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

O2- produced by the autoxidation of respiratory chain electron carriers, and other cellular reductants, inactivates bacterial and mammalian iron-sulfur-containing (de)hydratases including the citric acid cycle enzyme aconitase. Release of the solvent-exposed iron atom and oxidation of the [4Fe-4S]2+ cluster accompanies loss of catalytic activity. Rapid reactivation is achieved by iron-sulfur cluster reduction and Fe2+ insertion. Inactivation-reactivation is a dynamic and cyclical process which modulates aconitase and (de)hydratase activities in Escherichia coli and mammalian cells. The balance of inactive and active aconitase provides a sensitive measure of the changes in steady-state O2- levels occurring in living cells and mitochondria under stress conditions. Aconitases are also inactivated by other oxidants including O2, H2O2, NO, and ONOO- which are associated with inflammation, hyperoxia and other pathophysiological conditions. Loss of aconitase activity during oxidant stress may impair energy production, and the liberation of reactive iron may further enhance oxidative damage. Iron-sulfur center cycling may also serve adaptive functions by modulating gene expression or by signaling metabolic quiescence.
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PMID:Superoxide-driven aconitase FE-S center cycling. 917 19

Heme oxygenase (HO) activity leads to accumulation of the antioxidant bilirubin, and degradation of the prooxidant heme. Moderate overexpression of the inducible form, HO-1, is associated with protection against oxidative injury. However, the role of HO-2 in oxidative stress has not been explored. We evaluated survival, indices of oxidative injury, and lung and HO expression in HO-2 null mutant mice exposed to > 95% O2 compared with wild-type controls. Similar basal levels of major lung antioxidants were observed, except that the knockouts had a twofold increase in total glutathione content. Despite increased HO-1 expression from HO-1 induction, knockout animals were sensitized to hyperoxia-induced oxidative injury and mortality, and also had significantly increased markers of oxidative injury before hyperoxic exposure. Furthermore, during hyperoxia, lung hemoproteins and iron content were significantly increased without increased ferritin, suggesting accumulation of available redox-active iron. These results demonstrate that the absence of HO-2 is associated with induction of HO-1 and increased oxygen toxicity in vivo, apparently due to accumulation of lung iron. These results suggest that HO-2 functions to augment the turnover of lung iron during oxidative stress, and that this function does not appear to be compensated for by induction of HO-1 in the knockouts.
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PMID:Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. 948 70

We reported previously that Fischer-344 (F344) rats were more susceptible to hyperoxic lung injury than were Sprague Dawley (SD) rats. In the present study we exposed adult male F344 and SD rats to >95% oxygen for up to 48 h, and measured lung wet-to-dry weight ratios and lavage protein concentrations as indices of lung injury. In addition, we measured nonheme iron contents in the lung subcellular fractions and in bronchoalveolar lavages (BAL), and we derivatized samples from the subcellular compartments and lavages with 2,4-dinitrophenylhydrazine (DNPH), separated the proteins electrophoretically, and detected DNPH-derivatized proteins by western blotting. After 48 h of hyperoxia, BAL protein and nonheme iron concentrations were higher in F344 rats than in SD rats (2.17+/-0.77 versus 0.17+/-0.17 mg/ml, and 1.61+/-0.45 versus 0.45+/-0.18 nmol/ml, respectively, both P<0.05). In addition, two DNPH-reactive proteins of about 40 and 120 kDa were identified in the lavage fluids of hyperoxic F-344 rats that were not observed similarly in hyperoxic SD rats or in air-breathing rats of either strain. N-terminal amino acid sequences of the two DNPH-reactive proteins 100% identical over 16 residues to rat beta-casein, which is a potent neutrophil chemotaxin, and has been reported to be a product of cytotoxic T-lymphocytes. There were no significant alterations in iron contents in lung subcellular fractions in either strain of rat as a consequence of hyperoxia-exposure, nor were there any significant alterations in DNPH-reactive carbonyls, as determined by western blotting. These data suggest that increased iron concentrations in the airspaces reflect altered iron homeostasis, which may contribute to the greater susceptibility of F344 rats than SD rats to hyperoxic lung injury. The identification of oxidized beta-casein in the BAL of the hyperoxic F344 rats suggests a role for cytotoxic T-lymphocytes in hyperoxic lung inflammation and injury, although the nature of this possible involvement is not known at this time.
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PMID:Iron and oxidized beta-casein in the lavages of hyperoxic Fischer-344 rats. 948 14

The brain is susceptible to oxidative stress. This is due to the high content of polyunsaturated fatty acids, high rate of oxygen consumption, regional high concentrations of iron, and relatively low antioxidant capacity. These factors may predispose the premature infant to brain damage. Brain damage may be due to: 1. Brief anoxia followed by hyperoxia (mimics parturition oxidative stress); or 2. Prolonged exposure to hyperoxia (mimics oxidative stress from postpartum maintenance in a hyperoxic environment). We have developed two animal models to examine these forms of oxidative stress on the brains of rats. In Model I rats were exposed to brief anoxic anoxia (100% N2) followed by hyperoxia (100% O2). Using T2-weighted Magnetic Resonance Imaging (MRI) brain intensity decreased following the treatment suggesting water loss or free radical production. In vivo 1H-NMR showed brain water content appeared to increase, however variability rendered this result insignificant. Electron spin resonance (ESR) spin trapping, using a-phenyl-N-tert-butylnitrone (PBN) produced a free radical signal from the anoxic-anoxia hyperoxia treated animals which suggests the decrease in MRI T2-weighted image signal intensity was due to free radicals. In Model II, we examined the effects of prolonged normobaric hyperoxia (85% O2) on blood-brain barrier (BBB) integrity and brain phosphorous metabolism. BBB permeability increased following 1 week of hyperoxia. In addition, measurement of high energy phosphates, using in vivo 31P-NMR, showed the PCr/ATP ratio significantly decreased, the ATP/Pi ratio increased and the (ATP+PCr)/Pi ratio increased. Because the BBB is sensitive to oxidative stress its loss of integrity may be due to free radicals. The level of oxidative stress may result in brain elevation of ATP as an adaptation mechanism. In conclusion, anoxic-anoxia and prolonged hyperoxia exposure produce MRI visible changes in the brain. These two mechanisms may be important in the etiology of brain damage observed in many premature infants.
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PMID:Effect of oxidative stress on brain damage detected by MRI and in vivo 31P-NMR. 960 4

Iron uptake by cells may increase the intracellular pool of prooxidant iron prior to storage of iron within ferritin. Because hyperoxia is toxic to alveolar macrophages (AM) via mechanisms involving oxidant stress, we hypothesized that iron uptake by AM might promote hyperoxia-induced injury. To assess this hypothesis, we cultured AM recovered from healthy volunteers under conditions of normoxia or hyperoxia (60% or 95% oxygen) in media of varying iron content, including control media (3 microM iron) and media supplemented with iron (FeCl3; total iron 10, 20, or 40 microM). AM injury was assessed by measuring release of lactate dehydrogenase (LDH), phagocytic activity for yeast, and cytosolic concentrations of calcium ([Ca2+]i) as determined by ratio image analysis of AM loaded with the fluorescent calcium probe indo-1. There was dose-dependent accumulation of iron and ferritin synthesis in AM exposed to iron-supplemented media. Exposure of AM to hyperoxia (60% and 95% oxygen, 18 h) in control media increased LDH release and impaired phagocytic activity for yeast; however, similar hyperoxic exposures in iron-supplemented media significantly increased the cells' LDH release and decreased phagocytosis. Exposure to 95% oxygen increased the [Ca2+]i of AM over 18 h, but similar exposure in iron-supplemented media induced greater increases in [Ca2+]i. As compared with exposure to normoxia, exposure to hyperoxia (60% and 95% oxygen) also decreased iron uptake and, to a greater extent, ferritin synthesis by AM in iron-supplemented media. These data suggest that: (1) iron uptake promotes hyperoxic injury to AM; and (2) hyperoxia impairs the capacity of AM to sequester iron in ferritin.
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PMID:Iron uptake promotes hyperoxic injury to alveolar macrophages. 987 25

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

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

The hypotransferrinemic mouse (trf (hpx)) is a mutant strain exhibiting transferrin deficiency, marked anemia, hyperabsorption of iron, and elevated hepatic iron stores. We set out to investigate the relative roles of anemia and of transferrin in the malregulation of intestinal iron absorption in these animals. Transfusion of erythrocytes obtained from littermate controls increased hemoglobin levels and reduced reticulocyte counts in recipient animals. Although mucosal to carcass (59)Fe transfer was reduced, total duodenal iron uptake was not significantly affected. Iron absorption in homozygotes, in contrast to littermate controls, was not reduced by hyperoxia. Mouse transferrin injections, in the short term, increased delivery of iron to the marrow and raised hemoglobin levels. Although mucosal transfer and total iron uptake were reduced at the higher transferrin doses, total uptake was still higher than in controls. Daily injections of mouse/human transferrin for 3 weeks from weaning, normalized hemoglobin values, and markedly reduced liver iron and intestinal iron absorption values in trf (hpx) animals. When such daily-injected mice were left for a week to allow transferrin clearance, iron absorption values were significantly enhanced; hemoglobin or hepatic iron levels were, however, not significantly altered. These data indicate that hyperabsorption of iron in trf (hpx) mice is not solely because of the anemia; transferrin levels per se do affect iron absorption, possibly via a direct effect on the intestinal mucosa.
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PMID:Importance of anemia and transferrin levels in the regulation of intestinal iron absorption in hypotransferrinemic mice. 1055 6

To test whether the possibly enhanced sensitivity of aged cells to oxidative stress may depend on their content of ceroid/lipofuscin, AG-1518 human fibroblasts with various amounts of the pigment accumulated due to prolonged cultivation under normobaric hyperoxia were exposed to acute oxidative stress (2.5 microM naphthazarin, 15 min) and then returned to standard culture conditions. Twenty-four hours after the naphthazarin treatment, 37% of the cells were still vital, whereas others had undergone oxidative stress-induced apoptosis with ensuing postapoptotic necrosis. The average amount of ceroid/lipofuscin within the surviving cells was only about half of that of the initial population of cells, as measured before the naphthazarin exposure. This finding suggests that ceroid/lipofuscin-rich cells have an increased sensitivity to oxidative stress. The ceroid/lipofuscin quantity strongly positively correlated with the size of the acidic compartment (as evaluated by uptake of the weakly basic lysosomotropic fluorochrome acridine orange) and with its content of the lysosomal protease cathepsin D, as assayed by immunocytochemistry. We hypothesize that the enhanced sensitivity of ceroid/lipofuscin-loaded cells to oxidative stress may be caused by the increased amounts of lysosomal enzymes, known as mediators of oxidative damage, and/or by catalysis of intralysosomal oxidative reactions by lipofuscin-associated iron.
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PMID:Ceroid/lipofuscin-loaded human fibroblasts show increased susceptibility to oxidative stress. 1057 36


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