Although the pathogenesis of ARDS has been extensively studied the cellular and molecular events that lead to the acute lung injury in humams are not yet sufficiently defined to allow us either to predict who will develop ARDS or how to treat it. We propose to study patients at risk for developing ARDS and patients with well-established ARDS to understand better the pathogenesis and resolution of the acute lung injury. Based on available ARDS patient data and in vivo and in vitro data from animal models of acute lung injury, we hypothesize that the development of ARDS is the result of synergism between two or more leukocyte stimulating factors and that the propagation of the acute lung injury is dependent on the neutrophil. We specifically propose that endotoxin may cause neutrophil sequestration in the lungs and the stimulation of alveolar macrophages to produce chemotactic factors for neutrophils. Concommitant activation of complement could enhance neutrophil sequestration and, with the alveolar macrophage derived chemotactic factors, could cause neutrophil migration into the alveoli. The combination of LPS and chemotactic factors results in enhanced release of porteases, oxidants, and lipid inflammatory mediators from neutrophils which could both further recruit neutrophils and cause alveolar damage. Variation in cellular responsiveness to endotoxin could enhance or quench this cascade. The disappearance of complement fragments and endotoxin from the systemic circulation would halt the cascade and allow for the early fibroblast and the early and late type II cell proliferation. If allowed to proceed unhampered the repair process may restore normal lung architecture. The specific questions which will be answered include (a) Can the development of ARDS be predicted based on the presence of complement fragments and endotoxin in plasma and/or peripheral cellular responsiveness to endotoxin? (b) Which inflammatory mediators are present in ARDS and do their relative amounts relate to circulating levels of complement and endotoxin? (c) How is the repair phase of the acute lung injury initiated, and what factors influence the outcome of the repair process? The answers to these questions will provide us with a better understanding of the pathogenesis and resolution of ARDS and of how and when to direct therapeutic modalities.
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