OXIDANT STRESS IN NEONATAL PULMONARY HYPERTENSION

氧化剂会损害、改变肺的张力并导致肺的重塑 脉管系统窒息（缺血-再灌注）、缺氧和高氧可 导致氧化应激。患有持续性肺部疾病的婴儿 新生儿高血压（PPHN）经常暴露于一种或多种 这些刺激使我们假设， 氧化防御，特别是那些通过增加可用的 含硫氨基酸和肺超氧化物歧化酶（SOD），将 减少急性血管损伤和发育不良性重塑， 新生儿肺部的氧化剂过多患有PPHN的婴儿和小鼠 暴露于高氧显著降低这些血浆水平 氨基酸在他们急性疾病和暴露于高氧时， 分别当PPHN婴儿放置在体外膜上时 氧合器治疗和降低吸入氧分压，这些氨基 酸急剧增加。在小鼠中， 半胱氨酸与氧气暴露有关，而不是减少饮食 摄入此外，目前的研究结果表明，年轻，但不是 在肺中过度表达铜锌SOD的老年转基因小鼠， 降低高氧暴露期间的死亡率和肺损伤。 为了进一步研究这些新发现的重要性， 将通过气相色谱-质谱法测定含有氨基酸的 光谱法和谷胱甘肽（GSH/GSSG）以及还原和氧化血浆 硫醇（二硫化物和次磺酸形式）将通过 用分光光度法测定新生和幼龄小鼠血浆和肺中的浓度。 这些硫化合物中每一种的肺动静脉差异 将在暴露于常氧和高氧期间进行定量。第二、 可利用的肺巯基将通过施用N- 乙酰半胱氨酸和氧代噻唑烷羧酸（半胱氨酸前体） 或通过给予谷胱甘肽单异丙酯。第三，长期影响 肺Cu-Zn SOD、MnSOD和这些干预措施的长期增加 合并高氧肺血管中肺巯基增加 将研究损伤和重塑。四、等离子硫磺 含有氨基酸、谷胱甘肽（GSH/GSSG）和还原型和氧化型 硫醇将在患有PPHN和呼吸道疾病的人类婴儿中进行测量。 痛苦这些水平将与妊娠和 年龄，当前和既往吸入氧张力， 营养支持，窒息性肺动脉高压发作 （侵入性和非侵入性确定）， 支气管肺发育不良和存活率。肺动脉瓣摘除术 含硫氨基酸和GSH将在选定的 PPHN婴儿肺动脉导管，以及其他婴儿 因其他原因接受心导管插入术。因此，临床 硫醇作为抗氧化剂和作为氧化应激标志物的重要性 新生儿肺损伤和肺动脉高压的演变将是 测定

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.