EXTRACELLULAR SUPEROXIDE DISMUTASE IN PULMONARY FIBROSIS

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Interstitial pulmonary fibrosis is a potentially lethal, chronic response to lung injury. Although the biochemical mechanisms involved in the pathogenesis of interstitial pulmonary fibrosis are poorly understood, reactive oxygen species, which are known to play a role in inflammatory reactions, are believed to be involved in the progression of this disease. It has been proposed that the antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), can protect against the progression of pulmonary fibrosis. To test the hypothesis that EC-SOD plays a central role in this disease, transgenic mice that overexpress EC-SOD and knockout mice that do not express EC-SOD will be utilized in a model of bleomycin- induced pulmonary fibrosis. We will determine whether altered levels of EC-SOD in transgenic and knockout mice alters the response to bleomycin-induced lung injury. In addition, we will examine EC-SOD expression and1or biodistribution during the early stages of fibrotic injury, to determine if alterations in EC-SOD activity early in the development of the disease are critical to the pathogenesis of pulmonary fibrosis. Finally, we will examine the interactive effects of nitric oxide, superoxide and EC-SOD in our model to determine if nitric oxide is involved in the oxidative damage associated with pulmonary fibrosis.