In this project, we will examine the hypothesis that persistent pulmonary hypertension develops in association with inflammation of the lungs. This development is due to generation and release of toxic oxygen metabolites by activated neutrophils sequestered in the lungs resulting in release of vasoconstrictor lipid mediators (eicosanoids or platelet activating factor). We will combine physiological , morphological and biochemical techniques to characterize responses of the pulmonary circulation to thoracic irradiation, chronic air embolization and repeated intravenous infusions of endotoxin. Physiologic measurements will include pulmonary hemodynamics and gas exchange as well as assessment of the response of the pulmonary circulation to hyperoxia, hypoxia and the potent vasoconstrictor, PGH2-A (the 9-methylene cyclic ether analog of PGH2). Morphological studies will be conducted on lung biopsy tissue taken at baseline and at weekly or two weekly periods following the beginning of each intervention; in addition, the heart and lungs will be studied postmortem. Biochemical measurements will include lung tissue concentrations of antioxidant enzymes at baseline and over the course of the experiment; and measurement of lung lymph and blood plasma concentrations of eicosanoid metabolites, platelet activating factor and conjugated dienes. The oxygen metabolite hypothesis will be tested by determining the effects of the free radical scavenger, N-acetyl cysteine, and the xanthine oxidase inhibitor, allopurinol, on the responses of the lungs' circulation to chronic inflammation. Animals will also be studied following granulocyte depletion to determine whether neutrophils are essential to the pulmonary hypertensive response and to determine whether neutrophils are responsible for generation lipid mediators in the models to be studied. Effects of 5- lipoxygenase inhibitors (e.g., L-651, 39.2-00N10) and leukotriene receptor antagonists (e.g., FLP 55712) will be studied to determine whether lipoxygenase products participate in the pathogenesis of the response. These studies will elucidate the pathophysiology and pathogenesis of chronic pulmonary hypertension resulting from diffuse lung inflammation and will provide rationales for pharmacologic interventions which may prevent or reverse the effects of chronic inflammation on the lung circulation.
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