Despite progress in the last decade in understanding the basic pathogenetic mechanisms of acute lung injury and the acute respiratory distress syndrome (ALVARDS), fundamental questions remain unanswered and disease specific treatments are lacking. Experimental and clinical studies have established that intact alveolar fluid clearance is important to the resolution of ALI/ARDS. However, preliminary clinical studies indicate that less than half of ALI/ARDS patients have intact alveolar fluid clearance. The overall goal of the proposal is to study the mechanisms that regulate alveolar fluid clearance in ALVARDS. Strial samples of plasma and pulmonary edema fluid will be obtained from 375 patients with ALVARDS and 125 control patients with hydrostatic pulmonary edema. The rate of alveolar epithelial fluid clearance will be calculated from the rise in protein concentration in pulmonary edema fluid over time. The first goal (Aim 1) is to determine the mechanisms that impair alveolar fluid clearance in ALI/ARDS by measuring biological markers of lung epithelial and endothelial injury in the pulmonary edema fluid. Markers of specific mediators of injury such as reactive nitrogen-oxygen species will also be measured. Since the relative contributions of alveolar epithelial and lung endothelial injury to the overall severity of acute lung injury are not well understood, the prognostic value of these markers will also be investigated. The second goal (Aim 2) is to study soluble factors in the pulmonary edema fluid that can alter the rate of alveolar fluid clearance in the in situ mouse lung and the ex vivo human lung in the absence of alveolar epithelial injury. The studies proposed in this application will provide new and valuable insights into the pathogenesis of clinical acute lung injury, by applying innovative methods to the study of alveolar epithelial integrity and function and focusing on determinants of the resolution of acute lung injury, a potential new therapeutic target. In addition, the proposed studies will prepare the principal investigator for a career as an independent investigator in academic medicine. The training outlined in this proposal includes excellent mentoring, a rich scientific environment, and a curriculum of formal coursework in biostatistics, study design and scientific writing. The studies proposed are innovative, novel and hypothesis-driven and are designed to develop an independent research focus for the trainee. Combined with a compelling research project, the training will -provide the skills necessary for a successful career in biomedical research.
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