We request two years additional support for a SCOR in Pulmonary Vascular Diseases focused on studies of the pathogenesis and pathophysiology of acute lung injury in experimental models and in humans. Our goal is to develop and test new pharmacologic interventions for the treatment or cure of the adult respiratory distress syndrome (ARDS) in humans. We will use techniques of physiology, pathology, biochemistry, engineering, and molecular biology in a group of highly integrated laboratory and clinical projects. During these two years, we propose to determine the roles of the cytokines, endothelin and tumor necrosis factor alpha (TNF), in mediating endotoxin induced injury, to test the efficacy of a polyclonal antiTNF antiserum in an animal model of endotoxemia, and to investigate the hypothesis that generation of cytokines in this model is a consequence of oxidant stress. Further, we will determine whether production of cytokines is modulated by prostanoids in the endotoxin response. In an animal model of inflammation-related persistent pulmonary hypertension, we will determine the role of endothelin as a mediator and of alterations in elastin metabolism in the transition between acute lung injury and remodeling of the pulmonary vasculature. We will use indicator dilution and external scanning methods, coupled with sophisticated transport theory, to determine the pathophysiology of microcirculatory changes consequent to diffuse lung injury and to develop methods which can be applied in the clinical setting to measure physiologic variables which are related to severity and course of ARDS. In humans with ARDS, we will determine the effects of administration of the antioxidant, n-acetylcysteine, on the pathophysiology of lung dysfunction and on biochemical responses. The five projects will be supported by five core units which will consolidate measurements and procedures common to the several projects. This proposal requests continuation of currently supported projects and cores, and contains no request for support of new projects, cores, or responsible investigators. We propose new and exciting directions for the projects which promise to impact on the human syndrome.
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