This application is for a Program Project Grant to evaluate the pathogenesis and rapair of acute lung injury. Emphasis is to be placed on evaluating the role of exposure to high oxygen tensions in initiating or aggravating the course of acute lung injury. Two core units and six projects are proposed. The core units include (1) an Administrative Core and (2) a Pathology Core. Project 1 will involve morphometric, physiologic, radiologic and pharmacologic studies on a baboon model of oxygen-induced lung injury. Comparison of results obtained in the baboon with those found to occur in humans will help define those components of acute respiratory failure which are related to oxygen induced lung injury. Project 2 will study the patterns of distribution of the superoxide dismutase enzymes at cellular and subcellular levels using immunocytochemistry. Project 3 will study the response of cultured cells and animals to antioxidant stress following augmentation of cellular oxygen defenses using liposome-entrapped antioxidant enzymes. Project 4 will use both biochemical studies and three dimensional computer aided reconstruction of lung cells to define their ontogeny and their response to acute injury. Project 5 will characterize the repair of 02-induced lung injury in morphologic, biochemical and physiologic terms, and will investigate factors and mechanisms which can modulate the repair process. Project 6 will utilize near infrared optical monitoring (NIROS-Scopy) to noninvasively assess the oxidation state of cytochrome c oxidase in brain and skeletal muscle mitochondria. Developmental studies using animal models will be followed by measurements of distribution of organ blood flow and tissue oxygen sufficiency in patients. This will ultimately provide a rapid feedback on effects of treatment modalities being used in patients with Acute Respiratory Failure. The overall rationale for this Program Project Grant involves the application of multidisciplinary techniques to study basic mechanisms of oxygen-induced lung injury in small animals and then to apply these studies to primate models and to humans. The results will help define methods to minimize oxygen therapy in humans and to pharmacologically reduce the toxic effects when high levels of oxygen must be used in the treatment of acute lung injury.
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