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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that hyperoxia inhibits proliferation and increases the expression of the tumor suppressor p53 and its downstream target, the cyclin-dependent kinase inhibitor p21(CIP1/WAF1), which inhibits proliferation in the G1 phase of the cell cycle. To determine whether growth arrest was mediated through activation of the p21-dependent G1 checkpoint, the kinetics of cell cycle movement during exposure to 95% O2 were assessed in the Mv1Lu and A549 pulmonary adenocarcinoma cell lines. Cell counts, 5-bromo-2'-deoxyuridine incorporation, and cell cycle analyses revealed that growth arrest of both cell lines occurred in S phase, with A549 cells also showing evidence of a G1 arrest. Hyperoxia increased p21 in A549 but not in Mv1Lu cells, consistent with the activation of the p21-dependent G1 checkpoint. The ability of p21 to exert the G1 arrest was confirmed by showing that hyperoxia inhibited proliferation of HCT 116 colon carcinoma cells predominantly in G1, whereas an isogenic line lacking p21 arrested in S phase. The cell cycle arrest in S phase appears to be a p21-independent process caused by a gradual reduction in the rate of DNA strand elongation. Our data reveal that hyperoxia inhibits proliferation in G1 and S phase and demonstrate that p53 and p21 retain their ability to affect G1 checkpoint control during exposure to elevated O2 levels.
Am J Physiol Lung Cell Mol Physiol 2001 Apr
PMID:The role of p21(CIP1/WAF1) in growth of epithelial cells exposed to hyperoxia. 1123 1

Glutamine is an important mitochondrial substrate implicated in the protection of cells from oxidant injury, but the mechanisms of its action are incompletely understood. Human pulmonary epithelial-like (A549) cells were exposed to 95% O2 for 4 days in the absence and presence of glutamine. Cell proliferation in normoxia was dependent on glutamine, and glutamine deprivation markedly accelerated cell death in hyperoxia. Glutamine significantly increased cellular ATP levels in normoxia and prevented the loss of ATP in hyperoxia seen in glutamine-deprived cells. Mitochondrial membrane potential as assessed by flow cytometry with chloromethyltetramethylrosamine was increased by glutamine in hyperoxia-exposed A549 cells, and a glutamine dose-dependent increase in mitochondrial membrane potential was detected. Glutamine-supplemented, hyperoxia-exposed cells had a higher O2 consumption rate and GSH content. Electron and fluorescence microscopy revealed that, in hyperoxia, glutamine protected cellular structures, especially mitochondria, from damage. In hyperoxia, activity of the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase was partially protected by its indirect substrate, glutamine, indicating a mechanism of mitochondrial protection.
Am J Physiol Lung Cell Mol Physiol 2001 Apr
PMID:Glutamine protects mitochondrial structure and function in oxygen toxicity. 1123 20

The inducible nitric oxide (NO) synthase gene in alveolar macrophages (AMs) is a stress response gene that may contribute to tissue injury in the lung after respiration with high O(2) concentrations through extensive production of NO. In this study, we investigated the influence of hyperoxia on the NO pathway in rat AMs in vitro, its regulation by the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1, and the role of reactive oxygen species (ROS). AMs were treated with lipopolysaccharide (LPS) and/or interferon (IFN)-gamma and incubated under 21 or 85% O(2). Stimulation with LPS and IFN-gamma led to induction of the NO pathway that was further upregulated by hyperoxia. The binding activity of NF-kappaB, in contrast to that of AP-1, was activated on stimulation with LPS and IFN-gamma, and both were further increased under hyperoxia. The antioxidants pyrrolidine dithiocarbamate and N-acetyl-L-cysteine inhibited intracellular ROS production and the NO pathway under both normoxic and hyperoxic conditions but had diverse effects on the transcription factors. The results presented here indicate that hyperoxia can upregulate the NO pathway in stimulated AMs through increased production of intracellular ROS and activation of NF-kappaB and AP-1.
Am J Physiol Lung Cell Mol Physiol 2001 May
PMID:Hyperoxia upregulates the NO pathway in alveolar macrophages in vitro: role of AP-1 and NF-kappaB. 1129 May 14

The objective of this study was to determine whether endogenous nitric oxide (NO), specifically the inducible NO synthase isoform (iNOS: NOS II), reduces or amplifies lung injury in mice breathing at a high oxygen tension. Previous studies have shown that exogenous (inhaled) NO protects against hyperoxia-induced lung injury, and that endogenous NO derived from iNOS inhibits leukocyte recruitment and protects against lung injury induced by lipopolysaccharide. In the present study, hyperoxia (> 98% O(2) for 72 h) induced acute lung injury in both wild-type and iNOS-deficient mice as determined by elevated albumin and lactate dehydrogenase levels in bronchoalveolar lavage fluid (BALF) and by increased extravascular lung water. Lung injury was greater in iNOS-deficient mice than in wild-type mice and was associated with an increased number of polymorphonuclear leukocytes in BALF. iNOS messenger RNA expression levels increased in the lungs of wild-type hyperoxic mice. Nitrotyrosine, a marker of reactive NO species, was expressed in both wild-type and iNOS-deficient mice in hyperoxia, indicating an iNOS-independent pathway for protein nitration. We conclude that iNOS is capable of reducing pulmonary leukocyte accumulation and lung injury. The data indicate that iNOS induction serves as a protective mechanism to minimize the effects of acute exposure to hyperoxia.
Am J Respir Cell Mol Biol 2001 Apr
PMID:Antiinflammatory properties of inducible nitric oxide synthase in acute hyperoxic lung injury. 1130 31

To determine whether overexpression of antioxidant enzymes in lung epithelial cells prevents damage from oxidant injury, stable cell lines were generated with complementary DNAs encoding manganese superoxide dismutase (MnSOD) and/or catalase (CAT). Cell lines overexpressing MnSOD, CAT, or MnSOD + CAT were assessed for tolerance to hyperoxia or paraquat. After exposure to 95% O(2) for 10 d, 44 to 57% of cells overexpressing both MnSOD and CAT and 37 to 47% of cells overexpressing MnSOD alone were viable compared with 7 to 12% of empty vector or parental cells (P < 0.05). To assess if viable cells were capable of cell division after hyperoxic exposures (up to 5 d), a clonogenicity assay was performed. The clonogenic potential of cells overexpressing MnSOD + CAT and MnSOD alone were significantly better than those expressing CAT alone or empty vector controls. In addition, 54 to 72% of cells overexpressing both MnSOD and CAT survived in 1 mM paraquat compared with 58 to 73% with MnSOD alone and 27% with control cells. Overexpression of CAT alone did not improve survival in hyperoxia or paraquat. The combination of MnSOD + CAT did not provide additional protection from paraquat. Data demonstrate that overexpression of MnSOD protects cells from oxidant injury and CAT offers additional protection from hyperoxic injury when co-expressed with MnSOD.
Am J Respir Cell Mol Biol 2001 Apr
PMID:Overexpression of manganese superoxide dismutase protects lung epithelial cells against oxidant injury. 1130 37

Peroxiredoxin I (Prx I) and peroxiredoxin II (Prx II) are found in abundance in the cytoplasm of cells and catalyze the reduction of hydrogen peroxide with the use of electrons provided by thioredoxin. Here we examined Prx I and Prx II expression in rat lung during perinatal development and in response to hyperoxia. Prx I protein increased during late gestation and after birth fell to adult levels; conversely, Prx I mRNA increased after birth. Prx II protein concentration was unchanged in the perinatal period, but Prx II mRNA increased after birth. In response to hyperoxia begun on postnatal day 4, there was no change in Prx II expression; however, Prx I mRNA, protein, and enzymatic activity increased significantly. These data show that 1) Prx I and Prx II are developmentally regulated at the level of translational efficiency and 2) Prx I, but not Prx II, is inducible and is upregulated during the late-gestational preparation for the oxidative stress experienced by the lung at birth and during exposure to hyperoxia in the neonatal period.
Am J Physiol Lung Cell Mol Physiol 2001 Jun
PMID:Rat lung peroxiredoxins I and II are differentially regulated during development and by hyperoxia. 1135 Aug

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.
Am J Physiol Lung Cell Mol Physiol 2001 Jul
PMID:Cellular response of antioxidant metalloproteins in Cu/Zn SOD transgenic mice exposed to hyperoxia. 1140 60

The lung is a major target tissue for oxidative stress, including hyperoxia used to relieve tissue hypoxia. Unfortunately, severe hyperoxia damages DNA, inhibits proliferation, and kills cells, resulting in morbidity and mortality. Although hyperoxia induces the tumor suppressor p53 and its downstream target, the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1) (p21), their role in pulmonary injury remains unknown. Using p53- and p21-deficient mice we demonstrate that hyperoxia induces p21 in the absence of p53, suggesting that previous conclusions that p53 does not modify hyperoxic lung injury cannot be extrapolated to p21. In fact, mean survival of p21-deficient mice decreased by 40% and was associated with terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling staining of alveolar debris, indicative of DNA fragmentation and cell death. Ultrastructural analyses revealed that alveolar endothelial and type I epithelial cells died rapidly by necrosis. Although hyperoxia decreased DNA replication in p21-wild-type lungs, it had no effect on replication in p21-deficient lungs. Our findings suggest that p21 protects the lung from oxidative stress, in part, by inhibiting DNA replication and thereby allowing additional time to repair damaged DNA. Our findings have implications for patients suffering from the toxic effects of supplemental oxygen therapies.
Am J Respir Cell Mol Biol 2001 Jun
PMID:The cyclin-dependent kinase inhibitor p21 protects the lung from oxidative stress. 1141 35

We observed changes in the local cerebral blood flow (LCBF), red blood cell (RBC) concentration and RBC velocity in alpha-chloralose anesthetized rats using laser-Doppler flowmetry during activation of the somatosensory cortex following electrical stimulation of the hind paw under hyperoxia (PaO(2)=513.5+/-48.4 mmHg; mean+/-S.D.) and normoxia (PaO(2)=106.4+/-8.4 mmHg). Electrical stimuli of 5 and 10 Hz (pulse width 0.1 ms) with an intensity of 1.5 mA were applied for 5 s (n=13 at 5 Hz, n=9 at 10 Hz). Baseline levels of LCBF and RBC concentration under hyperoxia were, respectively, 5.6+/-3.3 and 8.8+/-3.0% lower than those under normoxia (P<0.05), and that of RBC velocity under hyperoxia was slightly higher than that under normoxia (NS), suggesting mild vasoconstriction at rest under hyperoxia. At 5 Hz stimulation, after normalization to each baseline level, normalized response magnitudes of LCBF, RBC concentration and RBC velocity under hyperoxia were, respectively, 68.2+/-48.0, 71.1+/-65.5 and 66.0+/-56.3% greater than those under normoxia (P<0.05). At 10-Hz stimulation, normalized response magnitudes of LCBF and RBC concentration under hyperoxia were, respectively, 44.6+/-32.0 and 55.9+/-43.5% greater than those under normoxia (P<0.05), although a significant difference in the normalized response magnitude of RBC velocity was not detected between both conditions. The evoked LCBF under hyperoxia increased earlier, by approximately 0.15 s, than that under normoxia regardless of the stimulus frequency (P<0.05). These results suggest the involvement of oxygen interaction on the regulation of LCBF during neuronal activation.
Comp Biochem Physiol A Mol Integr Physiol 2001 Jun
PMID:Hemodynamics of local cerebral blood flow induced by somatosensory stimulation under normoxia and hyperoxia in rats. 1142 9

The beneficial use of supplemental oxygen therapies to increase arterial blood oxygen levels and reduce tissue hypoxia is offset by the knowledge that it injures and kills cells, resulting in increased morbidity and mortality. Although many studies have focused on understanding how hyperoxia kills cells, recent findings reveal that it also inhibits proliferation through activation of cell cycle checkpoints rather than through overt cytotoxicity. Cell cycle checkpoints are thought to be protective because they allow additional time for injured cells to repair damaged DNA and other essential molecules. During recovery in room air, the lung undergoes a burst of proliferation to replace injured and dead cells. Failure to terminate this proliferation has been associated with fibrosis. These observations suggest that growth-suppressive signals, which inhibit proliferation of injured cells and terminate proliferation when tissue repair has been completed, may play an important role in the pulmonary response to hyperoxia. Because DNA replication is coupled with DNA repair, activation of cell cycle checkpoints during hyperoxia may be a mechanism by which cells protect themselves from oxidant genotoxic stress. This review examines the effect of hyperoxia on DNA integrity, pulmonary cell proliferation, and cell cycle checkpoints activated by DNA damage.
Am J Physiol Lung Cell Mol Physiol 2001 Aug
PMID:DNA damage and cell cycle checkpoints in hyperoxic lung injury: braking to facilitate repair. 1143 1


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