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)

Hyperoxia and mechanical ventilation cause acute lung injury which may be mitigated by prophylactic intratracheal (IT) administration of recombinant human CuZn superoxide dismutase (rhSOD). However, little is known about the localization, activity, and metabolism of rhSOD after IT administration by instillation or nebulization. Twenty-six newborn piglets were intubated, mechanically ventilated, and given either saline or fluorescently labeled rhSOD (5 mg/kg IT) by instillation or nebulization. Animals were killed 1, 6, or 12 h later. Intact rhSOD (% total fluorescence still associated with macromolecules) and total SOD activity in lung tissue were then determined. Results indicate that, after 1 and 6 h of administration, the majority of rhSOD present in the lung was still associated with the fluorescent label. By 12 h, most of the rhSOD was no longer fluorescently labeled. At 1 h, lung SOD activity increased by 100% compared with untreated control values, with activity remaining elevated at 6 and 12 h. Laser confocal microscopy of lung tissue showed that at 1 h, labeled rhSOD was found throughout the lung, inside a variety of cell types of airways, respiratory bronchioles, and alveoli. Deposition was more homogeneous after nebulization. Negative controls had minimal background fluorescence. These data indicate that after IT administration, rhSOD is rapidly incorporated into cells in the lung and significantly increases lung SOD activity. These observations have important implications for the clinical use of rhSOD in human trials.
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PMID:Localization and activity of recombinant human CuZn superoxide dismutase after intratracheal administration. 877 61

Copper-zinc superoxide dismutase (CuZn-SOD) is believed to play a major role in the first line of antioxidant defense by catalyzing the dismutation of superoxide anion radicals to form hydrogen peroxide and molecular oxygen. Recent studies have shown that missense mutations in this gene contribute, evidently through a gain-of-function mechanism, to about 20% of familial amyotrophic lateral sclerosis. To define further the physiologic role of this enzyme, a model of mice deficient in this enzyme was generated using gene targeting technology. Mice lacking this enzyme were apparently healthy and displayed no increased sensitivity to hyperoxia. However, they exhibited a pronounced susceptibility to paraquat toxicity. Most surprisingly, female homozygous knock-out mice showed a markedly reduced fertility compared with that of wild-type and heterozygous knock-out mice. Further studies revealed that although these mice ovulated and conceived normally, they exhibited a marked increase in embryonic lethality. These data, for the first time, suggest a role of oxygen free radicals in causing abnormality of female reproduction in mammals.
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PMID:Reduced fertility in female mice lacking copper-zinc superoxide dismutase. 951 86

Hyperoxia and ischemia-reperfusion cause profound lung cellular damage mediated, in part, by generation of oxygen radicals. We hypothesized that gene therapy can be used to overcome oxidant injury by augmenting intracellular antioxidant enzymes. Adult rats were injected intratracheally with an adenovirus (Ad) vector encoding human superoxide dismutase (CuZn-SOD) or catalase cDNA, a mixture of both Ad vectors, or a control Ad vector containing no exogenous gene. Expression of human catalase and CuZn-SOD was demonstrated 3 days later in distal lung epithelial cells and alveolar macrophages, using ELISA and immunochemistry. After exposure to 100% O2 for 62 hr, survival was greater in rats injected with the catalase and/or SOD Ad vectors than in control rats. Ischemia-reperfusion injury was evaluated in the isolated perfused lung model. Overexpression of SOD worsened ischemia-reperfusion injury. Interestingly, concomitant overexpression of catalase prevented this adverse effect, but did not protect against ischemia-reperfusion injury. We conclude that Ad-mediated transfer to lungs of both catalase and SOD cDNAs protects from pulmonary O2 toxicity. Absence of protection against ischemia-reperfusion using intratracheal Ad injections may be related to the lack of endothelial protection, despite epithelial expression of catalase and SOD.
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PMID:Gene therapy for oxidant injury-related diseases: adenovirus-mediated transfer of superoxide dismutase and catalase cDNAs protects against hyperoxia but not against ischemia-reperfusion lung injury. 968 20

Nitroxide stable free radicals have previously been found to afford protection in various biological systems against diverse types of oxidative stress, including, ischemia/reperfusion, hyperoxia, mechanical trauma, toxic xenobiotics, ionizing radiation, gastric and colonic irritants or strong oxidants. Dismutation of superoxide has originally been suggested to be one of the mechanisms that underlie the anti-oxidant effect of nitroxides. However, no direct evidence has been found, so far, to support this assumption. In the present study, superoxide and H2O2, generated enzymatically, were used to directly inactivate papain, a sulfhydryl enzyme, in vitro. The rate of papain inactivation served to assess the damage. The reaction mixtures contained a chelate in order to prevent the effect of adventitious redox-active metal ions, pre-empt the Fenton reaction and avoid hydroxyl-induced damage. Catalase or SOD alone partially protected the papain from inactivation. The protective effect of nitroxides resembled that of SOD in several aspects: a) nitroxides provided partial protection; b) the protective effect of nitroxides did not increase with the elevation of their concentration (above 0.5 mM); c) the combined addition of SOD and the nitroxide did not provide greater protection than that demonstrated by nitroxides or SOD separately; d) the effects of catalase with the nitroxide were additive; e) the nitroxide, like SOD itself, did not protect papain from H2O2-induced inactivation; f) the nitroxide was found not to be consumed in the course of the reaction but rather to be recycled. The results indicate that: (a) the main species responsible for the papain inactivation in a system in which the effect of transition metals is pre-empted, are O2-. and H2O2; (b) nitroxides inhibit the oxidative damage by removing superoxide not stoichiometrically, but rather catalytically as SOD-mimics; (c) nitroxides do not afford protection when the oxidative damage is induced directly by H2O2 (and not mediated by redox-active metals).
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PMID:An SOD-mimicry mechanism underlies the role of nitroxides in protecting papain from oxidative inactivation. 982 49

Extracellular superoxide dismutase (EC-SOD, or SOD3) is the major extracellular antioxidant enzyme in the lung. To study the biologic role of EC-SOD in hyperoxic-induced pulmonary disease, we created transgenic (Tg) mice that specifically target overexpression of human EC-SOD (hEC-SOD) to alveolar type II and nonciliated bronchial epithelial cells. Mice heterozygous for the hEC-SOD transgene showed threefold higher EC-SOD levels in the lung compared with wild-type (Wt) littermate controls. A significant amount of hEC-SOD was present in the epithelial lining fluid layer. Both Tg and Wt mice were exposed to normobaric hyperoxia (>99% oxygen) for 48, 72, and 84 hours. Mice overexpressing hEC-SOD in the airways attenuated the hyperoxic lung injury response, showed decreased morphologic evidence of lung damage, had reduced numbers of recruited inflammatory cells, and had a reduced lung wet/dry ratio. To evaluate whether reduced numbers of neutrophil infiltration were directly responsible for the tolerance to oxygen toxicity observed in the Tg mice, we made Wt and Tg mice neutropenic using anti-neutrophil antibodies and subsequently exposed them to 72 hours of hyperoxia. Both Wt and Tg neutrophil-depleted (ND) mice have less severe lung injury compared with non-ND animals, thus providing direct evidence that neutrophils recruited to the lung during hyperoxia play a distinct role in the resultant acute lung injury. We conclude that oxidative and inflammatory processes in the extracellular lung compartment contribute to hyperoxic-induced lung damage and that overexpression of hEC-SOD mediates a protective response to hyperoxia, at least in part, by attenuating the neutrophil inflammatory response.
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PMID:Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia. 1019 79

Lipopolysaccharide (LPS) treatment increases survival of rats, but not of mice, during hyperoxia. Manganese superoxide dismutase (Mn SOD) in the lung plays a critical role in LPS-induced tolerance to hyperoxia in rats. Therefore, we now compared the response of lung Mn SOD with treatment of mice and rats with LPS. LPS treatment of rats increased Mn SOD activity and protein concentration, did not change its specific activity, increased Mn SOD mRNA concentration 35-fold, and elevated Mn SOD synthesis 50% without changing general protein synthesis. LPS treatment of mice did not alter any of these parameters except for a 16-fold increase in Mn SOD mRNA concentration. Mn SOD translational efficiency (synthesis/mRNA concentration) was diminished 93% in rat lung and 76% in mouse lung by treatment with LPS. However, the absolute translational efficiency was twofold higher in lungs of LPS-treated rats than in lungs of LPS-treated mice. The failure of LPS to raise Mn SOD activity in mouse lungs is due, at least in part, to a smaller increase in Mn SOD mRNA and lower translational efficiency in LPS-treated mice than in LPS-treated rats.
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PMID:Regulation of lung manganese superoxide dismutase: species variation in response to lipopolysaccharide. 1033 25

Clinical use of nitric oxide (NO) is usually in conjunction with high oxygen concentrations, the effects of which may include lung neutrophil accumulation, apoptosis and upregulation of antioxidant enzyme activity. To define the effects of NO on neutrophils from young piglets and its relationship to lung neutrophil dynamics during hyperoxia we exposed thirty piglets to room air (RA), RA+NO (50 ppm NO), O2 (FiO2> or =0.96) or O2+NO for 5 days. Ten additional animals breathed RA+NO or O2+NO, then recovered in RA for 3 days before sacrifice. Neutrophil CD18 and intracellular oxidant production were measured by flow cytometry. Lung apoptosis were assessed by TUNEL assay. Lung myeloperoxidase, SOD and catalase were measured biochemically. When compared to RA group, there was significant reduction in neutrophil CD18 and intracellular oxidant production in the RA+NO group, but lung MPO was unchanged. The O2 and O2+NO groups did not differ in CD18 expression or in intracellular oxidant production, but had significant increase in lung myeloperoxidase compared to the RA group. Apoptosis increased significantly only in the O2+NO group. The O2 group showed significantly increased lung SOD and catalase activity compared to the RA group, whereas the RA+NO and O2+NO groups did not. We conclude that inhaled NO at 50 ppm decreases neutrophil CD18 expression as well as intracellular oxidant production. However, this effect does not impact lung neutrophil accumulation during concurrent hyperoxia. The combination of NO and O2 exposure produces an increase in lung apoptosis. Finally, NO may prevent upregulation of SOD and catalase activity during hyperoxia, potentially increasing injury.
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PMID:Independent and combined effects of prolonged inhaled nitric oxide and oxygen on lung inflammation in newborn piglets. 1065 29

Ceruloplasmin, metallothionein, and ferritin are metal-binding proteins with potential antioxidant activity. Despite evidence that they are upregulated in pulmonary tissue after oxidative stress, little is known regarding their influence on trace metal homeostasis. In this study, we have used copper- and zinc-containing superoxide dismutase (Cu/Zn SOD) transgenic-overexpressing and gene knockout mice and hyperoxia to investigate the effects of chronic and acute oxidative stress on the expression of these metalloproteins and to identify their influence on copper, zinc, and iron homeostasis. We found that the oxidative stress-mediated induction of ceruloplasmin and metallothionein in the lung had no effect on tissue levels of copper, iron, or zinc. However, Cu/Zn SOD expression had a marked influence on hepatic copper and iron as well as circulating copper homeostasis. These results suggest that ceruloplasmin and metallothionein may function as antioxidants independent of their role in trace metal homeostasis and that Cu/Zn SOD functions in copper homeostasis via mechanisms distinct from its superoxide scavenging properties.
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PMID:Cellular response of antioxidant metalloproteins in Cu/Zn SOD transgenic mice exposed to hyperoxia. 1140 60

Surfactant protein B (SP-B) is known to promote surfactant phospholipid film formation and reduce surface tension. Native SP-B is a homodimer in which subunit association is stabilized via covalent linkage through cysteine 48. We hypothesized that loss of the intersubunit bridge would alter SP-B function and lead to increased inflammation in response to challenge by hyperoxia or endotoxin. Transgenic mice in which SP-B cysteine 48 was mutated to serine were generated and crossed into the SP-B(-/-) background. Wild-type mice and transgenic mice carrying a single copy (SP-Bmon(+)) or two copies (SP-Bmon(++)) of the transgene were exposed to 95% O2 for 3 days or intratracheally injected with 10 microg of endotoxin. Interleukin-1beta, major intrinsic protein 2, and interleukin-6 in lung homogenates after 3 days of hyperoxia were significantly higher (P < 0.001) in SP-Bmon(+) mice than SP-Bmon(++) or wild-type mice. At 16 h after endotoxin injection, cytokines in lung tissues were higher in SP-Bmon(+) mice compared with wild-type mice (P < 0.05). Consistent with prolonged recovery in SP-Bmon(+) mice, the percentage of apoptotic cells in alveolar lavage was significantly lower in SP-Bmon(+) mice than in SP-Bmon(++) and wild-type mice. Overall, increased inflammation in SP-Bmon(+) mice was corrected to a large extent by increased gene dosage, indicating that formation of the intersubunit disulfide bridge is not critical for SP-B function.
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PMID:Intersubunit disulfide bridge is not required for the protective role of SP-B against lung inflammation. 1213 57

alpha-Tochopherol transfer protein (alpha TTP), a 32 kDa protein exclusively expressed in liver cytosol, has a high binding affinity for alpha-tochopherol. The factors that regulate the expression of hepatic alpha TTP are not clearly understood. In this study, we investigated whether or not exposure to hyperoxia (> 95% O2 for 48 h) could alter the expression of hepatic alpha TTP. We also examined the association between the expression of antioxidant enzymes (hepatic glutathione peroxidase (GPX) and Mn-superoxide dismutase (Mn-SOD)) and the expression of hepatic alpha TTP. The levels of thiobarbituric acid-reactive substances (TBARS) in both plasma and liver were significantly higher after rats were exposed to hyperoxia for 48 h when compared with the levels in control rats. Northern blotting showed a decrease in the expression of alpha TTP messenger RNA (mRNA) after hyperoxia, although the alpha TTP protein level remained constant. Expression of Mn-SOD mRNA and protein, as well as the expression of GPX mRNA, were stable after hyperoxia. These findings indicate that mRNA for hepatic alpha TTP, rather than Mn-SOD or GPX, may be highly responsive to oxidative stress.
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PMID:alpha-Tocopherol transfer protein expression in rat liver exposed to hyperoxia. 1244 18


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