The overall goal of this project is to characterize the cellular, biochemical, and physiologic mechanisms of lung injury after irradiation in sheep and to identify potentially useful interventions which may prevent the injury. We postulate that radiation causes a direct, free radical mediated injury of lung tissue and that this injury is compounded by the resulting inflammation, including humoral and cellular responses. To test these hypotheses, we will conduct studies in sheep where thoracic irradiation causes an immediate response and, after several weeks, radiation pneumonitis typical of the clinical syndrome. We will measure effects of radiation exposure on lung tissue antioxidant capacity and determine the effects of exogenous (n-acetylcysteine, allopurinol) and endogenous (endotoxin, hyperoxia) enhancement of lung antioxidant capacity on the response. We will determine the effects of severe granulocyte depletion on the radiation response in order to establish the role of acute inflammation. We will measure release of eicosanoids and platelet activating factor in the lungs after thoracic irradiation and collect lymphocytes and alveolar macrophages for in vitro measurements of lipid mediator production. We will determine effects of inhibitors of eicosanoids or platelet activating factor on radiation induced lung injury. We will measure trafficking of granulocytes, macrophages ad lymphocytes in lung tissue, blood and lung lymph after irradiation from the time of exposure to development of radiation pneumonitis and determine in vitro responses of lymphocytes during that period. We will determine whether interventions which alter the immediate radiation response affect the later development of radiation pneumonitis. The chronic sheep model which we will use permits assessment of lung function, serial biopsies for studies of lung structure and collection of blood, lung lymph and bronchoalveolar lavage specimens for measurements of mediators and isolation of cells. The studies will permit integration of physiological, structural, immunological and biochemical data collected in the same preparation in an effort to explain the pathogenesis of responses of the lungs to radiation, both acute responses and the delayed radiation pneumonitis. The studies will provide new insights into mechanisms of radiation injury to the lungs, serve as a basis for generalizations about responses of the lungs to oxidant injury and identify promising directions for development of therapies which may prevent radiation injury in humans.
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