White C W, Jackson J H, McMurtry I F, Repine J E
Webb-Waring Lung Institute, Department of Pediatrics, Children's Hospital, Denver, Colorado.
J Appl Physiol (1985). 1988 Dec;65(6):2607-16. doi: 10.1152/jappl.1988.65.6.2607.
Preexposure to hypoxia increased survival and lung reduced glutathione-to-oxidized glutathione ratios (GSH/GSSG) and decreased pleural effusions in rats subsequently exposed to continuous hyperoxia. In addition, lungs from hypoxia-preexposed rats developed less acute edematous injury (decreased lung weight gains and lung lavage albumin concentrations) than lungs from normoxia-preexposed rats when isolated and perfused with hydrogen peroxide (H2O2) generated by xanthine oxidase (XO) or glucose oxidase (GO). In contrast, when perfused with elastase or exposed to a hydrostatic left atrial pressure challenge, lungs isolated from hypoxia-preexposed rats developed the same acute edematous injury as lungs from normoxia-preexposed rats. The mechanism by which hypoxia preexposure conferred protection against H2O2 appeared to depend on hexose monophosphate shunt (HMPS)-dependent increases in lung glutathione redox cycle activity. First, before perfusion with GO, lungs from hypoxia-preexposed rats had increased glutathione peroxidase and glucose 6-phosphate dehydrogenase (but not catalase or glutathione reductase) activities compared with lungs from normoxia-preexposed rats. Second, after perfusion with GO, lungs from hypoxia-preexposed rats had increased H2O2 reducing equivalents, as reflected by increased GSH/GSSG and NADPH/NADPH+, compared with lungs from normoxia-preexposed rats. Third, pretreatment of rats with an HMPS inhibitor, (6-aminonicotinamide) or a glutathione reductase inhibitor, [1,3-bis(2-chloroethyl)-1-nitrosourea] prevented hypoxia-conferred protection against H2O2-mediated acute edematous injury in isolated lungs. These findings suggest that increased detoxification of H2O2 by glutathione redox cycle and HMPS-dependent mechanisms contributes to tolerance to hyperoxia and resistance to H2O2 of lungs from hypoxia-preexposed rats.
预先暴露于低氧环境可提高大鼠的存活率，增加肺组织中还原型谷胱甘肽与氧化型谷胱甘肽的比例（GSH/GSSG），并减少随后暴露于持续高氧环境的大鼠的胸腔积液。此外，与预先暴露于常氧环境的大鼠的肺相比，预先暴露于低氧环境的大鼠的肺在分离并用黄嘌呤氧化酶（XO）或葡萄糖氧化酶（GO）产生的过氧化氢（H2O2）灌注时，急性水肿性损伤较轻（肺重量增加和肺灌洗白蛋白浓度降低）。相反，当用弹性蛋白酶灌注或接受左心房静水压挑战时，从预先暴露于低氧环境的大鼠分离的肺与从预先暴露于常氧环境的大鼠分离的肺发生相同程度的急性水肿性损伤。预先暴露于低氧环境赋予对H2O2保护作用的机制似乎取决于磷酸己糖旁路（HMPS）依赖的肺谷胱甘肽氧化还原循环活性增加。首先，在灌注GO之前，与预先暴露于常氧环境的大鼠的肺相比，预先暴露于低氧环境的大鼠的肺中谷胱甘肽过氧化物酶和葡萄糖6-磷酸脱氢酶（但不是过氧化氢酶或谷胱甘肽还原酶）活性增加。其次，在灌注GO之后，与预先暴露于常氧环境的大鼠的肺相比，预先暴露于低氧环境的大鼠的肺中H2O2还原当量增加，这通过GSH/GSSG和NADPH/NADPH+增加得以体现。第三，用HMPS抑制剂（6-氨基烟酰胺）或谷胱甘肽还原酶抑制剂[1,3-双（2-氯乙基）-1-亚硝基脲]预处理大鼠可防止低氧环境赋予的对分离肺中H2O2介导的急性水肿性损伤的保护作用。这些发现表明，通过谷胱甘肽氧化还原循环和HMPS依赖机制增加对H2O2的解毒作用有助于预先暴露于低氧环境的大鼠的肺对高氧的耐受性和对H2O2的抗性。
