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)

Cells that are exposed to free radicals have increased levels of DNA strand breaks with accumulation of the tumor suppressor protein p53, which induces cell cycle arrest and/or apoptosis. Because oxidants injure pulmonary epithelial cells, it was hypothesized that exposure to hyperoxia promotes DNA strand breaks in lung epithelium, resulting in increased expression of p53 and loss of epithelial cell function. Adult male C57Bl/6J mice were exposed to > 95% oxygen for 72 h and DNA integrity was determined in their lungs by terminal transferase immunoreactivity. Both nonimmunoreactive and lightly stained nuclei were observed in cells comprising the airway and parenchyma. Exposure to hyperoxia resulted in a marked increase in the intensity of nuclear staining in distal bronchiolar epithelium and alveolar epithelial and endothelial cells. Airway epithelial cells from control lungs contained detectable levels of p53 protein, which markedly increased in both nuclei and cytoplasm of distal bronchiolar epithelial cells and to a lesser extent in alveolar epithelial cells that were morphologically consistent with type II cells. Western and Northern blot analyses revealed that hyperoxia increased total lung p53 protein expression but not levels of mRNA. Changes in terminal transferase immunoreactivity and p53 expression were not observed in large airway cells, fibroblasts underlying distal airway, or smooth muscle cells. Expression of SP-B mRNA modestly increased and Clara cell secretory protein and cytochrome P-450 2F2 mRNAs decreased, providing additional evidence that hyperoxia injured pulmonary epithelial cells. These findings support the concept that hyperoxia damages DNA of pulmonary epithelial cells, which respond by accumulating p53 and changes in epithelial cell-specific gene expression.
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PMID:Exposure to hyperoxia induces p53 expression in mouse lung epithelium. 944 44

Inhaled nitric oxide (NO) is an important new therapeutic agent used to treat pulmonary arterial hypertension in a variety of disease states. However, the effects of NO on cells in the lung are uncertain. Previously, we have shown that NO gas depresses neutrophil oxidative cell function and increases neutrophil cell death. The purpose of this in vitro study was to determine the mechanism of neutrophil death. We hypothesized that NO hastened cell death by inducing apoptosis. To mimic the clinical environment of patients with respiratory failure, we also studied the effects of hyperoxia on neutrophil cell viability and apoptosis. Isolated human neutrophils were exposed to 80% O2 (O2), NO at 20 ppm in room air (NO/RA), 20 ppm NO blended with 80% O2 (NO/O2), or RA alone (control) for 2 to 24 h. Experiments were repeated with NO concentrations of 5 and 50 ppm and with 20 ppm in the presence of superoxide dismutase (SOD). Neutrophils were also incubated in the absence or presence of neutrophil stimulant fMLP (10 nM). Neutrophil cell viability was measured by fluorescence viability/cytotoxicity assay. Neutrophil apoptosis was assessed by cell death detection ELISA for histone-associated DNA fragments, TdT transferase-mediated fluorescence-labeled dUTP nick end labeling (TUNEL) assay, and DNA fragmentation gel electrophoresis. NO/O2-exposed neutrophils showed decreased viability at 2 h (31.7 +/- 3.7%, mean % viability +/- SD) compared with control (94.7 +/- 4.7%), O2 (75.6 +/- 9.3%), and NO/RA (62.8 +/- 14.9%; P < 0.05 by ANOVA; n = 9). Although control neutrophils demonstrated marked apoptosis at 24 h, there was no significant apoptosis at 2, 4, or 6 h (P < 0.001 by Kruskal-Wallis, n = 20) as assessed by ELISA and TUNEL assays. When compared with RA controls at 2 h, neutrophils exposed to NO/O2 showed significantly more apoptosis (292% of control, range: 106 to 2,488%, P < 0.001 by ANOVA and Kruskal-Wallis) but not with exposure to NO/RA or O2 alone. These findings were confirmed by TUNEL assay (n = 4, P < 0.05). NO/ RA and NO/O2-exposed neutrophils demonstrated both evidence of necrosis and enhanced DNA fragmentation at 2 h by gel electrophoresis (n = 2). Fifty parts per million NO produced similar findings, but exposure to 5 ppm NO did not induce significant DNA fragmentation. Coincubation with SOD inhibited NO/ O2-associated apoptosis, suggesting peroxynitrite contributed to cell death. Stimulation with fMLP did not alter apoptosis induced in neutrophils exposed to NO/RA or NO/O2. We conclude that exogenous NO gas, at clinically relevant concentrations under hyperoxic conditions, induces cell death in neutrophils in part by enhancing DNA fragmentation.
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PMID:Exogenous nitric oxide enhances neutrophil cell death and DNA fragmentation. 949 Jun 60

High concentrations of oxygen, indispensable for the treatment of severe hypoxemia from neonatal as well as adult respiratory distress syndrome, increase the risk of oxygen toxicity. Biochemical mechanisms are lipid peroxidation, protein sulfhydryl oxidation, enzyme inactivation, and DNA damage. Recent reports suggest that cytokines might be involved in free radical injury as well as in adaptive response to hyperoxic injury. However, actual signal transduction pathways involving cytokines have not yet been clarified. In this study we exposed cultured human umbilical vein endothelial cells (HUVECs) to either ambient air or 100% oxygen, and compared for the rate of DNA synthesis ([3H]thymidine uptake) at different time points up to 72 h. After exposing the cells to each treatment condition, we extracted RNA, constructed complementary DNA using reverse transcriptase, amplified the specific DNA segments of cytokines by polymerase chain reaction (PCR), and used the PCR products for gel electrophoresis to examine the bands which signified mRNA levels of corresponding cytokines. There was a significant decrease in the rate of DNA synthesis as early as 24 h. The mRNA expression of IL-1 beta and TNFa seemed less influenced by hyperoxia, while IL-8 and TGF beta showed marked increase in mRNA levels at 6 h of 100% oxygen exposure.
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PMID:Hyperoxia influences mRNA expression of cytokines in cultured human umbilical vein endothelial cells. 952 79

Impairment of lung aconitase activity, citric acid cycle, and mitochondrial respiration by hyperoxia necessitates the elevation of glycolysis for energy production and of pentose shunt activity for reducing equivalents. The molecular mechanisms that allow increased glucose utilization are unknown. Adult male and female rats were adapted to sublethal hyperoxia, equivalent to 83% oxygen at sea level, or air for 7 days. Lung RNA and protein increased in hyperoxia (197 and 57%, respectively), whereas total DNA was unchanged. In hyperoxia, lung total hexokinase (HK) activity increased threefold, and mRNAs for HK-II and -III were specifically upregulated. HK-I mRNA was unchanged. mRNAs for HK-II and -III gradually increased during the first 72 h in hyperoxia. HK-II mRNA was significantly elevated at 72 h, preceding changes in lung cell populations. Although virtually absent in air, HK-II activity was highly expressed in hyperoxia. Among lung glucose transporters, specific expression of mRNAs for GLUT-4 (insulin dependent) and sodium-glucose cotransporter-1 was decreased, whereas that for GLUT-1 was minimally changed. Adaptation to hyperoxia involves coordinated changes in gene expression for the proteins regulating pulmonary glucose transport.
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PMID:Changes in pulmonary expression of hexokinase and glucose transporter mRNAs in rats adapted to hyperoxia. 953 Jan 66

Acute lung injury is a frequent and treatment-limiting consequence of therapy with hyperoxic gas mixtures. To determine if IL-11 is protective in oxygen toxicity, we compared the effects of 100% O2 on transgenic mice that overexpress IL-11 in the lung and transgene (-) controls. IL-11 markedly enhanced survival in 100% O2 with 100% of transgene (-) animals dying within 72-96 h and > 90% of transgene (+) animals surviving for more than 10 d. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment. Significant differences in copper zinc superoxide dismutase and catalase activities were not noted and the levels of total, reduced and oxidized glutathione were similar in transgene (+) and (-) animals. Glutathione reductase, glutathione peroxidase, and manganese superoxide dismutase activities were slightly higher in transgene (+) as versus (-) mice after 100% O2 exposure, and IL-11 diminished hyperoxia-induced expression of IL-1 and TNF. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-11 markedly diminished this cell death response. These studies demonstrate that IL-11 markedly diminishes hyperoxic lung injury. They also demonstrate this protection is associated with small changes in lung antioxidants, diminished hyperoxia-induced IL-1 and TNF production, and markedly suppressed hyperoxia-induced DNA fragmentation.
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PMID:Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. 957 62

A rat clonal pheochromocytoma cell line (PC12) was cultured under normoxic (21% O2) and hyperoxic (50% O2) conditions. PC12 cells underwent apoptotic cell death when they were cultured in charcoal-stripped medium in a high-oxygen atmosphere. Vitamin E homologs, alpha-tocopherol (alphaT), beta-tocopherol (betaT), gamma-tocopherol (gammaT), and delta-tocopherol (deltaT), were added to the culture medium to study their biological activities. AlphaT was more effective than gammaT and deltaT in preventing hyperoxia-induced cell death. Addition of exogenous alphaT to charcoal-treated medium prevented lactate dehydrogenase (LDH) leakage from PC12 cells and also inhibited the apoptosis, which was accompanied by DNA fragmentation. Additional alphaT was rapidly concentrated in PC12 cells, suggesting that it exerts antioxidant effects. Our data show that PC12 cell death under high-oxygen conditions is due to apoptosis and that, among the vitamin E homologs, alphaT most effectively prevents hyperoxic apoptosis.
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PMID:alpha-Tocopherol protects PC12 cells from hyperoxia-induced apoptosis. 957 8

Mice exposed to 100% O2 die after 3 or 4 d with diffuse alveolar damage and alveolar edema. Extensive cell death is evident by electron microscopy in the alveolar septa, affecting both endothelial and epithelial cells. The damaged cells show features of both apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane). The electrophoretic pattern of lung DNA indicates both internucleosomal fragmentation, characteristic of apoptosis, and overall degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bax, bcl-x, and Fas, which are known to be expressed in certain types of apoptosis. However, we did not detect an increased activity of proteases belonging to the apoptosis "executioner" machinery, such as CPP32 (caspase 3), ICE (caspase 1), or cathepsin D. Furthermore, administration of an ICE-like protease inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manifested an increased resistance to hyperoxia-induced lung damage. These results show that both necrosis and apoptosis contribute to cell death during hyperoxia. Multiple apoptotic pathways seem to be involved in this, and an antiapoptotic strategy does not attenuate alveolar damage.
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PMID:Oxygen toxicity in mouse lung: pathways to cell death. 976 53

Melatonin was recently reported to be an effective free radical scavenger and antioxidant. Melatonin is believed to scavenge the highly toxic hydroxyl radical, the peroxynitrite anion, and possibly the peroxyl radical. Also, secondarily, it reportedly scavenges the superoxide anion radical and it quenches singlet oxygen. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase (all of which are antioxidative enzymes), thereby increasing its antioxidative capacity. Also, melatonin, at least at some sites, inhibits nitric oxide synthase, a pro-oxidative enzyme. In both in vivo and in vitro experiments melatonin has been shown to reduce lipid peroxidation and oxidative damage to nuclear DNA. While these effects have been observed primarily using pharmacological doses of melatonin, in a small number of experiments melatonin has been found to be physiologically relevant as an antioxidant as well. The efficacy of melatonin in inhibiting oxidative damage has been tested in a variety of neurological disease models where free radicals have been implicated as being in part causative of the condition. Thus, melatonin has been shown prophylactically to reduce amyloid beta protein toxicity of Alzheimer's disease, to reduce oxidative damage in several models of Parkinson's disease (dopamine auto-oxidation, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), to protect against glutamate excitotoxicity, to reduce ischemia-reperfusion injury, to lower neural damage due to gamma-aminolevulinic acid (phorphyria), hyperbaric hyperoxia and a variety of neural toxins. Since endogenous melatonin levels fal 1 markedly in advanced age, the implication of these findings is that the loss of this antioxidant may contribute to the incidence or severity of some age-associated neurodegenerative diseases.
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PMID:Oxidative damage in the central nervous system: protection by melatonin. 977 Feb 44

Hyperoxic lung injury results in decreased cell proliferation, DNA damage, and cell death. Because the cyclin-dependent kinase inhibitor p21(Cip1/WAF1) (p21) inhibits cell proliferation in G1/S, enhances DNA repair, and regulates apoptosis in some cells, we hypothesized that the expression of p21 would increase in lungs of C57Bl/6J male mice exposed to and recovered from > 95% oxygen. A low level of p21 messenger RNA (mRNA) expression was detected by Northern blot analysis of room air-exposed lungs. Exposure to hyperoxia resulted in a modest increase in p21 mRNA expression by 24 h, followed by a marked induction by 48 to 72 h. In situ hybridization revealed that p21 mRNA abundance increased in bronchiolar epithelium and in resident alveolar cells, but not in smooth-muscle cells or large airway epithelium. Hyperoxia increased the expression of p21 protein by 24 h and continued to increase at 48 and 72 h. Immunohistochemical staining showed that p21 protein accumulated in the bronchiolar epithelium and in alveolar regions that had increased p21 mRNA expression. In contrast, the expression of the cyclin-dependent kinase inhibitor p27(Kip1) was not altered by hyperoxia. To determine whether p21 expression was altered during the repair process, mice were exposed to hyperoxia for 64 h and allowed to recover for up to 4 d in room air. The abundance of p21 mRNA and protein decreased by 1 to 2 d of recovery and returned to room air-exposed levels by 3 to 4 d of recovery. These findings support the concept that bronchiolar epithelial and alveolar cells damaged by hyperoxia express molecules such as p21, which may participate in regulating cell proliferation, DNA repair, and cell death.
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PMID:Accumulation of p21(Cip1/WAF1) during hyperoxic lung injury in mice. 980 42

Different DNA-damaging treatments produce a senescence-like phenotype. Young human fibroblasts are transferred to a senescence-like state after 4 to 6 weeks of culture under 40% ambient oxygen partial pressure. In order to understand the causes of senescence it would be advantageous to know how well this state equals accelerated senescence. Therefore, we measured the expression of genes with known senescence-specific expression pattern in human fibroblasts, which were irreversibly proliferation-inhibited by chronic hyperoxic treatment. A senescence-specific gene expression pattern was confirmed by semiquantitative RT-PCR for eight out of nine examined genes in BJ foreskin fibroblasts and for four out of four genes in MRC-5 lung fibroblasts. For all these cases, gene expression under hyperoxia was similar to that in senescent cells, suggesting that chronic mild hyperoxia is a valid model for accelerated senescence.
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PMID:Similar gene expression pattern in senescent and hyperoxic-treated fibroblasts. 982 40


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