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)

HA-1 hamster fibroblasts receiving fresh media every 24 h were continuously passaged in progressively increasing O2 concentrations for 18 mo (designated O2R95). These cells were significantly more resistant than parental HA-1 to clonogenic inactivation mediated by 95% O2 without media replacement. The O2R95 cell line exhibited increases in the activities of catalase (CAT), Mn superoxide dismutase (MnSOD), Cu,Zn superoxide dismutase (Cu,Zn SOD), and glutathione peroxidase (GPx). O2R95 cells demonstrated uniformly distributed increased staining for CAT, MnSOD, Cu,Zn SOD, and GPx proteins, as determined by immunohistochemistry. Cellular resistance to and metabolism of 4-hydroxy-2-nonenal (4HNE), a toxic byproduct of lipid peroxidation implicated in mechanisms of O2 toxicity, was examined in HA-1 and O2R95 cell lines. O2R95 cells were significantly more resistant to 4HNE cytotoxicity, which was accompanied by a significant increase in 4HNE metabolism. O2R95 cells also demonstrated an increase in total glutathione (GSH) and glutathione S-transferase (GST) activity, an enzymatic system believed to be involved with 4HNE metabolism. Furthermore, homogenates from O2R95 cells consumed greater quantities of 4HNE in the presence of NADPH (but not NADH, NAD+, or NADP+), suggesting that an enzyme(s) utilizing NADPH contributes to 4HNE metabolism, resistance to 95% O2 and 4HNE as well as increased total GSH, antioxidant enzyme activities, and NADPH-dependent metabolism of 4HNE, persisted in O2R95 cells for 75 days of growth in 21% O2. These findings are compatible with the hypothesis that aldehydic byproducts of lipid peroxidation contribute to mechanisms of O2 toxicity and the selective pressure exerted by exposure of cells to hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A stable O2-resistant cell line: role of lipid peroxidation byproducts in O2-mediated injury. 161 58

Heme oxygenase (HO) is the rate-limiting enzyme in the production of bilirubin from heme, and HO-1 is its inducible isoenzyme. In the metabolic pathway of HO a potential oxidant, heme, is degraded, a potential antioxidant, bilirubin, is generated, and a potent sequestering agent of redox active iron, ferritin, is thought to be coinduced. Therefore, the sum of the reactions of HO may be useful in antioxidant defense. To explore the role of HO in protection against oxidative stress, we examined HO-1 expression in Chinese hamster fibroblasts (HA-1) as well as stable hydrogen peroxide (H2O2)-resistant (OC-14) and 95% O2-resistant (O2R95) variant cell lines derived from HA-1, after exposure to 72 h of hyperoxia (95% O2-5% CO2). Total HO activity, HO-1 protein, and HO-1 mRNA steady-state levels were assessed before exposure and daily during exposure to hyperoxia. Controls were exposed to 95% air-5% CO2. Confluent monolayers of O2R95 and OC-14 cells had increased basal immunoreactive HO-1 protein levels relative to HA-1 cells when the cells were grown in normoxia, and O2R95 had higher total basal HO activity. When exposed to hyperoxia for up to 3 days, O2R95 cells, which were resistant to oxygen-induced killing, did not show induction of HO-1 mRNA or increased immunoreactive protein, whereas OC-14 and HA-1, which were relatively more sensitive than O2R95 to oxygen-related cytotoxicity, demonstrated significant increases in HO-1 expression during exposure to hyperoxia. Basal ferritin protein levels were highest in the O2R95 cells, intermediate in OC-14, and lowest in HA-1, but ferritin protein did not increase further, with hyperoxic exposure, in any of the cell lines. We conclude that increased constitutive HO-1 expression is associated with resistance to hyperoxia, whereas induction of HO-1 mRNA is an index of oxidative injury, since it only occurs after cells have sustained cytotoxic injury. We also conclude that increased ferritin expression does not necessarily accompany increased HO-1 expression in oxidant stress. We speculate that HO-1 plays a role in protection against hyperoxic damage.
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PMID:Differences in basal and hyperoxia-associated HO expression in oxidant-resistant hamster fibroblasts. 889 16

The role of heme oxygenase (HO)-1 was evaluated in the oxygen-resistant hamster fibroblast cell line, O2R95, which moderately overexpress HO when compared with the parental cell line, HA-1. To suppress HO-1 expression, O2R95 were transfected with HO-1 antisense oligonucleotide or treated with tin-mesoporphyrin (SnMP). To increase HO-1 expression, cells were transfected with HO-1 cDNA in a pRC/cytomegalovirus (CMV) vector. All cells were challenged with a 48-h exposure to 95% O2 (hyperoxia). When HO activity was suppressed, O2R95 cells had significantly decreased cell viability, increased susceptibility to lipid peroxidation, and increased protein oxidation in hyperoxia. In contrast, further overexpression of HO-1 did not improve resistance to oxygen toxicity. Antisense-transfected cells and SnMP-treated cells with lowered HO activity showed increased levels of cellular heme compared with controls. In the HO-1 cDNA-transfected O2R95 cells, cellular heme was lowered compared with controls; however, cellular redox active iron levels were increased. We conclude that HO mediates cytoprotection to oxygen toxicity within a narrow range of expression. We speculate that this protective effect may be mediated in part through increased metabolism of the pro-oxidant heme but that higher levels of HO activity obviate protection by increased redox active iron release.
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PMID:Heme oxygenase-mediated resistance to oxygen toxicity in hamster fibroblasts. 916 65

It is often postulated that the cytoprotective nature of heme oxygenase (HO-1) explains the inducible nature of this enzyme. However, the mechanisms by which protection occurs are not verified by systematic evaluation of the physiological effects of HO. To explain how induction of HO-1 results in protection against oxygen toxicity, hamster fibroblasts (HA-1) were stably transfected with a tetracycline response plasmid containing the full-length rat HO-1 cDNA construct to allow for regulation of gene expression by varying concentrations of doxycycline (Dox). Transfected cells were exposed to hyperoxia (95% O(2)/5% CO2) for 24 h and several markers of oxidative injury were measured. With varying concentrations of Dox, HO activity was regulated between 3- and 17-fold. Despite cytoprotection with low (less than fivefold) HO activity, high levels of HO-1 expression (greater than 15-fold) were associated with significant oxygen cytotoxicity. Levels of non-heme reactive iron correlated with cellular injury in hyperoxia whereas lower levels of heme were associated with cytoprotection. Cellular levels of cyclic GMP and bilirubin were not significantly altered by modification of HO activity, precluding a substantial role for activation of guanylate cyclase by carbon monoxide or for accumulation of bile pigments in the physiological consequences of HO-1 overexpression. Inhibition of HO activity or chelation of cellular iron prior to hyperoxic exposure decreased reactive iron levels in the samples and significantly reduced oxygen toxicity. We conclude that there is a beneficial threshold of HO-1 overexpression related to the accumulation of reactive iron released in the degradation of heme. Therefore, despite the ready induction of HO-1 in oxidant stress, accumulation of reactive iron formed makes it unlikely that exaggerated expression of HO-1 is a cytoprotective response.
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PMID:Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. 1050 83