ANTIOXIDANT DEFENSE MECHANISM IN VASCULAR INJURY OF THE NEWBORN

氧化剂可损伤、改变张力，并导致肺重塑。 脉管系统。窒息(缺血-再灌流)、低氧和高氧可 导致氧化应激。患有持续性肺病的婴儿 新生儿高血压(PPHN)经常接触一种或多种 这些刺激使我们产生了这样的假设：增加肺 氧化防御，特别是那些通过增加可获得性而产生的 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重塑 新生儿肺内氧化剂过多。PPHN婴儿和小鼠 暴露在高氧环境中会显著降低血浆中这些物质的水平 在急性疾病和暴露在高氧环境中的氨基酸， 分别进行了分析。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 酸的含量急剧增加。在小鼠中，血浆持续下降 半胱氨酸与氧气暴露有关，而不是与饮食减少有关 入口处。此外，目前的研究结果表明，年轻的，但不是 在肺中过度表达铜锌超氧化物歧化酶的年长转基因小鼠 降低高氧暴露期间的死亡率和肺损伤。 为了进一步调查这些新发现的重要性，硫磺 用气相色谱-质谱法测定含氨基酸 光谱学、谷胱甘肽(GSH/GSSG)和还原和氧化血浆 硫醇(二硫化物和磺酸形式)将通过以下方法测量 用分光光度法测定新生和幼龄小鼠的血浆和肺组织中的含量。 每种硫化物的肺动静脉差异 会在常氧和高氧暴露期间被量化。第二, 给药后肺内可利用的巯基将增加。 乙酰半胱氨酸和恶唑烷羧酸(半胱氨酸前体) 或给予谷胱甘肽单异丙酯。第三，多头的影响 肺内铜锌超氧化物歧化酶、锰超氧化物歧化酶及这些干预措施的长期增加 高氧性肺血管病变合并肺内巯基增多 将对损伤和重塑进行调查。第四，血浆硫 含氨基酸，谷胱甘肽(GSH/GSSG)和还原和氧化 将在患有PPHN和呼吸道疾病的婴儿中检测硫醇 苦恼。这些水平将与妊娠和 年龄，现在和以前激发的氧分压和 营养支持，窒息肺动脉高压的发作 (侵入性和非侵入性确定)、发展 支气管肺发育不良，并存活。肺提取液 含硫氨基酸和谷胱甘肽将在选定的 有肺动脉导管的PPHN婴儿和其他婴儿 因其他原因行心导管术的。因此，临床上 硫醇作为抗氧化剂和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 下定决心。

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.