The goal of the renewal application continues to be the understanding of the pathogenesis of non-cardiac pulmonary edema that occurs after insults elsewhere in the body (e.g. sepsis or non-thoracic trauma and shock). Two major hypothesis will be studied. The first is that indirect lung microvascular injury is mediated by formed elements of the blood, i.e. is blood-borne. The second is that many elements of what is commonly called the """"""""acute inflammatory response"""""""" combine to cause changes characteristic of acute lung injury. The performance of repeated limited bronchoalveolar lavage in patients who are at high risk for the adult respiratory distress syndrome (ARDS), in those who have the acute syndrome, and in those who are resolving the syndrome is central to the investigation of these hypotheses. Lavage fluid will be fractionated and components examined for the presence of mediators of cellular activation, for surfactant activity, and for acute phase proteins. Results of these studies will be correlated with clinical variables collected simultaneously. Mechanisms of lung injury in animals and in isolated perfused lungs will be investigated concurrently. Potential mediators of endotoxin-induced lung injury including the cytokines interleukin l and tumor necrosis factor, leukotrienes, and platelet activating factor will be assayed for. In vitro studies using purified mediators and cultured cells will look at cell to cell interactions in up-regulating and down-regulating cellular injury and the acute inflammatory response. Animal models and in vitro systems have been specifically chosen to study aspects that cannot be well-defined in humans, e.g., ultrastructural morphology and biology of limited injury, mechanisms of resolution and structural reorganization, and inter-organ interactions.
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