The purpose of these studies is to examine the postulated mechanisms of neurogenic pulmonary edema and to test the proposed hypotheses to explain the pathogenesis of neurogenic pulmonary edema. We will study using the rabbit model of neurogenic pulmonary edema, the roles of pulmonary hypertension and vasoconstriction, of increased lung vascular permeability to fluid and solutes, of sympathetic activation, and of fibrin and neutrophil sequestration in the lung. The studies will also determine whether varying the dosages of intercisternal fibrinogen and thrombin produce lung vascular lesions and pulmonary edema and determine whether products of fibrinogen (i.e. fibrinopeptides) or products of fibrinolysis (i.e. fibrin degradation products) also mediate neurogenic pulmonary edema. Studies will examine whether increased vascular hydrostatic pressure leads to increased endothelial permeability to protein and determine the degree and duration of the hypertension required to induce lung vascular injury. Related studies will determine whether the mode of hypertension (i.e. left atrial lung versus pulmonary arterial hypertension) influences the development of increased lung vascular permeability and of pulmonary edema. The role of pulmonary vascular compliance in increasing lung vascular permeability and extravascular lung water content will also be examined since this mechanism has been postulated to be a factor in the pathogenesis of neurogenic pulmonary edema. Studies will characterize whether severe pulmonary hypoperfusion occurs in the model of neurogenic pulmonary edema, and whether the ischemia and reperfusion contribute to the development of neurogenic pulmonary edema. The role of sympathetic mechanisms in modulating pulmonary transvascular fluid filtration and protein flux after lung vascular injury will be examined. Studies will utilize the neurogenic pulmonary edema model in the rabbit, the in situ sheep lung lymph fistula preparation, and the in vitro endothelial monolayer. The long-term goal of these studies is to provide a better description of the pathogenesis of neurogenic pulmonary edema.
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