HYPOXIA INCREASES GLUTATHIONE REDOX CYCLE AND PROTECTS RAT LUNGS AGAINST OXIDANTS
HYPOXIA INCREASES GLUTATHIONE REDOX CYCLE AND PROTECTS RAT LUNGS AGAINST OXIDANTS
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DOI：
10.1152/jappl.1988.65.6.2607
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发表时间：
1988-12-01
影响因子：
3.3
通讯作者：
REPINE, JE
中科院分区：
文献类型：
--
作者：
WHITE, CW;JACKSON, JH;REPINE, JE
低氧预暴露增加大鼠的存活率和肺还原型谷胱甘肽与氧化型谷胱甘肽的比值（GSH/GSSG），并减少随后暴露于持续高氧的胸腔积液。此外，缺氧预暴露大鼠的肺发生急性水肿性损伤（减少肺增重和肺灌洗液白蛋白浓度）比常氧预暴露大鼠的肺时，分离和灌注过氧化氢（H2 O2）产生的黄嘌呤氧化酶（XO）或葡萄糖氧化酶（GO）。与此相反，当灌注弹性蛋白酶或暴露于静水压左心房压力挑战，肺缺氧暴露大鼠分离出相同的急性水肿性损伤的肺从常氧预暴露大鼠。缺氧预暴露对H2 O2的保护机制似乎取决于肺谷胱甘肽氧化还原循环活性的增加依赖于磷酸己糖分流（HMPS）。首先，在用GO灌注之前，与常氧预暴露大鼠的肺相比，低氧预暴露大鼠的肺具有增加的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。第二，与正常氧预暴露大鼠的肺相比，经GO灌注后，低氧预暴露大鼠的肺具有增加的H2 O2还原当量，如GSH/GSSG和NADPH/NADP+增加所反映的。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，可防止缺氧对H2 O2介导的急性水肿损伤的保护作用。这些结果表明，通过谷胱甘肽氧化还原循环和HMPS依赖的机制增加H2 O2的解毒作用有助于低氧预暴露大鼠肺对高氧的耐受和对H2 O2的抵抗。
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 hypoxiapreexposed rats developed the same acute edematous injury as lungs from normoxia-prexposed 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 hypoxiapreexposed rats had increased H2O2 reducing equivalents, as reflected by increased GSH/GSSG and NADPH/NADP+, 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.