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)

The rat gamma-glutamyl transferase mRNA transcripts I, II, and III are derived from three alternative promoters, P(I), P(II), and P(III). In the adult only mRNA III is expressed in the lung. We show that mRNA III gene expression is developmentally regulated in the fetal lung; it is first expressed in gestation. In contrast to the adult lung, the fetal lung expresses mRNA I, II, and III. The switch from the fetal to the adult pattern of gammaGT mRNA expression begins within the first 24 h of birth and is complete by 10 d of age. gammaGT mRNA II disappears within 24 h, mRNA I disappears by 10 d leaving mRNA III as the sole transcript. Alveolar epithelial type 2 cells (AT2) isolated from the adult lung express only mRNA III. When cultured in 21% O2 mRNA III is maintained, but when cultured in 3% O2 the fetal pattern of mRNA I, II and III expression is induced. When AT2 cells in hypoxia are exposed to carbon monoxide, mRNA II is suppressed suggesting that a heme-binding protein (responsive to oxygen) may suppress mRNA II expression and may be responsible for the decrease in lung mRNA II seen after birth. A reporter gene under the control of DNA sequences from the gammaGT P(III) promoter is activated in transient transfection studies in response to hyperoxia, while a deletion construct retaining an antioxidant responsive element is not. Oxygen appears to regulate each of the alternative promoters of the gammaGT gene, such that P(II) is rapidly repressed by a heme-dependent mechanism, P(I), is more gradually repressed by a nonheme mechanism and P(III) is activated by a putative oxygen response element. We hypothesize that similar oxygen-dependent mechanisms regulate other genes in the developing lung at birth.
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PMID:Three alternative promoters of the rat gamma-glutamyl transferase gene are active in developing lung and are differentially regulated by oxygen after birth. 860 44

All forms of aerobic life are faced with the threat of oxidation from molecular oxygen (O2) and have evolved antioxidant defenses to cope with this potential problem. However, cellular antioxidants can become overwhelmed by oxidative insults, including supraphysiologic concentrations of O2 (hyperoxia). Oxidative cell injury involves the modification of cellular macromolecules by reactive oxygen intermediates (ROI), often leading to cell death. O2 therapy, which is a widely used component of life-saving intensive care, can cause lung injury. It is generally thought that hyperoxia injures cells by virtue of the accumulation of toxic levels of ROI, including H2O2 and the superoxide anion (O2-), which are not adequately scavenged by endogenous antioxidant defenses. These oxidants are cytotoxic and have been shown to kill cells via apoptosis, or programmed cell death. If hyperoxia-induced cell death is a result of increased ROI, then O2 toxicity should kill cells via apoptosis. We studied cultured epithelial cells in 95% O2 and assayed apoptosis using a DNA-binding fluorescent dye, in situ end-labeling of DNA, and electron microscopy. Using all approaches we found that hyperoxia kills cells via necrosis, not apoptosis. In contrast, lethal concentrations of either H2O2 or O2- cause apoptosis. Paradoxically, apoptosis is a prominent event in the lungs of animals injured by breathing 100% O2. These data indicate that O2 toxicity is somewhat distinct from other forms of oxidative injury and suggest that apoptosis in vivo is not a direct effect of O2.
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PMID:Cellular oxygen toxicity. Oxidant injury without apoptosis. 866 47

The induction of 8-hydroxyguanine (oh8Gua) endonuclease, a DNA repair enzyme for an oxidatively modified guanine, oh8Gua was studied in various growth conditions in Escherichia coli (AB1157). Anaerobically grown E. coli were found to have a very low activity of this enzyme while aerobically grown cells showed activity about 20 times that of the anaerobic level. Under the same condition, superoxide dismutase (SOD) showed about 6-fold increase in activity. A shift in growth conditions from anaerobic to aerobic resulted in rapid induction of this enzyme, and this induction was blocked (but not completely) by chloramphenicol. It is indicated that molecular oxygen is an effective stimulator to the induction of this enzyme and its induction depends partly on protein synthesis. Superoxide-producing compounds such as paraquat and menadione also increased the activity of endonuclease as well as SOD, but H2O2 showed no effect. Thus, superoxides are also implied as a stimulator. In contrast, hyperoxia induced only SOD not the endonuclease. This induction of the endonuclease by hyperoxia was only observed in a SOD-deficient strain (QC774). The aerobic activity of the endonuclease in QC774 was the same as that of wild types (AB1157, GC4468). It is implied that the responsiveness of oh8Gua endonuclease to superoxides is less sensitive than that of SOD. The endonuclease was also induced by a temperature shift from 30 to 43 degrees C and treatment with nalidixic acid. Among the stimuli used, molecular oxygen seems to be most effective for its induction. The inducible nature of this enzyme will serve as an important mechanism for the protection of oxidative DNA damage in the aerobic environment.
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PMID:Induction of E. coli oh8Gua endonuclease by oxidative stress: its significance in aerobic life. 867 25

Sublethal exposure to hyperoxia in vivo induces oxidative damage that leads to destruction of the pulmonary endothelium, pleural effusion, and eventual pulmonary fibrosis. DNA is a potential target for reactive oxygen species in this system; the principle types of damage to DNA during hyperoxia are single-strand breaks and oxidant damage to bases. Poly(ADP-ribosyl)ation, a posttranslational modification of nuclear proteins, is stimulated by strand breaks in DNA and is required for effective repair of many types of DNA lesions. In this study we have measured lung tissue NAD+ and poly(ADP-ribose) concentrations in response to hyperoxia and niacin deficiency in rats. Male weaning Fischer-344 rats consumed niacin-deficient (ND) or niacin-replete pair-fed (PF) diets for 7 d. Rats from each diet group (n = 6) were then housed in normobaric 85% oxygen for 5 d. Normoxic controls were maintained in air. Hyperoxia increased lung poly(ADP-ribose) concentration by 35% in PF rats, but did not significantly increase levels in ND rats. Niacin deficiency decreased lung NAD+ in normoxic rats, but surprisingly, this deficit was partially reversed by hyperoxia. Liver NAD+ levels increased by 21% during hyperoxia in both diet groups. Heart and kidney NAD+ were unaffected by hyperoxia. Blood was the only tissue measured in which NAD+ was decreased by hyperoxia. Dietary treatment did not affect the increase in the lung wt/b. wt. ratio resulting from hyperoxia. This is the first report in the literature of lung tissue poly(ADP-ribose) measurement. Results show that hyperoxia causes a marked increase in lung poly (ADP-ribose) concentration, but also suggest an adaptation of whole-animal NAD+ metabolism to hyperoxia during niacin deficiency.
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PMID:Lung poly(ADP-ribose) and NAD+ concentrations during hyperoxia and niacin deficiency in the Fischer-344 rat. 872 36

Hyperoxia is a well-characterized model of injury and repair of the lung. Type 1 cell damage is followed by type 2 cell proliferation and differentiation which restore normal structure and function. The epidermal growth factor receptor (EGFR) network is known to be a potent modulator of epithelial cell growth. Here we examine the EGFR network on isolated rat type 2 cells and SV40T-T2, a type 2 cell line, under normoxic conditions, after 24 and 48 h of in vitro hyperoxia, and after 24 h of normoxic recovery. EGF induces tyrosine phosphorylation of EGFRs in type 2 cells and SV40T-T2 cells, which decreases with hyperoxia and increases above normoxic levels in recovering cells, suggesting biphasic changes in receptor number or function with injury. The EGFR appears to be stimulated in an autocrine fashion in these cells. There is decreased DNA synthesis and proliferation in SV40T-T2 and isolated type 2 cells treated with tyrphostin B56, a specific EGFR inhibitor. Pretreatment with suramin, which binds to growth factor, results in increased EGFR tyrosine phosphorylation after stimulation, suggesting disruption of normal autocrine receptor downregulation. We have also identified transforming growth factor-alpha (TGF-alpha) in conditioned media (CM) from normoxic and hyperoxic SV40T-T2 and type 2 cells. Finally, we show increased EGF bioactivity in both bronchoalveolar lavage (BAL) from hyperoxic rats and CM from hyperoxic cells compared with normoxic controls. These findings support an integral role for an autocrine EGFR network in the type 2 cell response to injury.
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PMID:The epidermal growth factor receptor network in type 2 pneumocytes exposed to hyperoxia in vitro. 877 93

To clarify a mechanism for oxygen tolerance in young rats, 3 and 8 week-old rats were exposed to 100% oxygen. All 8 week-old (8W) rats died between 48 and 72h, whereas most 3 week-old (3W) rats survived for more than 72 h under hyperoxia. It was assumed that this difference is attributable to oxygen tolerance in 3W rats compared with 8W rats. To clarify this difference, we measured the change in the activity of DNA polymerase, which is related to the final step of DNA repair. DNA polymerase activity in crude lung extracts from 3W rats increased up to 72 h after oxygen exposure. On the other hand, the activity in 8W rats was decreased at 24 h and 48 h. The activity of DNA polymerase beta, which is related to nuclear DNA (nDNA) repair, was approximately seven times higher in 3W rats than in 8W rats. DNA polymerase beta activities in 3W rats decreased up to 48 h with oxygen exposure, but recovered to pre-exposure levels by 72 h. Moreover, an induction of DNA polymerase gamma, which is related to mitochondrial DNA (mtDNA) replication and/or repair, was observed only in 3W rat lungs after 24 h of oxygen exposure. From these results, we conclude that the induction of DNA polymerase beta and DNA polymerase gamma in lung tissue plays a key role in oxygen tolerance in very young rats.
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PMID:Induction of DNA polymerase beta and gamma in the lungs of age-related oxygen tolerant rats. 878 68

Heme oxygenase (HO) catalyzes the rate-limiting step in the degradation of heme to biliverdin, which is reduced by biliverdin reductase to bilirubin. Heme oxygenase-1 (HO-1) is inducible not only by its heme substrate, but also by a variety of agents causing oxidative stress. Although much is known about the regulation of HO-1 expression, the functional significance of HO-1 induction after oxidant insult is still poorly understood. We hypothesize and provide evidence that HO-1 induction serves to protect cells against oxidant stress. Human pulmonary epithelial cells (A549 cells) stably transfected with the rat HO-1 cDNA exhibit marked increases of HO-1 mRNA levels which were correlated with increased HO enzyme activity. Cells that overexpress HO-1 (A549-A4) exhibited a marked decrease in cell growth compared with wild-type A549 (A549-WT) cells or A549 cells transfected with control DNA (A549-neo). This slowing of cell growth was associated with an increased number of cells in G0/G1 phase during the exponential growth phase and decreased entry into the S phase, as determined by flow cytometric analysis of propidium iodide-stained cells and pulse experiments with bromodeoxyuridine. Furthermore, the A549-A4 cells accumulated at the G2/M phase and failed to progress through the cell cycle when stimulated with serum, whereas the A549-neo control cells exhibited normal cell cycle progression. Interestingly, the A549-A4 cells also exhibited marked resistance to hyperoxic oxidant insult. Tin protoporphyrin, a selective inhibitor of HO, reversed the growth arrest and ablated the increased survival against hyperoxia observed in the A549-A4 cells overexpressing HO-1. Taken together, our data suggest that overexpression of HO-1 results in cell growth arrest, which may facilitate cellular protection against non-heme-mediated oxidant insult such as hyperoxia.
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PMID:Overexpression of heme oxygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia. 881 11

Alveolar epithelial injury occurs universally in common respiratory illnesses associated with diffuse lung damage. After alveolar injury, type II cells proliferate and reestablish epithelial integrity, thereby restoring normal lung structure and function. However, the regulation of type II cell proliferation and alveolar epithelial repair is poorly understood. Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding growth factor that has been shown to be mitogenic for cultured alveolar type II cells. In this study, we determined the effect of intratracheal instillation of rhHGF/SF on type II cell proliferation in vivo. To quantify the alveolar type II cell proliferative response, we developed a double-label immunohistochemical technique to detect replicating alveolar type II cells in formalin-fixed lung sections that utilized the identification of proliferating cells by bromodeoxyuridine (BrdUrd) incorporation into DNA and alveolar type II cells by 3F9 immunoreactivity. BrdUrd detection was optimized by enzymatic antigen recovery and silver intensification of the horseradish peroxidase reaction product. Intratracheal instillation of rhHGF/SF induced a time- and dose-dependent increase in type II cell proliferation. The type II cell labeling index increased to 12.3 +/- 6.0% 48 h after 1.0 mg/kg rhHGF/SF administration, compared with 2.6 +/- 0.9% after PBS instillation. To compare the normal type II cell reparative response with the level of proliferation after exogenous rhHGF/SF administration, we measured the specific alveolar type II cell labeling index in rat lung sections obtained from animals exposed to hyperoxia for 50 h and then allowed to recover in room air. After 1 day of recovery, the alveolar type II cell labeling index was 0.45 +/- 0.2%. The specific labeling index increased to 5.4 +/- 1.3% at 2 days and then declined to 0.31 +/- 0.16% 5 days after hyperoxia exposure. In animals not exposed to hyperoxia, the alveolar type II cell labeling index was 0.6 +/- 0.14%. These studies demonstrated that intratracheal instillation of rhHGF/SF promoted alveolar type II cell proliferation in vivo. The maximal level of type II cell proliferation after rhHGF/SF administration was more than twice that reached during recovery from hyperoxia exposure. Thus, intratracheal instillation of HGF/SF may provide a potential strategy to promote type II cell proliferation and augment alveolar epithelial repair after lung injury.
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PMID:Intratracheal administration of hepatocyte growth factor/scatter factor stimulates rat alveolar type II cell proliferation in vivo. 891 64

To understand the molecular mechanisms that upregulate the activities of pulmonary antioxidant enzymes in adult rats during exposure to 85% oxygen, the relative contents of corresponding mRNA in normal and hyperoxic lungs were determined. Hyperoxic exposure drastically induced the expression of lung manganese-containing superoxide dismutase (MnSOD) mRNA. Maximal induction of MnSOD mRNA occurred at days 3 and 5 of exposure to hyperoxia, reaching a 600 and a 340% increase over the levels of air-exposed rats, respectively. In addition, hyperoxia induced lung mRNA for glucose-6-phosphate dehydrogenase, glutathione peroxidase, glyceraldehyde-3-phosphate dehydrogenase, alpha-tubulin, and gamma-actin to different extends at various days of exposure. Hyperoxia had little or no effect on the levels of mRNA for copper/zinc-containing superoxide dismutase (CuZnSOD), catalase, heat shock protein (HSP70), and creatine kinase. Nuclear run-on experiments showed that the transcriptional rate of the MnSOD gene is enhanced in hyperoxic rat lungs by approximately 400% at day 3 of exposure compared with that of controls. The specific activities of CuZnSOD and MnSOD in these lung samples per unit of lung protein or DNA were also determined. The activity of CuZnSOD in hyperoxic lungs was found to be unchanged compared with controls, except a 20% decrease at day 7 of exposure when standardized against protein content of lung homogenate. Changes of CuZnSOD activity were more dramatic in hyperoxic lungs (a 40% increase at days 3, 5, 7, and 14 of exposure) when enzyme activity was normalized using lung DNA content. Surprisingly, no proportional increase of lung MnSOD enzyme activity was observed at days 3 and 5 of oxygen exposure. The increase of MnSOD activity per unit of lung protein also did not parallel the increase in MnSOD protein content at days 5, 7, and 14 of exposure. These data suggest that, in addition to transcriptional activation, translational and/or posttranslational regulation of the MnSOD gene expression may play a critical role in controlling lung MnSOD activity on hyperoxic exposure.
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PMID:Antioxidant enzyme expression in rat lungs during hyperoxia. 896 16

Tolerance to hyperoxia usually depends on an increase in lung antioxidant enzyme activity. Antioxidant-surfactant liposomes, encapsulating the antioxidant enzymes CuZn-superoxide dismutase (CuZnSOD) and catalase in synthetic surfactant lipids, increase lung antioxidant activity following intratracheal instillation in premature and term rabbits. We investigated whether the exogenous antioxidant enzymes encapsulated in these liposomes inhibit the endogenous antioxidant enzyme synthesis in the premature rabbit lung. Premature rabbits, delivered at 28 days of gestation, were treated intratracheally with antioxidant-surfactant liposomes, surfactant liposomes without antioxidant enzymes, or air placebo at birth and exposed to hyperoxia for 24 h. A comparison group was killed after breathing room air at birth. The right lungs of the pups were assayed for CuZnSOD and catalase activities and DNA content, the left lungs of the same pups were used to quantitate the concentrations of CuZnSOD and catalase mRNA using cRNA probes. Lung CuZnSOD and catalase mRNA quantities increased during exposure to hyperoxia, but were not affected by exogenous antioxidant enzymes. These data suggest that intratracheal instillation of CuZnSOD and catalase does not down-regulate mRNA transcription of these antioxidant enzymes in the premature rabbit lung.
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PMID:Lung CuZn-superoxide dismutase and catalase gene expression in premature rabbits treated intratracheally with antioxidant-surfactant liposomes. 898 40

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