Pulmonary hypertension which occurs in newborn infants is a serious disorder of unknown cause. Treatment is unsatisfactory because the mortality is high and survivors often have disabling reactive airway disease. Because the manifestations of the disease, i.e., pulmonary hypertension, bronchoconstriction, and pulmonary edema, are reminiscent of the actions of certain lipids, the leukotrienes, it is possible that leukotrienes and/or related lipids such as prostanoids and platelet activating factor (PAF) are involved in the pathogenesis. Some of these substances (PAF, leukotrienes, thromboxane) constrict airways and vessels, while others (prostacyclin) act as dilators. The working hypothesis for this proposal is that an excess of constrictor substances and/or a deficiency of dilator substances cause the disease process. The approach is, first, to determine in animal models of pulmonary hypertension whether the appearance (or disappearance) of these lipids are related to the pulmonary hypertension, and whether inhibitors will block both the lipid substances and the hypertension. This approach will be followed in newborn calves made hypertensive at high altitude (our hypoxia model) and in rats given the pyrrolizidine alkaloid, monocrotaline (our lung injury model). Also if the lipids under consideration cause persistence of hypertension after birth they could be involved in maintaining high pulmonary vascular resistance in the calf at high altitude prior to birth. The approach, second, is to determine whether an analysis of lung lavage from affected infants yield values appropriate for the course of the illness. If the study suggested possible mechanisms of the hypertension and perhaps indicated better modes of therapy, it would make a contribution to the care of newborns with persistent pulmonary hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Research Manpower Review Committee (MR)
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University of Colorado Denver
Schools of Medicine
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