Based on the evident importance of alveolar epithelial and endothelial function in pathogenesis of acute lung injury, the applicants propose to use practical, well validated methods to study the pathogenic contribution of both the alveolar epithelial and lung endothelial barriers in clinical acute lung injury. The methods for measuring alveolar barrier function and assessing endothelial and epithelial barrier injury may provide meaningful pathogenic and prognostic indicators early in the course of clinical acute lung injury. These prognostic indicators may provide rational guidelines for stratifying patients for clinical trials of new therapeutic agents that can be directed primarily at attenuating lung or alveolar epithelial injury. The first specific aim of this proposal will test the hypothesis that the ability of the alveolar epithelial barrier to remove excess alveolar fluid in the early phase of acute lung injury is a critical determinant of recovery from acute lung injury. The second objective of the study will test the hypothesis that the concentration of markers of both endothelial and epithelial injury in alveolar edema fluid (and plasma) will provide insights into the relative contributions of the endothelial and epithelial injury to the pathogenesis of human acute lung injury. The study design enables data collection to begin early in the course of acute lung injury. Data analysis will attempt to identify the impact of changes in independent variables: alveolar epithelial function (concentrating ability) and indices of epithelial/endothelial injury) and predefined outcomes including improvement (50 percent improvement in the acute lung injury (ALI) score) and survival to discharge.
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