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

Terminal gas-exchange units in the lung of many species are, at birth, relatively large structures termed saccules. Saccules septate postnatally forming smaller units that constitute the final alveoli. In the rat, septation occurs intensively during the first 2 postnatal wk after which it has been considered to stop. Treatment with dexamethasone or exposure to hyperoxia during the first 2 postnatal wk markedly inhibits septation as evidenced by the formation of fewer and bigger alveoli than in normally developed rats. Deferoxamine, an iron chelator, has been reported to protect the lung from the effects of exposure to hyperoxia in early postnatal life. In this study, we investigated the effects of these treatments during the 3rd and 4th postnatal wk, that is, after the early period of rapid alveolarization. Our results show that treatment with dexamethasone no longer had any inhibitory effect on alveoli formation; that exposure to hyperoxia continued to inhibit the formation of new alveoli, resulting in bigger and less numerous alveoli; that treatment of animals exposed to hyperoxia with deferoxamine still protected their lungs against hyperoxic inhibition; and that elastin fiber length density in the lung was significantly reduced in hyperoxic-exposed animals. These results suggest that septation continues beyond the 2nd postnatal wk and does not stop abruptly at age 14 d in air-breathing rats and that hyperoxic inhibition of alveolarization during the 3rd and 4th postnatal wk is due to the inhibition of septation of existing or newly generated gas-exchange units during that period of lung development.
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PMID:The formation of alveoli in rat lung during the third and fourth postnatal weeks: effect of hyperoxia, dexamethasone, and deferoxamine. 813 76

Normal lung development involves septation of the large air saccules present at birth to form smaller diameter alveoli with a much increased surface area for respiratory exchange. This process in the newborn animal is markedly inhibited by hyperoxia, and the altered lung morphology that results may be permanent. We tested whether treatment of neonatal rats with the new 21-aminosteroid (21-AS) drug, U-74389F (15 mg/kg/d), could protect against O2-induced inhibition of normal lung development. By morphometric analysis after 10 d in > 95% O2, the lungs of the animals treated with this potent iron chelator and inhibitor of lipid peroxidation showed a substantial protective effect--with reduced mean air space diameter and significantly increased internal surface area compared with O2 control pups. [Air control mean air space diameter = 47.4 microns, internal surface area = 1014 cm2; O2 controls = 61.0 microns (increases 29%), 769 cm2 (decreases 24%); O2 21-AS = 53.4 microns (increases 13%), 919 cm2 (decreases 9%); p < 0.05 between O2 groups.] Similarly, inhibition of lung elastin deposition (involved in septation process) during hyperoxia was significantly ameliorated by 21-AS treatment. In addition, follow-up studies of young adult rats demonstrated permanently enlarged lung alveoli and reduced surface area after neonatal high O2 exposure. These chronic morphologic effects were also significantly reduced by neonatal 21-AS treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protection against acute and chronic hyperoxic inhibition of neonatal rat lung development with the 21-aminosteroid drug U74389F. 837 24

Free radical generation by hyperoxic endothelial cells was studied using electron paramagnetic resonance (EPR) spectroscopy and the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Studies were performed to determine the radical species produced, whether mitochondrial electron transport was involved, and the effect of the radical generation on cell mortality. Sheep pulmonary microvascular endothelial cell suspensions exposed to 100% O2 for 30 min exhibited prominent DMPO-OH and, occasionally, additional smaller DMPO-R signals thought to arise from the trapping of superoxide anion (O2-.), hydroxyl (.OH), and alkyl (.R) radicals. Superoxide dismutase (SOD) quenched both signals suggesting that the observed radicals were derived from O2-.. Studies with deferoxamine suggested that the generation of .R occurred secondary to the formation of .OH from O2-. via an iron-mediated Fenton reaction. Blocking mitochondrial electron transport with rotenone (20 microM) markedly decreased radical generation. Cell mortality increased slightly in oxygen-exposed cells. This increase was not significantly altered by SOD or deferoxamine, nor was it different from the mortality observed in air-exposed cells. These results suggest that endothelial cells exposed to hyperoxia for 30 min produce free radicals via mitochondrial electron transport, but under the conditions of these experiments, this radical generation did not appear cause cell death.
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PMID:Hyperoxic sheep pulmonary microvascular endothelial cells generate free radicals via mitochondrial electron transport. 838 Aug 15

Previously we have shown that a group of patients treated for iron overdose with prolonged deferoxamine (DFO) infusion died of adult respiratory distress syndrome (ARDS). We now describe a model to investigate the mechanism of this pulmonary toxicity. Mice treated with 1 oral dose of iron (Fe) and then multiple injections of DFO, or with the chelated product ferrioxamine alone, did not develop lung lesions, even at doses which induced mortality. To potentiate any possible free radical reaction, other groups of mice were treated similarly while exposed to 75-80% O2 over a 4-day period. Ten of 12 mice receiving 0.75 mg Fe and then DFO (10 mg, 4 times/day for 4 days) with hyperoxia died suddenly. At autopsy the lungs were dark red and solid; sections showed hyaline membranes and alveolar exudates of edema, fibrin, and PMN. Electron microscopy showed massive destruction of the alveolar epithelium; using cerium chloride, a free radical reaction product was demonstrated at the alveolar surface. Lung lavage fluid contained 10-12 x normal levels of protein when the Fe-DFO-O2 group was compared to air or O2 controls. Mice receiving DFO or Fe, plus O2, showed only slight injury and a small increase in alveolar protein. The results indicate that Fe plus DFO generates free radicals in the lung, a reaction potentiated by hyperoxia to produce an ARDS-like picture. This suggests that the pulmonary toxicity of DFO in iron-poisoned patients is due to its prooxidant activity resulting in free radical destruction of the airblood barrier.
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PMID:Pulmonary toxicity of deferoxamine in iron-poisoned mice. 851 75

To study whether nitric oxide (NO) affects surfactant function, 36 young rats inhaled one of the following humidified environments for 24 h: 1) air; 2) 95% O2; 3) air and 100 parts/million (ppm) NO; and 4) 95% O2 and 100 ppm NO. The treatments did not change the recovery of phospholipid from bronchoalveolar lavage (BAL). Exposure to NO of animals that breathed either air or 95% O2 increased the minimum surface tension of surfactant from BAL at low (1.5 mumol/ml), but not at high (4 mumol/ml), phosphatidylcholine concentration. After inhaled NO, the nonsedimentable protein of BAL decreased the surface activity of surfactant (1 mumol phosphatidylcholine/ml) more than the protein from the controls. NO treatment of animals that breathed either air or 95% O2 affected neither the quantity nor the molecular weight distribution of nonsedimentable protein. Hyperoxia increased the amount of the nonsedimentable protein, whereas NO increased the iron saturation of transferrin. The surfactant fraction and the nonsedimentable protein from BAL were separately exposed to 80 ppm NO in vitro. NO exposure had no effect on the surface activity of surfactant fraction. NO exposure of nonsedimentable protein from the control animals (no NO) increased the inhibition of the surface activity and changed the adsorption spectrum of the protein, suggesting conversion of hemoglobin to methemoglobin. Nonsedimentable protein from NO-exposed animals contained methemoglobin. We propose that surfactant dysfunction caused by inhaled NO is in part due to alteration of protein(s) in epithelial lining fluid that in turn inactivates surfactant.
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PMID:Surfactant dysfunction after inhalation of nitric oxide. 880 10

In respiratory failure, transferrin (TF) with variable iron saturation accumulates in the alveolar space. Binding free iron to TF may inhibit metal-catalyzed formation of free radicals. The aim of this study was to evaluate whether the degree of the iron-saturation of TF influences the severity of respiratory failure and surfactant responsiveness. Surfactant deficiency and lung edema was induced in 42 paralyzed and ventilated young rabbits by bronchoalveolar lavage (BAL); 19 of these animals were preexposed to 100% O2 for 40 hours. The animals received (1) exogenous surfactant intratracheally (100 mg/kg in 4 ml/kg saline); (2) surfactant and Fe(3+)-TF (50 or 25 mg/kg); or (3) surfactant and iron-free TF (50 mg/kg). One hour after administration of TF, 13-25% of exogenous TF was recovered by BAL. Administration of Iron-free TF significantly decreased the iron saturation of TF in BAL. In acute respiratory failure induced by BAL, Fe(3+)-TF decreased the efficacy of exogenous surfactant in improving the gas exchange, and increased surfactant inhibition, while iron-free TF had no effect. By contrast, in respiratory failure induced by hyperoxia and BAL, iron-free TF improved the efficacy of exogenous surfactant, but Fe(2+)-TF had no effect. After administration of iron-free TF, surfactant isolated from BAL was more surface-active than surfactant from BAL of the other hyperoxia-treated animals. In animals exposed to hyperoxia, treatment with iron-free TF decreased malondialdehyde content of BAL. We propose that low iron saturation of TF decreases oxidant stress and favors the recovery from respiratory failure.
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PMID:Transferrin modifies surfactant responsiveness in acute respiratory failure: role of iron-free transferrin as an antioxidant. 885 99

Iron is an important catalyst for free oxygen radicals and lipid peroxidation reactions which may play a role in the pathogenesis of several diseases in premature infants. During the early neonatal period, extracellular iron is available in excessive amounts. We hypothesized that administration of erythropoietin (EPO) mobilizes iron from plasma and inhibits iron-catalyzed reactions. To evaluate this hypothesis, recombinant human EPO (rhEPO) was administered s.c. to premature rabbits delivered at 29-d gestation: one group was kept in room air (RA) and the other in a 100% oxygen environment. Within each group, the animals were randomized to receive placebo or rhEPO at 400 or at 800 U/kg on d 0 and 2 of life. On d 3 or 4, plasma iron and iron saturation of transferrin were assessed. Lipid peroxidation was analyzed in plasma and bronchoalveolar lavage fluid (BAL). Nonsedimentable protein (NSP) and phospholipid content were measured in BAL. Erythropoiesis was evaluated in liver and bone marrow. Treatment with rhEPO decreased plasma iron, decreased iron saturation of transferrin, increased reticulocytes, and increased erythropoiesis in liver and bone marrow in both RA and hyperoxia group. Oxygen exposure increased NSP in BAL and decreased the ability of BAL to inhibit lipid peroxidation as measured by malondialdehyde (MDA) generation compared with RA exposure. In O2-exposed animals, EPO treatment increased the ability of both plasma (EPO 800) and BAL (EPO 400 and 800) to inhibit lipid peroxidation and decreased NSP in BAL (EPO 400). In addition, rhEPO treatment decreased alveolar thickening and proteinaceous exudate in the hyperoxia group. We propose that by stimulating erythropoiesis, rhEPO mobilizes non-heme iron and decreases oxidant injury that depends on the availability of transient metal.
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PMID:Recombinant human erythropoietin: possible role as an antioxidant in premature rabbits. 886 72

Heme oxygenase (HO) is the rate-limiting enzyme in the production of bilirubin from heme, and HO-1 is its inducible isoenzyme. In the metabolic pathway of HO a potential oxidant, heme, is degraded, a potential antioxidant, bilirubin, is generated, and a potent sequestering agent of redox active iron, ferritin, is thought to be coinduced. Therefore, the sum of the reactions of HO may be useful in antioxidant defense. To explore the role of HO in protection against oxidative stress, we examined HO-1 expression in Chinese hamster fibroblasts (HA-1) as well as stable hydrogen peroxide (H2O2)-resistant (OC-14) and 95% O2-resistant (O2R95) variant cell lines derived from HA-1, after exposure to 72 h of hyperoxia (95% O2-5% CO2). Total HO activity, HO-1 protein, and HO-1 mRNA steady-state levels were assessed before exposure and daily during exposure to hyperoxia. Controls were exposed to 95% air-5% CO2. Confluent monolayers of O2R95 and OC-14 cells had increased basal immunoreactive HO-1 protein levels relative to HA-1 cells when the cells were grown in normoxia, and O2R95 had higher total basal HO activity. When exposed to hyperoxia for up to 3 days, O2R95 cells, which were resistant to oxygen-induced killing, did not show induction of HO-1 mRNA or increased immunoreactive protein, whereas OC-14 and HA-1, which were relatively more sensitive than O2R95 to oxygen-related cytotoxicity, demonstrated significant increases in HO-1 expression during exposure to hyperoxia. Basal ferritin protein levels were highest in the O2R95 cells, intermediate in OC-14, and lowest in HA-1, but ferritin protein did not increase further, with hyperoxic exposure, in any of the cell lines. We conclude that increased constitutive HO-1 expression is associated with resistance to hyperoxia, whereas induction of HO-1 mRNA is an index of oxidative injury, since it only occurs after cells have sustained cytotoxic injury. We also conclude that increased ferritin expression does not necessarily accompany increased HO-1 expression in oxidant stress. We speculate that HO-1 plays a role in protection against hyperoxic damage.
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PMID:Differences in basal and hyperoxia-associated HO expression in oxidant-resistant hamster fibroblasts. 889 16

Ferritin is an iron storage protein that is regulated at the transcriptional and transcriptional levels, resulting in a complex mixture of tissue- and condition-specific isoforms. The protein shell of ferritin is composed of 24 subunits of two types (heavy or light), which are encoded by two distinct and independently regulated genes. In the present studies, the isoform profile for lung ferritin differed from other tissues (liver, spleen, and heart) as determined by isoelectric focusing (IEF) and polyacrylamide gel electrophoresis (PAGE). Lung ferritin was composed of equal amounts of heavy and light subunits. Differences in isoform profiles were the result of tissue-specific differential expression of the ferritin subunit genes as demonstrated by Northern blot analyses. Like heart ferritin, lung ferritin exhibited a low iron content that did not increase extensively in response to iron challenge, which contrasts with ferritins isolated from liver or spleen. When animals were exposed to hyperoxic conditions (95% oxygen for up to 60 h), ferritin heavy subunit mRNA levels did not markedly change at any of the investigated time points. In contrast, ferritin light subunit mRNA increased severalfold in response to hyperoxic exposure. Investigation of the cytoplasmic distribution of ferritin mRNA showed that a substantial portion was associated with the ribonucleoprotein (RNP) fraction of the cytosol, suggesting that a pool of untranslated ferritin mRNA exists in the lung. Upon hyperoxic insult, all ferritin light subunit mRNA pools (RNP, monosomal, polysomal) were elevated, although a specific shift from RNP to polysomal pools was not evident. Therefore, the increase in translatable ferritin mRNA in response to hyperoxia resulted from transcriptional rather than specific translational activation. The observed pattern of light chain-specific transcriptional induction of ferritin is consistent with the hypothesis that hyperoxic lung injury is at least partially iron mediated.
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PMID:Pulmonary ferritin: differential effects of hyperoxic lung injury on subunit mRNA levels. 911 60

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


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