The overall objective is to determine the role of lipid mediators, specifically that of platelet activating factor (PAF) and eicosanoids, in control of vascular reactivity in the developing lung. Much work has been done in understanding the regulation of total pulmonary vascular resistance but little is known regarding the selective control of pulmonary arterial and venous tone. The role of veins in control of microvascular pressures and edema formation has not been studied adequately. Intense venoconstriction can result in dramatic increases in microvascular pressures and microvascular surface area for fluid filtration, resulting in rapid edema formation. One objective of this proposal is to correlate the physiological behavior of pulmonary arteries and veins with the local biochemical events in the vessels. Data from preliminary studies indicate that pulmonary veins exhibit considerable vasoactivity, sometimes more than arteries and that distinct age related differences in lung vascular reactivity exist.
The specific aims of this proposal are designed to test the hypotheses that in the developing lung: 1) veins are more reactive than arteries in the fetus and newborn as compared to the older animal; 2) lipid mediators, particularly PAF and eicosanoids, play a major role in regulation of vascular tone, specially in the perinatal period; 3) differences in local lipid metabolism and production of lipid mediators within the vessel wall may account for differences in arterial and venous reactivity; 4) age related differences in lung vascular reactivity may be related to age related differences in lung metabolism of lipid mediators. The ovine pulmonary circulation will be studied. To test the hypotheses, studies will be done in lungs in vivo as well as in an isolated perfused lung preparation. Vascular pressures will be measured in the microcirculation using the micropipette servonull method. This will allow the separate study of the responses of pulmonary arteries and veins. Studies will also be done in isolated segments of intrapulmonary arteries and veins. To investigate the role of PAF and eicosanoids, specific receptor blockers and inhibitors of synthetic enzymes will be utilized and the local production of these mediators by the lung vasculature will be measured. The role of endothelium derived nitric oxide in PAF effects in the pulmonary circulation will be studied. Newborn infants, both immature and mature, often suffer from disorders of lung blood flow associated with pulmonary vascular hypertension and/or lung edema, the causes of which are not always known. Knowledge derived from this proposal should allow the development of strategies to prevent and treat respiratory disorders associated with pulmonary vascular hypertension and/or pulmonary edema in the perinatal period.
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