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

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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.