来说，这些研究将为急性肺损伤的机制提供重要的见解，并可能导致 开发新的治疗策略，既适用于已确诊的ARDS患者，也适用于那些有发展ARDS风险的患者。