The overall goal of my research is to understand the adaptive and maladaptive changes that occur in the pulmonary microcirculation during the perinatal period. The focus of this proposal is to determine the factors that affect lung microvascular pressures and the hydrostatic pressure gradient for fluid filtration in lungs of the immature newborn. The central hypothesis on which this application is based, is that in the immature as compared to the mature newborn, the mechanisms by which lung microvascular pressures are kept low during postnatal life are not adequately developed, resulting in higher filtration pressures and a greater tendency to edema formation. We believe that an extreme example of inadequate control of lung microvascular pressures in the immature lung, resulting in stress failure of lung capillaries, is the clinical entity of pulmonary hemorrhage in the newborn.
The specific aims of this research proposal are designed to test the following hypotheses in the postnatal immature lung: 1. In the immature lung with respiratory distress syndrome (RDS), venous resistance is high, resulting in higher microvascular pressures. 2. In the immature lung following surfactant therapy, development of increased blood flow through a patent ductus arteriosus results in very high capillary pressures, stress failure of capillaries and pulmonary hemorrhage. 3. High alveolar surface tension and low lung volumes result in lower arterial and higher venous resistances leading to higher microvascular pressures. 4. High venous resistance results from a) veins being more responsive than arteries to most endogenous vasoactive agents, and the more immature the lung, greater the venous responsiveness as compared to arteries; and b) the profile of endogenous vasoactive substances that is synthesized locally within the venous vessel wall is such that vasoconstriction is the predominant effect. Studies will be done in the ovine species. Lungs of preterm, 122 and 130 d gestation (term 150 d) lambs will be studied after delivery. Experiments will be done in lambs in vivo, in isolated perfused lungs and in isolated segments of intrapulmonary arteries and veins. Lung microvascular pressures will be measured by micropuncture in isolated lamb lungs and in vivo. Control experiments will be done in immature lambs treated with surfactant and in term mature lambs. Information derived from these studies should enable us to reduce the incidence of pulmonary edema and hemorrhage in the immature newborn and thereby reduce the mortality and morbidity associated with premature birth.
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