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

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 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.