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

描述（由申请方提供）：危重患者发生急性肺损伤（ALI）有几个明确定义的风险因素，包括败血症、肺炎和创伤。然而，关于改变ALI发展的易感性和相关不良结局（如多器官系统衰竭和死亡）的因素，仍有不完全的了解。越来越多的文献表明炎症和凋亡通路的失调与ALI的发生有关。特别是，Fas/FasL途径，已知是免疫应答的重要调节剂，已经涉及在ALI患者的肺中观察到的炎症和肺泡上皮细胞凋亡。动物研究表明，肺中Fas/FasL通路的激活导致早期炎症、肺泡上皮细胞凋亡和纤维化，人体研究表明，ALI患者的不良结局与可溶性FasL的血浆和支气管肺泡灌洗液水平升高相关。这些发现表明，影响Fas/FasL系统功能的遗传变异可能会影响ALI的易感性和相关死亡率。这项建议的目的是：1）表征一组危重患者中Fas/Fas配体（FasL）途径中的常见遗传变异与对ALI的易感性之间的关联，2）确定在患有ALI的患者中Fas/FasL途径中的遗传多态性对基因产物和炎症标志物的血浆水平的影响，和3）确定体外Fas刺激后外周单核细胞中Fas/FasL途径中遗传变体的功能意义。急性肺损伤是严重肺功能障碍的综合征，其使约7%的重症监护室入院复杂化，并且在美国每年造成74，000例死亡。ALI的病因仍然知之甚少，阻碍了有效治疗方法的发展。更好地了解Fas/FasL通路（调节细胞死亡和炎症）中常见遗传变异对ALI发展的影响，将提供有关ALI因果机制的重要信息，并可能导致ALI的新疗法。 公共卫生相关性：急性肺损伤（ALI）是严重肺功能障碍的综合征，其使大约7%的重症监护病房入院复杂化，并且在美国每年造成74，000例死亡。ALI的病因仍然知之甚少，阻碍了有效治疗方法的发展。更好地了解Fas/FasL通路（调节细胞死亡和炎症）中常见遗传变异对ALI发展的影响，将提供有关ALI因果机制的重要信息，并可能导致ALI的新疗法。

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.