We request support for investigations aimed at understanding the pathogenesis and pathophysiology of pulmonary edema and lung injury and developing diagnostic tools and therapies which will improve the care of patients with ARDS. Proposed studies will address the cell biology, immunology, biochemistry, morphology and physiology of lung injury in several laboratory models and in patients. We will study the pathogenesis of lung injury produced by endotoxin, hyperoxia and irradiation. We propose that endothelial injury is an initial event common to these forms of lung injury and that the resulting alterations in endothelial structure or function trigger an inflammatory response which compounds the injury. The direct endothelial injury is postulated to involve toxic oxygen metabolites, proteinase/antiproteinase imbalance and alterations in endothelial cyclic nucleotide metabolism. We suggest that neutrophols, lymphocytes and macrophages participate in the response by directly affecting lung cells and by altering cell-cell interactions through humoral mediators, including eicosanoids and platelet activating factor (PAF). Production of mediators by endothelial cells may also alter their communications with inflammatory cells. These hypotheses will be investigated in sheep and in in vitro preparations in which the same insults are studied and the two kinds of information integrated. In isolated lungs and animals, we will study physical factors affecting normal and abnormal lung fluid balance and vascular function. We will develop methods for on-line measurements of pulmonary vascular functions, including permeability and free radical generation and test those methods in animals with the goal of applying them to humans. In humans undergoing hemodialysis and humans with ARDS, we will further investigate single pass indicator methods as tools for understanding lung dysfunction and predicting outcome; and we will conduct clinical trials of novel pharmacologic therapies. In patients with ARDS, we will determine the role of reversible bronchoconstriction in gas exchange and investigate the mechanics of interactions of patients with mechanical ventilators in order to develop improved ventilator therapy. This program will provide information spanning a spectrum from basic investigations to clinical studies which will provide new insights into mechanisms of lung failure and new approaches to prevention and therapy in patients with diffuse lung injury.
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