Regulation of Hypoxia Inducible Factor -1a in Alveolar Epithelial Cells in Lung Contusion

 描述（由申请人提供）： 肺挫伤（LC）是机动车事故和爆炸伤受害者常见的伤害。它也是发生 ALI、ARDS 和呼吸机相关肺炎的独立危险因素。 LC 在生理上最相关的后果是缺氧。我们实验室最近的工作表明，HIF1a 调节尤其是 II 型肺泡上皮细胞中的 HIF1a 调节是 LC 后 lng 损伤和炎症的发病机制。当前的提案包括三个具体目标。具体目标 1 包括 LC 中 HIF-1a 的表征以及它如何调节缺氧细胞的命运。此外，还将评估 HIF-2a 的作用。具体目标 2 评估 HIF-1a 以及与 IL-1ß 的相互作用在 LC 中性粒细胞聚集和激活的发病机制中的作用。提议对 IL-1ß 启动子决定簇以及琥珀酸和炎性小体在 IL-1ß 激活中的作用进行研究。具体目标 3 检查 HIF-1a 在肺表面活性物质调节中的作用。将对 HIF1a 下调对表面活性剂 II 型 AEC 的影响进行详细的定性和定量分析。目的包括研究 AEC 中继发于 HIF 活性的表面活性蛋白 C 的表达和调节。这种新的、与现状有本质不同的改变改变了急性炎症反应，从而使 LC 进展为 ALI/ARDS，为危重创伤患者的治疗开辟了具体目标。

 DESCRIPTION (provided by applicant): Lung contusion (LC) is a common injury sustained by victims of motor vehicular accidents and blast trauma. It is also an independent risk factor for the development of ALI, ARDS and Ventilator Associated Pneumonia. The most physiologically relevant consequence of LC is hypoxia. Recent work in our laboratory has indicated that HIF1a regulation especially in type II alveolar epithelial cells is responsible for the pathogenesis of lng injury and inflammation following LC. The current proposal includes three specific aims. Specific aim 1 includes characterization of HIF-1a in LC and how it regulates the fate of hypoxic cells. Additionally the role of HIF-2 a will be evaluated. Specific Aim 2 evaluates the role of HIF-1a and interaction with IL-1ß in the pathogenesis of neutrophil aggregation and activation in LC. A study of promoter determinants of IL-1ß and the role of succinate and inflammasome in activation of IL-1ß is proposed. Specific aim 3 examines the role of HIF-1a in regulation of pulmonary surfactant. Detailed qualitative and quantitative analyses of the effect of HIF1a down regulation on type II AEC on surfactant will be performed. The aim includes studies of expression and regulation of Surfactant protein C secondary to HIF activity in AEC. This new and substantively different departure from the status quo for altering the acute inflammatory response and thereby the progression of LC to ALI/ARDS opens specific targets for therapy in the care of the critically ill trauma patients.