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)

Exposure of cultured pulmonary artery endothelial cells to 95% O2 resulted in the following sequence of events: decrease in [3H]thymidine incorporation after 24 h; increase of intracellular glutathione (GSH) and loss of cellular protein after 48 h; increase of spontaneous and decrease of provoked prostacyclin formation as well as increased release of cellular LDH after 72 h. This oxygen toxicity model was used to study the following 2 questions. (1) What is the relative importance of the GSH redox cycle compared to catalase as antioxidative defense against hyperoxia? Endothelial cells were grown in selenium-depleted medium to inhibit glutathione peroxidase activity. Endothelial GSH biosynthesis was inhibited by buthionine sulfoximine. Catalase activity was reduced by aminotriazole. Endothelial cells with an impaired GSH redox cycle were easily killed by hyperoxia within 24 h, while inhibition of catalase did not enhance the susceptibility of endothelial cells to hyperoxia. (2) Can endothelial GSH content be increased by exogenous sulfhydryl reagents and does this result in an increase of endothelial cells' resistance to hyperoxia? Exogenous GSH, N-acetylcysteine, cysteine, and L-2-oxothiazolidine-4-carboxylate (L-2-oxo) increased intracellular GSH. All sulfhydryl reagents (with the exception of L-2-oxo) protected endothelial cells from hyperoxia. Concentrations of exogenous GSH and N-acetylcysteine that did not increase intracellular GSH reduced hyperoxia-induced endothelial cell injury. Thus the capacity of the GSH redox cycle rather than intracellular GSH levels or catalase determines endothelial cells' resistance to hyperoxia.
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PMID:Glutathione redox cycle is an important defense system of endothelial cells against chronic hyperoxia. 192 73

A full-length hemopexin cDNA was isolated from a rat liver cDNA library and the derived amino acid sequence was obtained. Rat hemopexin shows a 76% amino acid homology with human hemopexin. The amino-terminal domain of rat hemopexin contains two histidine residues that are conserved in the human and rat sequences and are the most likely heme axial ligands. Analogous to human hemopexin, the rat hemopexin consists of 10 internal repeating peptide motifs characteristic of the pexin gene family. A complete conservation of cysteine residues is seen between the human and rat sequences suggesting an identical disulfide bridge structure in both proteins. Our analysis of the primary structure of rat hemopexin reveals characteristics typical for members of the pexin gene family and suggests a conserved evolutionary role for the C-terminal (non-heme-binding) domain of this protein. The full-length rat hemopexin cDNA was used to analyze changes in hemopexin gene expression during development and experimental inflammation. RNA blot analysis showed a single 2.0-kb hemopexin mRNA present in fetal liver at day 14. Hemopexin-specific mRNA was not detected in embryonic or fetal tissues at earlier stages of development and was confined to the liver throughout fetal, newborn, and adult life. The abundance of hemopexin mRNA was found to increase throughout gestation, with a sharp increase in the first postnatal weeks, reaching maximum levels in adult animals. Endotoxin-induced inflammation resulted in a 5-fold increase in hepatic hemopexin mRNA content within 48 h without associated changes in hemopexin transcript size. Adult animals exposed to hyperoxia (95% oxygen) showed a 3-fold increase in hepatic hemopexin mRNA content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rat hemopexin. Molecular cloning, primary structural characterization, and analysis of gene expression. 198 69

Of three possible early biochemical changes which were investigated in rats after hyperoxia, one was shown to be a useful marker of damage in this species. Mitochondrial oxygen uptake measured in lung homogenates has already been reported to be impaired after 24 h. With a purified mitochondrial fraction, we found significant impairment after only 3 h exposure to 100% oxygen. To our knowledge, this is the earliest significant change reported in this species. The antioxidants N-acetyl cysteine, dimethyl sulphoxide and allopurinol were found to ameliorate the injury. This suggests a possible link with the pulmonary damage and survival of rats in hyperoxia, which may be modulated also by antioxidant therapy.
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PMID:An early marker of hyperoxic lung injury in the rat and its pharmacological modulation. 206 85

Metabolites of arachidonic acid (AA) released into bronchoalveolar lavage fluid of animals exposed to hyperoxia have previously been implicated as mediators of pulmonary oxygen toxicity. The alveolar macrophage (AM) represents an important potential source of these eicosanoids. We have therefore investigated the effects of in vitro hyperoxia (95% O2/5% CO2) versus normoxia (95% air/5% CO2) on the metabolism of AA in the AM of the rat. Exposure to 95% O2 for up to 72 h did not impair the viability or affect the protein content of cultured AMs. Hyperoxia for 24 to 72 h increased the accumulation of free AA liberated from endogenous stores in cultures of resting AMs. Despite this increase in free AA, no changes in synthesis of thromboxane B2, prostaglandin (PG) E2, PGF2 alpha, leukotriene (LT) B4, or LTC4 were observed in resting AMs exposed to hyperoxia for up to 72 h. This was not due to degradation of eicosanoids in hyperoxia. However, formation of cyclooxygenase metabolites from exogenously supplied AA was reduced in hyperoxia-incubated AMs, suggesting that hyperoxia inhibited the cyclooxygenase enzyme. In AMs stimulated with calcium ionophore A23187, both AA release and synthesis of cyclooxygenase and lipoxygenase eicosanoids were augmented after incubation in hyperoxia for 24 to 72 h. The increase in A23187-stimulated LTB4 synthesis caused by hyperoxia was inhibited by the antioxidants catalase, superoxide dismutase, and the intracellular cysteine loading agent L-2-oxothiazolidine-4-carboxylic acid, suggesting that the augmentation by hyperoxia of A23187-induced AA metabolism was mediated by reactive oxygen metabolites. Thus, hyperoxia has complex effects on AA metabolism in the AM, which include the ability to augment the release of AA and formation of bioactive eicosanoids. These findings support a possible role for eicosanoid synthesis by the AM in the pathogenesis of oxygen toxicity of the lung.
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PMID:Complex effects of in vitro hyperoxia on alveolar macrophage arachidonic acid metabolism. 215 14

The transport activity for cystine in cultured human fibroblasts decreased after incubation of the cells under a low oxygen concentration. After the incubation for 48 h under 3% oxygen, the Vmax of the transport was decreased to less than one-third of that of the control cells, with little change in Km. The similar transport activity was observed in the cells cultured under 3% oxygen for 10-40 days with several times of passages. When these low oxygen-cultured cells were incubated under room air, the activity was enhanced with a lag of about 4 h and was almost completely restored within 24 h. This restoration required protein synthesis. The cystine transport activity increased by 50% after exposure of the cells to hyperoxia (40% oxygen). From these results it is concluded that the transport activity for cystine is induced by oxygen. In contrast, little change in the transport activities for alanine and leucine occurred in the cells exposed to the corresponding hypoxia or hyperoxia. Since the cystine transported into the cells is reduced to cysteine and the cysteine readily exits to the culture medium where it autoxidizes to cystine, a cystine-cysteine cycle across the plasma membrane has been postulated. Since the autoxidation of cysteine in the culture medium was markedly slowed down under the low oxygen concentration, the change in the cystine transport activity in response to the oxygen concentration was regarded as pertinent. Induction of the cystine transport activity may constitute a protective mechanism against the oxidative stress, to which the culture cells are exposed, by providing the cells with cysteine which is mainly incorporated into glutathione.
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PMID:Induction of cystine transport activity in human fibroblasts by oxygen. 280 85

When bovine pulmonary artery endothelial monolayers were exposed to hyperoxia (95% O2 and 5% Co2), they responded by selectively elevating the intracellular concentration of glutathione without affecting the activities of glutathione peroxidase or glutathione reductase, L-2-Oxothiazolidine-4-carboxylate, an intracellular cysteine-delivering agent, further enhanced the intracellular concentration of glutathione in oxygen-exposed endothelial cells and protected them from the lethal effect of hyperoxia. In contrast, buthionine sulfoximine, a potent inhibitor of gamma-glutamylcysteine synthetase, reduced the glutathione concentration and rendered the cells more sensitive to the toxic effect of oxygen. Both L-2-oxothiazolidine-4-carboxylate and buthionine sulfoximine had no effect on the activities of glutathione peroxidase or glutathione reductase. Our results suggest that L-2-oxothiazolidine-4-carboxylate may have the potential of preventing oxygen toxicity.
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PMID:L-2-oxothiazolidine-4-carboxylate protects cultured endothelial cells against hyperoxia-induced injury. 327 Mar 44

Rats fed 3% casein diets for 6 days showed an increased susceptibility to greater than 98% oxygen [mean survival time 46.9 +/- 4.1 (SD) h] compared with animals fed 25% casein diets (mean survival time 60 +/- 5 h). The 3% casein diet did not reduce the responses to hyperoxia of lung glucose-6-phosphate dehydrogenase, glutathione peroxidase, and glutathione reductase (NAD(P)H), which maintain tissue levels of reduced glutathione or lung superoxide dismutase levels. While supplementation of the 3% casein diet with the sulfur-containing amino acids (cysteine, cystine, or methionine) prevented the increased oxygen toxicity, supplementation with leucine, a nonsulfur-containing amino acid, had no effect on potentiation of toxicity. Animals fed the unsupplemented 3% casein diet failed to show an elevation of lung glutathione in response to hyperoxia. When the 3% casein diet was supplemented with cysteine, total lung glutathione levels increased normally during oxygen exposure. Supplementation of the 25% protein diet with cysteine did not further protect these animals. We conclude that potentiation of oxygen toxicity by dietary protein deficiency in the rat is due to the low sulfur-containing amino acid content of the diet; the mechanism of increased toxicity by hyperoxia is probably related to an inability to increase glutathione levels due to a shortage of the cysteine component of the glutathione tripeptide.
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PMID:Potentiation of oxygen toxicity in rats by dietary protein or amino acid deficiency. 682 98

Tolerance and adaptation to hyperoxia have been correlated with increases in antioxidant enzymes. This study evaluated whether selenium deficiency would prevent an increase in glutathione peroxidase (GSHPX), a selenium-containing enzyme, during oxygen exposure, and, thus, inhibit adaptation. Because the Torula yeast-based diet, which was used to produce selenium deficiency, was also deficient in cysteine and methionine, the effects of these deficiencies were also evaluated. When rats were exposed to 80% oxygen for 1 week, mortality was 80% for rats deficient in both selenium and the sulfur-containing amino acids, 40% for selenium-deficient rats, 35% for cysteine- and methionine-deficient rats, and 0% for rats fed either a standard laboratory diet or a selenium, cysteine-, and methionine-supplemented Torula yeast diet. However, only one of the six surviving rats with low selenium and none of the rats from any other dietary group died during a subsequent 96 hours of 98% oxygen, indicating adaptation to hyperoxia (LD50 for unadapted rats is 72 hours.) GSHPX activity (per gram of dry weight) was decreased 85% in lungs from unexposed rats fed the low selenium diets. After oxygen exposure, lung GSHPX activity was elevated in all dietary groups. Rats fed the high selenium diets had a 47% increase in enzyme activity, whereas rats with high selenium had a 214% increase. Although hyperoxia caused a relatively high percentage increase in the low Se rats, the resulting absolute GSHPX activity was only 34 to 70% of that of unexposed high selenium rats. The results indicate that both selenium and sulfur-containing amino acids contribute to antioxidant defense. However, although the stress of hyperoxic exposure produces an increase in glutathione peroxidase activity, the absolute lung GSHPX activity is better correlated with tolerance than with adaptation to hyperoxia.
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PMID:Roles of selenium and sulfur-containing amino acids in protection against oxygen toxicity. 687 43

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

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


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