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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL047804-03
Application #
2223886
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1992-08-13
Project End
1997-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
City
Torrance
State
CA
Country
United States
Zip Code
90502
Ibe, Basil O; Portugal, Ada M; Usha Raj, J (2002) Metabolism of platelet activating factor by intrapulmonary vascular smooth muscle cells. Effect of oxygen on phospholipase A2 protein expression and activities of acetyl-CoA acetyltransferase and cholinephosphotransferase. Mol Genet Metab 77:237-48
Raj, Usha; Shimoda, Larissa (2002) Oxygen-dependent signaling in pulmonary vascular smooth muscle. Am J Physiol Lung Cell Mol Physiol 283:L671-7
Ibe, B O; Raj, J U (2001) Leukotriene metabolism by intrapulmonary vessels of newborn lambs: effect of platelet-activating factor. Exp Lung Res 27:331-48
Ibe, B O; Pham, H H; Kaapa, P et al. (2001) Maturational changes in ovine pulmonary metabolism of platelet-activating factor: implications for postnatal adaptation. Mol Genet Metab 74:385-95
Ibe, B O; Sander, F C; Raj, J U (2000) Platelet-activating factor receptors in lamb lungs are downregulated immediately after birth. Am J Physiol Heart Circ Physiol 278:H1168-76
Ibe, B O; Sander, F C; Raj, J U (2000) Platelet activating factor acetylhydrolase activity in lamb lungs is up-regulated in the immediate newborn period. Mol Genet Metab 69:46-55
Gao, Y; Tolsa, J F; Botello, M et al. (1998) Developmental change in isoproterenol-mediated relaxation of pulmonary veins of fetal and newborn lambs. J Appl Physiol 84:1535-9
Ibe, B O; Hibler, S; Raj, J U (1998) Platelet-activating factor modulates pulmonary vasomotor tone in the perinatal lamb. J Appl Physiol 85:1079-85
Gao, Y; Tolsa, J F; Raj, J U (1998) Heterogeneity in endothelium-derived nitric oxide-mediated relaxation of different sized pulmonary arteries of newborn lambs. Pediatr Res 44:723-9
Gao, Y; Tolsa, J F; Shen, H et al. (1998) Effect of selective phosphodiesterase inhibitors on response of ovine pulmonary arteries to prostaglandin E2. J Appl Physiol 84:13-8

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