Hypoxia increases glutathione redox cycle and protects rat lungs against oxidants.
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.
White
C W
CW
Webb-Waring Lung Institute, Department of Pediatrics, Children's Hospital, Denver, Colorado.
Jackson
J H
JH
McMurtry
I F
IF
Repine
J E
JE
D015120:6-Aminonicotinamide / Q000494:pharmacology; D000818:Animals; D002330:Carmustine / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000633:toxicity*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism*; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D055370:Lung Injury; D008297:Male; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D011654:Pulmonary Edema / Q000209:etiology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D015120:6-Aminonicotinamide; D009249:NADP; D006861:Hydrogen Peroxide; D005978:Glutathione; D002330:Carmustine