Oxidants can damage, alter tone in, and lead to remodeling of the lung vasculature. Asphyxia (ischemia-reperfusion), hypoxia, and hyperoxia can lead to oxidant stress. That infants with persistent pulmonary hypertension of the newborn (PPHN) are frequently exposed to one or more of these stimuli has led us to the hypothesis that increasing lung oxidant defenses, specifically those produced by increasing available sulfur-containing amino acids and lung superoxide dismutase (SOD), will decrease acute vascular injury and dysplastic remodeling due to excessive oxidants in the newborn lung. Infants with PPHN and mice exposed to hyperoxia have markedly decreased plasma levels of these amino acids during their acute illness and exposure to hyperoxia, respectively. When PPHN infants are placed on extracorporeal membrane oxygenator therapy and decreased inspired oxygen tension, these amino acids increase dramatically. In mice, sustained decreases in plasma cysteine are related to oxygen exposure rather than decreased dietary intake. In addition, current findings indicate that young, but not older, transgenic mice overexpressing copper-zinc SOD in the lung have decreased mortality and lung injury during hyperoxic exposure. To further investigate the importance of these new findings, sulfur containing amino acids will be determined by gas chromatography-mass spectroscopy, and glutathione (GSH/GSSG) and reduced and oxidized plasma thiols (disulfide and sulfenic acid forms) will be measured by spectrophotometric methods in plasma and lung of newborn and young mice. Pulmonary arteriovenous differences in each of these sulfur compounds will be quantitated during exposure to normoxia and hyperoxia. Second, available lung sulfhydryls will be increased by administering n- acetylcysteine and oxothiazolidine carboxylic acid (cysteine precursors) or by giving glutathione monoisopropyl ester. Third, the effects of long term increases in lung Cu-Zn SOD, in MnSOD, and of these interventions combined with increased lung sulfhydryls in hyperoxic pulmonary vascular injury and remodeling will be investigated. Fourth, plasma sulfur containing amino acids, glutathione (GSH/GSSG) and reduced and oxidized thiols will be measured in human infants with PPHN and respiratory distress. These levels will be correlated with gestational and chronologic age, current and previous inspired oxygen tension and nutritional support, episodes of asphyxia pulmonary hypertension (invasively and non-invasively determined), development of bronchopulmonary dysplasia, and survival. Pulmonary extraction of sulfur-containing amino acids and GSH will be quantitated in selected infants with PPHN with pulmonary artery catheters, and in other infants undergoing cardiac catheterization for other reasons. Thus, the clinical importance of thiols as antioxidants and as markers of oxidant stress in the evolution of neonatal lung injury and pulmonary hypertension will be determined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL046481-03
Application #
3758924
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Ivy, D Dunbar; Lee, Dong-Seok; Rairigh, Robyn L et al. (2004) Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs. Biol Neonate 86:155-9
Grover, Theresa R; Parker, Thomas A; Zenge, Jeanne P et al. (2003) Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 284:L508-17
Storme, Laurent; Parker, Thomas A; Kinsella, John P et al. (2002) Chronic hypertension impairs flow-induced vasodilation and augments the myogenic response in fetal lung. Am J Physiol Lung Cell Mol Physiol 282:L56-66
Grover, Theresa R; Zenge, Jeanne P; Parker, Thomas A et al. (2002) Vascular endothelial growth factor causes pulmonary vasodilation through activation of the phosphatidylinositol-3-kinase-nitric oxide pathway in the late-gestation ovine fetus. Pediatr Res 52:907-12
Parker, T A; Afshar, S; Kinsella, J P et al. (2001) Effects of chronic estrogen-receptor blockade on ovine perinatal pulmonary circulation. Am J Physiol Heart Circ Physiol 281:H1005-14
Rairigh, R L; Parker, T A; Ivy, D D et al. (2001) Role of inducible nitric oxide synthase in the pulmonary vascular response to birth-related stimuli in the ovine fetus. Circ Res 88:721-6
Parker, T A; le Cras, T D; Kinsella, J P et al. (2000) Developmental changes in endothelial nitric oxide synthase expression and activity in ovine fetal lung. Am J Physiol Lung Cell Mol Physiol 278:L202-8
Cornfield, D N; Resnik, E R; Herron, J M et al. (2000) Chronic intrauterine pulmonary hypertension decreases calcium-sensitive potassium channel mRNA expression. Am J Physiol Lung Cell Mol Physiol 279:L857-62
Parker, T A; Kinsella, J P; Galan, H L et al. (2000) Prolonged infusions of estradiol dilate the ovine fetal pulmonary circulation. Pediatr Res 47:89-96
Parker, T A; Ivy, D D; Galan, H L et al. (2000) Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 278:L374-81

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