The overall objective of this renewal application is to determine the mechanisms that impair the resolution of clinical acute lung injury. Pulmonary edema fluid and plasma obtained from patients with early acute lung injury will be used to carry out these clinical studies. The proposed studies are based on results obtained during the current funding period, namely that alveolar fluid clearance is impaired in the majority of patients with clinical acute lung injury.
Aim 1 is designed to determine if biochemical evidence of injury to the alveolar epithelium is associated with impaired alveolar fluid clearance and worse clinical outcomes in patients with acute lung injury. The hypothesis will be tested that alveolar fluid clearance is abnormal in patients with acute lung injury because of injury to alveolar epithelial type I or type II cells by measuring concentrations of type I and type II cell-specific proteins.
In aim 2, the hypothesis will be tested that alveolar epithelial oxidant injury from reactive oxygen species, as reflected by elevated levels of nitrite and nitrate in the pulmonary edema fluid and plasma of patients with acute lung injury, will be associated with decreased alveolar fluid clearance and worse clinical outcomes. Since there is convincing evidence in vivo that plasminogen-activator inhibitor-1 (PAI-1), an inhibitor of fibrinolytic activity, impairs the resolution of experimental lung injury, aim 3 will focus on the relationship of PAI-1 to impaired alveolar fluid clearance, the duration of mechanical ventilation and mortality in patients with acute lung injury. The objective will be to determine the biological and prognostic significance of elevated concentrations of PAI-1 in pulmonary edema fluid and plasma obtained from patients with acute lung injury and the relationship of PAI-1 to impaired alveolar fluid clearance, a longer duration of mechanical ventilation, and a higher mortality. The studies in aim 3 will be closely integrated with the studies in aims 1 and 2 to discover new mechanisms that link alveolar epithelial injury to impaired fluid transport and the development of fibroproliferative response in the lung. Attention will be given to what is required to carry out systematic, well-controlled clinical studies with adequate attention to clinical variables, selection of patients for the studies, control patients with hydrostatic pulmonary edema, as well as statistical considerations.
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