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.
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