The role of common genetic variation in the Fas pathway in acute lung injury

描述(由申请人提供)：有几个明确定义的危险因素导致重症患者发生急性肺损伤(ALI)，包括败血症、肺炎和创伤。然而，关于ALI发生的易感性因素以及相关的不良结局，如多器官系统衰竭和死亡，目前还没有完全的了解。越来越多的文献表明，炎症和细胞凋亡途径的失调在ALI的发生发展中起着重要作用。特别是，Fas/FasL通路被认为是免疫反应的重要调节因子，参与了ALI患者肺组织的炎症和肺泡上皮细胞凋亡。动物研究表明，Fas/FasL途径的激活导致早期炎症、肺泡上皮细胞凋亡和纤维化，人类研究表明ALI患者的不良结局与血浆和支气管肺泡灌洗液中可溶性FasL水平的升高有关。这些结果表明，影响Fas/FasL系统功能的基因变异可能影响ALI的易感性和相关死亡率。本研究的目的是：1)研究危重病患者中常见的Fas/Fas配体(FasL)通路基因变异与ALI易感性之间的关系；2)确定Fas/FasL通路基因多态性对ALI患者血浆中基因产物和炎症标志物水平的影响；3)确定Fas体外刺激后外周血单核细胞Fas/FasL通路基因变异的功能意义。急性肺损伤是一种严重的肺功能障碍综合征，约占重症监护病房入院人数的7%，在美国每年导致7.4万人死亡。ALI的病因仍然知之甚少，阻碍了有效治疗方法的发展。深入了解调节细胞死亡和炎症的Fas/FasL通路中常见的基因变异对ALI发生发展的影响，将为ALI的发病机制提供重要的信息，并可能为ALI的治疗提供新的方法。 公共卫生相关性：急性肺损伤(ALI)是一种严重的肺功能障碍综合征，在美国每年导致约7%的重症监护病房入院并导致7.4万人死亡。ALI的病因仍然知之甚少，阻碍了有效治疗方法的发展。深入了解调节细胞死亡和炎症的Fas/FasL通路中常见的基因变异对ALI发生发展的影响，将为ALI的发病机制提供重要的信息，并可能为ALI的治疗提供新的方法。

DESCRIPTION (provided by applicant): There are several clearly defined risk factors for the development of acute lung injury (ALI) in critically ill patients including sepsis, pneumonia and trauma. However, there remains incomplete understanding regarding the factors that alter susceptibility to the development of ALI and related poor outcomes such as multi-organ system failure and death. A growing body of literature implicates the dysregulation of inflammation and apoptotic pathways in the development of ALI. In particular, the Fas/FasL pathway, known to be an important modulator of the immune response, has been implicated in the inflammation and alveolar epithelial cell apoptosis observed in the lungs of patients with ALI. Animal studies have demonstrated that activation of the Fas/FasL pathway in the lung leads to early inflammation, alveolar epithelial apoptosis and fibrosis and human studies have shown that adverse outcomes in patients with ALI are associated with increased plasma and bronchoalveolar lavage fluid levels of soluble FasL. These findings suggest that genetic variation affecting the function of the Fas/FasL system could influence susceptibility to ALI and related mortality. The aims of this proposal are to: 1) characterize associations between common genetic variation in the Fas/Fas ligand (FasL) pathway and susceptibility to ALI in a cohort of critically ill patients, 2) determine the effect of genetic polymorphisms in the Fas/FasL pathway on the plasma levels of gene products and markers of inflammation in patients with ALI, and 3) determine the functional significance of genetic variants in the Fas/FasL pathway in peripheral monocytes after Fas stimulation in vitro. Acute Lung Injury is a syndrome of severe lung dysfunction which complicates approximately 7% of intensive care unit admissions and accounts for 74,000 deaths annually in the US. The causes of ALI remain poorly understood, preventing the development of effective therapies. A better understanding of the impact of common genetic variation in the Fas/FasL pathway, which regulates cell death and inflammation, on the development of ALI would provide important information regarding causal mechanisms of ALI and could lead to new therapies for ALI. PUBLIC HEALTH RELEVANCE: Acute lung injury (ALI) is a syndrome of severe lung dysfunction which complicates approximately 7% of intensive care unit admissions and accounts for 74,000 deaths annually in the US. The causes of ALI remain poorly understood, preventing the development of effective therapies. A better understanding of the impact of common genetic variation in the Fas/FasL pathway, which regulates cell death and inflammation, on the development of ALI would provide important information regarding causal mechanisms of ALI and could lead to new therapies for ALI.