UMLS:C0242706 - FACTA Search

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Query: UMLS:C0242706 (hyperoxia)
5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon inducers, poly I:poly C, endotoxin, hepatic RNA, and Tilorone, were administered to rats at different time points in relation to the onset of hyperoxic exposure (O2 greater than 97%). All interferon inducers tested significantly reduced the mortality of rats when compared with the control groups. In hyperoxia alone, malondialdehyde, a product of lipid peroxidation, was significantly increased and the microsomal enzyme NADPH cytochrome c reductase decreased as measured in the whole lung. With the administration of either endotoxin or poly I:poly C these two parameters remained within the range of control values. These data suggest that the administration of interferon inducers protects against hyperoxic microsomal damage. After the administration of these interferon inducers with or without hyperoxia the increased activity of heme oxygenase and marked reduction of the heme content of microsomes were demonstrated. Since cytochrome P-450 and b5 are the major hemoproteins of microsomes and the known source of oxygen-free radical generation, the results obtained in this study appear to indicate that the depression of the hemoprotein of microsomes by the administration of interferon inducers may be largely responsible for the protective effects of these agents against hyperoxia.
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PMID:Protective effect of interferon inducers against hyperoxic pulmonary damage. 654 2

A broad array of oxidative stresses modulates gene expression in a variety of mammalian cells. One goal of this review was to characterize cellular responses to oxidative injury, how these processes are regulated, and the outcome for a particular cell or tissue. Many genes induced in response to specific oxidant stresses have been identified and include transcription factors, replication proteins, proteases, protease inhibitors, proteins affecting cell proliferation and various antioxidants, i.e. heme oxygenase, MT, and MnSOD. The latter enzyme is induced after a number of cytokines and oxidant stresses including hyperoxia and mineral dusts causing inflammation. Moreover, increases in mRNA levels of TNF and IL-1, cytokines inducing MnSOD, are observed after exposure to UV and ionizing radiation. Since increased electron flow could lead to generation of more AOS within mitochondria, increased levels of MnSOD might be necessary to maintain normal functioning of the mitochondria after oxidative stress. Alterations in cell growth are intrinsically related to the pathogenesis of many diseases. Paradoxically, some of the responses of cells to oxidative stress reflect cytotoxicity and cytostasis, whereas others result in increased cell proliferation. For example, induction of gadd genes observed after oxidative stress is related to growth arrest of cells, a response which might enable the cell to repair oxidative damage prior to replication. This phenomenon might prevent fixation of mutations associated with oxidative DNA damage. On the other hand, increased mRNA expression and activity of ODC, observed after exposure of cells to UV or asbestos is associated with increased cell proliferation. In addition, increased mRNA expression of cellular proto-oncogenes observed after exposure to oxidants could also be related to increased DNA synthesis or proliferation. Figure 5 provides a general scheme of cell responses to oxidative stress and possible ramifications. AOS can react with a number of target molecules including proteins, lipids, and DNA. These interactions elicit a number of signals including activation of gene regulatory factors (transcription factors) which in turn activate oxidative stress-responsive genes or regulons. Consequently, a number of proteins are produced with distinctive functions including DNA repair enzymes, antioxidants, proteases inhibitors, cytokines and proteins affecting cell proliferation. These cellular responses to AOS can lead to restoration of normal cellular function and adaptation to oxidative stress, cell death or aberrant proliferation. It is the latter two responses which can lead to a variety of disease states including cancer.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cell and tissue responses to oxidative damage. 837 69

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

Exposure to high partial pressures of oxygen are toxic to the lung, and much of the damage observed is related to injury of the pulmonary microvasculature. In this study, we evaluated the response of the pulmonary microvascular endothelial cell to high oxygen concentrations, using two-dimensional protein gel electrophoresis as a direct molecular assay of differences between cells exposed to room air or hyperoxia. We observed a differential expression of five specific proteins within 24 h of a hyperoxic insult that we termed hyperoxia-responsive proteins. After 4 h of hyperoxia there was a decrease in two of the proteins. From 8 to 24 h we observed a repression of a third and an induction of the other two proteins. One of the induced proteins was also increased by heat shock and hydrogen peroxide and has characteristics similar to heat shock protein (HSP) 32 (heme oxygenase 1). Western analysis using an antibody specific to rat heme oxygenase 1 verified that this oxygen-responsive protein is heme oxygenase 1. The response of the other four hyperoxia-responsive proteins appears to be specific to oxygen and not a general stress response, since they were not changed in response to heat shock or hydrogen peroxide. Based on RNA inhibitor and pulse chase experiments, these changes may result from transcriptional/posttranscriptional mechanisms or hyperoxia-dependent protein turnover.
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PMID:Hyperoxia-responsive proteins in rat pulmonary microvascular endothelial cells. 892 10

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

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

Rat fetal lung cells (RFL-6) were transiently transfected with a full-length rat heme oxygenase (HO)-1 cDNA construct and then exposed to hyperoxia (95% O2-5% CO2) for 48 h. Total HO activity and HO-1 protein were measured as well as cell viability, lactate dehydrogenase (LDH) release, protein oxidation, lipid peroxidation, and total glutathione to measure oxidative injury. HO-1 overexpression resulted in increased total HO activity (2-fold), increased HO-1 protein (1.5-fold), and increased cell proliferation. Immunohistochemistry revealed perinuclear HO-1 localization, followed by migration to the nucleus by day 3. Decreased cell death, protein oxidation, and lipid peroxidation but increased LDH release and glutathione depletion were seen with HO-1 overexpression. Reactive iron content could not explain the apparent loss of cell membrane integrity. With the addition of tin mesoporphyrin, total HO activity was decreased and all changes in injury parameters were normalized to control values. We conclude that moderate overexpression of HO-1 is protective against oxidative injury, but we speculate that there is a beneficial threshold of HO-1 expression.
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PMID:Protective effects of transient HO-1 overexpression on susceptibility to oxygen toxicity in lung cells. 1007 Jan 8

The endothelium of the lung is sensitive to the toxic effects of oxygen, and early evidence of toxicity is characterized by protein leak and extravasation of red blood cells. The overproduction of oxygen free radicals plays a critical role in the pathophysiology of a hyperoxic lung injury. Recently, heme oxygenase 1 (HO-1), the rate-limiting enzyme in the metabolism of heme, has been found to have a protective role in oxidant injury. Our laboratory and others have identified HO-1 as a hyperoxia-inducible protein. In this study, we characterized HO-1 expression and evaluated its regulation in human pulmonary endothelial cells. Hyperoxia results in a relatively small increase in HO-1 expression; however, this induction is potentiated by heme and dramatically potentiated in the presence of free iron. This is probably more reflective of the in vivo situation in which there is extravasation of heme and iron products. We also found that HO-1 expression depended on chelatable iron. The iron chelator desferrioxamine not only inhibited the iron- dependent potentiation of HO-1 in response to hyperoxia but also inhibited both hyperoxia and basal expression. On the basis of inhibitor studies and nuclear run-on assays, we demonstrated that this induction is transcriptionally dependent. We also evaluated 4.5 kb of the human HO-1 promoter region and demonstrated that this region has promoter activity to the stimulus heme; however, there was no evidence of promoter activity to either iron or hyperoxia. This diversity of promoter activity to heme, heavy metals, and hyperoxia is unique to the human HO-1 gene.
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PMID:Iron regulates hyperoxia-dependent human heme oxygenase 1 gene expression in pulmonary endothelial cells. 1010 Oct 13

Findings in recent years strongly suggest that the stress-inducible gene heme oxygenase (HO)-1 plays an important role in protection against oxidative stress. Although the mechanism(s) by which this protection occurs is poorly understood, we hypothesized that the gaseous molecule carbon monoxide (CO), a major by-product of heme catalysis by HO-1, may provide protection against oxidative stress. We demonstrate here that animals exposed to a low concentration of CO exhibit a marked tolerance to lethal concentrations of hyperoxia in vivo. This increased survival was associated with highly significant attenuation of hyperoxia-induced lung injury as assessed by the volume of pleural effusion, protein accumulation in the airways, and histological analysis. The lungs were completely devoid of lung airway and parenchymal inflammation, fibrin deposition, and pulmonary edema in rats exposed to hyperoxia in the presence of a low concentration of CO. Furthermore, exogenous CO completely protected against hyperoxia-induced lung injury in rats in which endogenous HO enzyme activity was inhibited with tin protoporphyrin, a selective inhibitor of HO. Rats exposed to CO also exhibited a marked attenuation of hyperoxia-induced neutrophil infiltration into the airways and total lung apoptotic index. Taken together, our data demonstrate, for the first time, that CO can be therapeutic against oxidative stress such as hyperoxia and highlight possible mechanism(s) by which CO may mediate these protective effects.
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PMID:Carbon monoxide provides protection against hyperoxic lung injury. 1019 67

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

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