NHLBI CLINICAL INVESTIGATOR AWARD PROGRAM

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The goal of the proposed research is to characterize physiologic and metabolic alterations of lung vasculature, as well as mechanisms of those alterations, following lung injury resulting in increased permeability pulmonary edema. Injuries to lung by alpha-naphthylthiorea, hyperoxia, radiation, hydroxyl radicals and monocrotaline will be studied. Their effects on the regulation of vascular tone and responsiveness to pressor stimuli, as well as on metabolic functions of the pulmonary circulation, will be compared using isolated, perfused rat lungs. The possibility that alterations in mediator release could account for observed changes in the regulation of vascular tone will be assessed using mediator inhibitor studies and serial measurements of concentrations of potential mediators. To determine whether physiologic and metabolic alterations caused by acute lung injury persist in the face of repeated or prolonged injury, we plan to conduct long-term experiments following certain injuries. These experiments will involve pulmonary hemodynamic measurements in intact animals, as well as serial physiologic and metabolic studies on their isolated lungs. Because injury to the endothelial cell may play a central role in the response of the pulmonary circulation to lung injury, we also plan to correlate responses to injury observed in the intact lung with responses of endothelial cells in culture. Our aim is to improve understanding of responses of the lung vasculature to lung injuries resembling the Adult Respiratory Distress Syndrome, and thereby provide clues to improved clinical management.