Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because glutathione (GSH) is an important antioxidant, we hypothesized that changes in lung and systemic availability of GSH and its precursor amino acid, cysteine, are induced by exposure to hyperoxia and that these changes could be modulated by toxic O2 metabolites. In organs and plasma of mice exposed to hyperoxia, we measured GSH and sulfur-containing amino acids (SAAs), the latter by capillary gas chromatography-mass spectrometry. In relatively O2-resistant Swiss-Webster mice, lung GSH increased during O2 exposure, whereas liver GSH (the major storage pool of cysteine) and liver and plasma cysteine all decreased. Pair-feeding studies suggested that nutritional deprivation alone did not cause the decrease in plasma cysteine. In lung, SAAs were not decreased by O2 exposure. In fact, cystathionine increased sixfold, and gamma-cystathionase was not inhibited. These findings suggest that hyperoxia increases transsulfuration pathway activity and that cystathionase rate limits this process in lung. In comparative studies, lung GSH increased in O2-resistant high-CuZn superoxide dismutase (SOD) transgenic mice but not in genetically similar, nontransgenic controls (CBYB/6 x B6D/2) during hyperoxic exposure. In addition, liver GSH and plasma cysteine decreased in nontransgenic control but not in high-SOD mice, whereas lung cystathionine increased similarly in both groups. Thus, superoxide or its secondary products can modulate, at least in part, the changes in cysteine and GSH. Nonetheless, regardless of strain or SOD status, hyperoxic exposure consistently caused thiol and SAA changes, including increased lung cystathionine and oxidized GSH, demonstrating a strong association between these dynamic changes and oxidant stress.
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PMID:O2-induced changes in lung and storage pool thiols in mice: effect of superoxide dismutase. 848 94

We have investigated the relationship between intracellular glutathione levels and the inducibility of the mRNAs encoding the major antioxidant enzymes Cu,Zn superoxide dismutase (Cu,Zn SOD), catalase (CAT), glutathione peroxidase (GP), and the stress protein heme oxygenase (HO) following exposure of human umbilical vein endothelial cells (HUVEC) to either hypoxanthine-xanthine oxidase or 95% O2. Treatment of HUVEC with 2 and 200 microM buthionine sulfoximine (BSO) for 16 h reduced total glutathione (GSH) levels by 51 and 95%, respectively, whereas treatment with 100 microM diethylmaleate (DEM) for 24 h increased the cellular GSH content by 58%. None of these treatments affected the responsiveness of HUVEC to a subsequent oxidant challenge, in terms of antioxidant enzymes activities and mRNA levels. On the contrary, HO mRNA was significantly induced by both BSO and DEM, as well as by hyperoxia, albeit to a different extent. We conclude that intracellular redox changes do not appear to regulate the expression of the mRNAs encoding Cu,Zn SOD, CAT, and GP. Furthermore, factors other than endogenous thiols may play a role in the control of HO mRNA expression.
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PMID:Variable glutathione levels and expression of antioxidant enzymes in human endothelial cells. 849 25

The main objective of this study was to determine if glutathione (GSH) supplementation attenuated hyperoxic lung injury. Preterm (29 days) rabbits were delivered and exposed for 24 h to 1) room air, 2) room air and GSH, 3) 95% oxygen and GSH. GSH supplements (1 mM) were delivered in the nutritional support of 10% dextrose and saline through a peritoneal catheter. Animals assigned to oxygen had decreased lung volumes at 35 cmH2O, decreased lung compliance, increased edema, decreased cell viability, and decreased lung tissue and lavage-reduced/oxidized GSH levels, compared with control animals. Despite exposure to hyperoxia, animals supplemented with GSH were not different from room air controls with respect to lung mechanics, edema, cell viability, or tissue and lavage GSH. These studies suggest that GSH supplementation maintains normal lavage and lung tissue GSH levels in preterm animals exposed to hyperoxia and attenuates the changes in lung mechanics associated with oxygen-induced lung injury.
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PMID:Glutathione supplements protect preterm rabbits from oxidative lung injury. 863 37

In the present work, we have studied glutathione transferase (GST) activity and GST subunits distribution in the liver of young and aged rats kept under hypoxic or hyperoxic normobaric conditions as model of oxidative stress. A significant decrease of GST activity was detected in young hypoxic rat liver, whereas a significant increase occurred in aged hypoxic liver. No significant alteration of activity was obtained in both young and aged rat livers subjected to hyperoxic treatment. Substrate specificity measurements, SDS/PAGE analysis and reverse-phase HPLC, of GSH-affinity purified fractions were used to study the changes in the GST subunits pattern occurring in the liver of rat as a consequence of hypoxic and hyperoxic treatment. The results demonstrate that young and aged rat liver has a different constitutive GST subunit pattern which are markedly and differentially altered in hypoxia or hyperoxia. The hyperoxic treatment caused an increase of GST subunit 3 in aged, but not in young liver. In aged liver, both the hypoxic and hyperoxic treatment produced a decrease of GST subunit 4. After hypoxic treatment GST subunit 3 significantly increased in both young and aged liver. GST subunit 1a increased in both young and adult liver after hyperoxia. Following hypoxia a decrease of subunit 1a was seen in both young and aged liver. After hypoxic treatment, subunit 6 doubled in young, but not in aged, livers. It was concluded that the alterations in GST subunit expression occurring in the liver as a consequence of hypoxic or hyperoxic treatment respond to the necessity of a better protection of liver against the products of oxidative metabolism.
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PMID:Alteration of glutathione transferase subunits composition in the liver of young and aged rats submitted to hypoxic and hyperoxic conditions. 867 34

By participating in glutathione (GSH) synthesis, gamma-glutamyl transpeptidase (GGT) influences the GSH redox cycle, which is a major contributor in protecting against reactive oxygen metabolites. This study determined the effect of prolonged exposure of neonatal rats to > 98% oxygen on expression of GGT and on GSH metabolism. Lungs of neonatal rats chronically exposed to hyperoxia had increased expression of GGT mRNA, resulting in significantly higher GGT protein levels and enzyme activity than in lungs of animals raised in room air. Hyperoxia also upregulated glucose-6-phosphate dehydrogenase, but Na-K-ATPase activity was not changed. GGT mRNA, protein level, and enzyme activity returned to control levels after recovery in room air for 3 days. Levels of GSH, glutathione disulfide, and protein-bound GSH (S-glutathiolated protein) rose with hyperoxia and fell during recovery. S-glutathiolation is likely a mechanism for protection and a regulatory modification of protein sulfhydryl groups. Hyperoxia-induced upregulation of GGT and the concomitant increase in protein S-glutathiolation appear to be additional components fundamental in protecting the lung against oxidative injury.
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PMID:Hyperoxia enhances expression of gamma-glutamyl transpeptidase and increases protein S-glutathiolation in rat lung. 877 34

To investigate the mechanisms regulating hyperoxia-induced intercellular adhesion molecule-1 (ICAM-1) expression, we studied the effects of antioxidants on ICAM-1 expression, and the relationship between ICAM-1 expression and extracellular glutathione levels in human pulmonary artery endothelial cells (HPAEC) and human umbilical vein endothelial cells (HUVEC). Cells were cultured to confluence and exposed to hyperoxia (90% O2) for 48 h with or without various antioxidants, including superoxide dismutase (SOD), catalase, N-acetylcysteine (NAC), and glutathione. The levels of ICAM-1 expression in the endothelial cells and the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the media were examined by flow cytometry and spectrophotometry, respectively. After exposure to hyperoxia, ICAM-1 expression was increased, and the supernatant total glutathione was decreased as compared with those at normoxia. SOD did not change ICAM-1 expression. The hyperoxia-induced increase in ICAM-1 expression was even greater with the addition of catalase. The ICAM-1 expression was decreased and the GSH concentration was increased with the addition of NAC. There were negative relationships between the level of ICAM-1 expression and the supernatant total glutathione concentration in catalase-treated HPAEC (R = 0.822, P < 0.0005) and HUVEC (R = 0.567, P < 0.01). Negative relationships were also demonstrated between the level of ICAM-1 expression and the total extracellular glutathione concentrations in NAC-treated HPAEC (R = 0.877, P < 0.0005) and HUVEC (R = 0.727, P < 0.0005). Exogenous GSH decreased ICAM-1 expression in both hyperoxia-exposed HPAEC and HUVEC, while exogenous GSSG did not. These results suggest that extracellular GSH plays a role in regulating hyperoxia-induced ICAM-1 expression in HPAEC and HUVEC.
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PMID:Modulation of ICAM-1 expression by extracellular glutathione in hyperoxia-exposed human pulmonary artery endothelial cells. 881 Jun 35

Although the effect of hyperoxia on antioxidant enzymes is well known, the effect of subtoxic levels of hyperoxia on gamma-glutamyltransferase (gamma-GT), involved in the degradation and uptake of extracellular GSH for intracellular GSH synthesis, is unknown. The aim of the study was to investigate (1) the effects of in vitro hyperoxia on gamma-GT activity of type II cells and (2) the effects of the lazaroid U-74389G and N-acetylcysteine (NAC) on the hyperoxia-induced changes in gamma-GT and antioxidant enzyme activities. At 48 h after isolation, rat type II cells were exposed for 2 days to air, 60% O2 or 85% O2 with or without 30 microM U-74389G or 100 microM NAC. After the exposure, the cells were harvested and assayed for superoxide dismutase (SOD), glutathione peroxidase (GPx), gamma-GT activity, and GSH levels. In another series of experiments 85% O2-exposed cells, with or without U-74389G, were used for Northern blotting of gamma-GT mRNA. Exposure to 60% O2 decreased gamma-GT and GSH by -47 and -34%, respectively, while SOD and GPx activities remained unchanged. After 85% O2-exposure gamma-GT decreased by -55%, SOD and GPx increased by +55 and +87%, respectively, while GSH decreased by -35%. NAC treatment decreased gamma-GT activity by -42% in the air-exposed cells. After 60% O2, U-74389G led to significantly higher gamma-GT (+117%) and GSH (+26%) while NAC only led to higher GSH (+28%) compared to the oxygen-exposed cells not treated with NAC or U-74389G. After 85% O2 U-74389G increased gamma-GT, SOD, and GSH by +72, +58, and +68%, respectively, while NAC only increased SOD (+49%) and GSH (+26%) compared to the oxygen-exposed cells not treated with NAC or U-74389G. The 85% O2 exposure, with or without U-74389G, had no effect on gamma-GT mRNA levels. The results show that hyperoxia decreases rat type II cell gamma-GT activity in vitro. This effect was not related to an altered regulation at mRNA level and it was not associated with the hyperoxia-induced decrease in intracellular GSH, since restoration of the GSH levels by NAC did not restore gamma-GT activity. The lazaroid U-74389G with vitamin E-like properties effectively prevented the decrease in gamma-GT and GSH, so that direct inactivation of the membrane-bound gamma-GT by hyperoxia is the most likely mechanism.
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PMID:Decrease in gamma-glutamyltransferase activity in rat type II cells exposed in vitro to hyperoxia: effects of the 21-aminosteroid U-74389G. 920 59

The regulating mechanism of hyperoxia-induced ICAM-1 expression has not been elucidated. We studied the effect of antioxidants, including superoxide dismutase (SOD), catalase and N-acetylcysteine (NAC), on hyperoxia-induced ICAM-1 expression in human pulmonary artery endothelial cells (HPAEC) and human umbilical vein endothelial cells (HUVEC). Cells were cultured to confluence and exposed to either hyperoxic or normoxic gas with or without various kinds of antioxidants. The levels of ICAM-1 expression in the endothelial cells and the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the media were examined by flow cytometry and by spectrophotometry, respectively. After 48-hour exposure to hyperoxia, ICAM-1 expression was increased (HPAEC; 161 +/- 21% and HUVEC; 163 +/- 16%) and total glutathione concentration in the media was decreased as compared with normoxia. SOD did not change the GSH and GSSG concentrations in the media. Catalase dose-dependently decreased the supernatant GSSG concentration in both HPAEC and HUVEC, while the GSH concentration was nearly constant. NAC dose-dependently increased the supernatant GSH concentrations in both HPAEC and HUVEC. There was no difference in the supernatant GSSG concentrations between the NAC-treated HPAEC and HUVEC. There was no difference in ICAM-1 expression in either HPAEC or HUVEC with SOD treatment. ICAM-1 expressions in 100 U/ml (236 +/- 20%) and 1,000 U/ml (315 +/- 36%) of catalase were increased in HPAEC, and that in 1,000 U/ml (440 +/- 209%) of catalase was increased in HUVEC. Five and 10 U/ml of NAC decreased ICAM-1 expression in HPAEC (141 +/- 26% and 113 +/- 11%) and HUVEC (119 +/- 23% and 106 +/- 7%), respectively. These results suggest that extracellular glutathione may play a role in regulating hyperoxia-induced ICAM-1 expression in HPAEC and HUVEC.
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PMID:Effect of antioxidants on hyperoxia-induced ICAM-1 expression in human endothelial cells. 926 67

Disulfiram (Antabuse) (DSF) has been reported to protect rats and other animals from the effects of hyperbaric hyperoxia at 4 to 6 ATA (atmospheres). In contrast, DSF and diethyldithiocarbamate (DDC), its metabolite, accelerate the toxic effects in rats of 100% oxygen at 1 to 2 ATA. We have examined the effects of DSF and DDC on glutathione (GSH) levels in bovine pulmonary artery endothelial cells and Chinese hamster ovary cells. Increases in intracellular GSH occurred 8 to 24 h after addition of DSF to the culture media. These increases in intracellular GSH were associated with increases in the rate of uptake of cystine into the cells. DDC was a less effective inducer of cystine uptake and increased intracellular GSH levels than was DSF. At the concentrations used, neither DDC nor DSF caused significant decreases in intracellular superoxide dismutase levels. Exogenous sulfhydryl compounds including GSH and cysteine partially blocked the induction of cystine transport by DSF or DDC, suggesting that the induction might be mediated through a sulfhydryl reaction between DSF and some cellular components. The increases in GSH in the cultured cells were not significant by 4 h of exposure. In contrast, other stress proteins including heme oxygenase are induced by 2 to 4 h after DSF addition. In previously reported in vivo studies, DSF treatment protected against hyperbaric oxygen damage after as little as 1 to 4 h pre-exposure. This suggests that effects of DSF exposure other than GSH augmentation may be responsible for the protective effects seen in vivo.
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PMID:Induction of cystine transport and other stress proteins by disulfiram: effects on glutathione levels in cultured cells. 927 11

The effect of hyperoxia on gamma-glutamyltransferase (gamma-GT), an important enzyme for the uptake of precursor molecules for intracellular synthesis of glutathione (GSH), has not been established. Our aim was to investigate the effects of prolonged subtoxic levels of hyperoxia on gamma-GT activity and GSH levels in lung tissue, epithelial lining fluid (ELF), and isolated rat type II cells immediately after their isolation and 48 h later when kept in culture in normoxia. Seventeen male Wistar rats were divided in three groups (n = 5-7) and were exposed to air or to 60 or 85% O2 for 7 days. Pulmonary gamma-GT activity increased in the 60 and 85% O2-exposed animals (1.6- and 3.2-fold, respectively), and tissue GSH levels increased only in the 60% O2 group (1.3-fold). In isolated type II cells from 60 and 85% O2-exposed animals, gamma-GT activity decreased by -70 and -88%, respectively, which was supported by cytochemical staining. Type II cell gamma-GT mRNA expression tended only to decrease after 85% O2. Type II cell gamma-GT activity strongly correlated with ELF gamma-GT (r = 0.60, P < 0.001), and ELF gamma-GT strongly correlated with ELF GSH (r = 0.75, P < 0.0001). When in culture, type II cell gamma-GT activity and GSH levels remained, respectively, 2.5- and 1.9-fold lower in the 60% O2-exposed group, but, in the 85% O2-exposed group, gamma-GT activity increased 2.1-fold, and GSH levels dropped to the levels of the control cells. Hyperoxia led to a concentration-dependent decrease in gamma-GT activity in rat type II cells, possibly by direct inactivation, but led to an increase in whole lung tissue gamma-GT. There seemed to be a negative feedback between intracellular GSH levels and type II cell gamma-GT activity. gamma-GT levels in the ELF were correlated with type II cell gamma-GT activity, but ELF gamma-GT did not seem to play an active role in the regulation of the ELF GSH pool. Hyperoxia decreased ELF GSH levels, possibly by increased degradation of GSH in the parenchymal lung tissue as a result of the increased gamma-GT activity.
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PMID:Changes in gamma-glutamyltransferase activity in rat lung tissue, BAL, and type II cells after hyperoxia. 931 87


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