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)

We have previously demonstrated that the lungs of mice can exhibit increased programmed cell death or apoptosis after hyperoxic exposure in vivo. In this report, we show that hyperoxic exposure in vitro can also induce apoptosis in cultured murine macrophage cells (RAW 264.7) as assessed by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end-labeling, and nucleosomal assays. To further delineate the signaling pathway of hyperoxia-induced apoptosis in RAW 264.7 macrophages, we first show that hyperoxia can activate the mitogen-activated protein kinase (MAPK) pathway, the extracellular signal-regulated kinases (ERKs) p42/p44, in a time-dependent manner as assessed by increased phosphorylation of ERK1/ERK2 by Western blot analyses. Neither the c-Jun NH(2)-terminal kinase/stress-activated protein kinase nor the p38 MAPK was activated by hyperoxia in these cells. Chemical or genetic inhibition of the ERK p42/p44 MAPK pathway by PD-98059, a selective inhibitor of MAPK kinase, and dominant negative mutants of ERK, respectively, attenuated hyperoxia-induced apoptosis as assessed by DNA laddering and nucleosomal ELISAs. Taken together, our data suggest that hyperoxia can induce apoptosis in cultured murine macrophages and that the MAPK pathway mediates hyperoxia-induced apoptosis.
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PMID:Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells. 1048 67

Therapy with high oxygen concentrations (hyperoxia) is often necessary to treat patients with respiratory failure. However, hyperoxia may exacerbate the development of acute lung injury, perhaps by increasing lung epithelial cell death. Therefore, interrupting lung epithelial cell death is an important protective and therapeutic strategy. In the present study, hyperoxia (95% O(2)) results in murine lung epithelium cell death by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end labeling, and Annexin V-fluorescein isothiocyanate flow cytometry assay. We show that hyperoxia increases superoxide production, as assessed by nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity and flow cytometric assay, and increases phospho-extracellular signal-regulated kinase (ERK)1/2 by Western blot analysis. These processes are inhibited by a reactive oxygen species inhibitor, diphenylene iodonium (DPI), and by an inhibitor of the mitogen-activated protein (MAP) or ERK kinase (MEK)/ERK1/2 pathway, PD98059. ERK1/2 activation in hyperoxia is also inhibited by DPI. Hyperoxia-induced cell death is associated with cytochrome c release, subsequent caspase 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, which can all be suppressed by DPI and PD98059. However, the broad caspase inhibitor z-VAD-FMK protects cells from death without affecting superoxide generation and ERK1/2 activation. Taken together, our data suggest that hyperoxia, by virtue of activating NADPH oxidase, generates reactive oxygen species (ROS), which mediates cell death of lung epithelium via ERK1/2 MAPK activation, and functions upstream of caspase activation in lung epithelial cells.
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PMID:Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium. 1259 56

Respiratory failure is a serious consequence of lung cell injury caused by treatment with high inhaled oxygen concentrations. Human lung microvascular endothelial cells (HLMVEC) are a principal target of hyperoxic injury (hyperoxia). Cell stress can cause release of ATP, and this extracellular nucleotide can activate purinoreceptors and mediate responses essential for survival. In this investigation, exposure of endothelial cells to an oxidative stress, hyperoxia, caused rapid but transient ATP release (20.03 +/- 2.00 nm/10(6) cells in 95% O(2) versus 0.08 +/- 0.01 nm/10(6) cells in 21% O2 at 30 min) into the extracellular milieu without a concomitant change in intracellular ATP. Endogenously produced extracellular ATP-enhanced mTOR-dependent uptake of glucose (3467 +/- 102 cpm/mg protein in 95% oxygen versus 2100 +/- 112 cpm/mg protein in control). Extracellular addition of ATP-activated important cell survival proteins like PI 3-kinase and extracellular-regulated kinase (ERK-1/2). These events were mediated primarily by P2Y receptors, specifically the P2Y2 and/or P2Y6 subclass of receptors. Extracellular ATP was required for the survival of HLMVEC in hyperoxia (55 +/- 10% surviving cells with extracellular ATP scavengers [apyrase + adenosine deaminase] versus 95 +/- 12% surviving cells without ATP scavengers at 4 d of hyperoxia). Incubation with ATP scavengers abolished ATP-dependent ERK phosphorylation stimulated by hyperoxia. Further, ERK activation also was found to be important for cell survival in hyperoxia, as treatment with PD98059 enhanced hyperoxia-mediated cell death. These findings demonstrate that ATP release and subsequent ATP-mediated signaling events are vital for survival of HLMVEC in hyperoxia.
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PMID:Extracellular ATP-mediated signaling for survival in hyperoxia-induced oxidative stress. 1476 47

Oxidative stress plays a major role in hyperoxia-induced acute lung injury. We have shown previously that mice lacking the Nrf2 are more susceptible to hyperoxia than are wild-type mice. Nrf2 activates antioxidant response element (ARE)-mediated gene expression involved in cellular protection against toxic insults. The present study was designed to investigate the mechanisms that control the activation of Nrf2 by hyperoxia using a non-malignant murine alveolar epithelial cell line, C10. No significant alteration in the levels of Nrf2 mRNA and protein was found following exposure to hyperoxia. In contrast, hyperoxia caused the translocation of Nrf2 from the cytoplasm to the nucleus within 30-60 min of exposure. Consistent with these observations, gel shift and reporter analyses demonstrated a correlation between the hyperoxia-enhanced ARE DNA-binding activity of Nrf2 and an up-regulation of ARE-driven transcription. Inhibition of NADPH oxidase with diphenyleneiodonium (DPI) blocked both Nrf2 translocation and ARE-mediated transcription. Inhibition of the MEK/ERK pathway caused a similar effect. Consistent with this finding, hyperoxia stimulated ERK-1 and ERK-2 phosphorylation, whereas DPI or N-acetyl-l-cysteine blocked such activation. Hyperoxia stimulated the phosphorylation of endogenous Nrf2, but not in the presence of U0126, suggesting a critical role for ERK signaling in the activation of Nrf2. Consistent with this notion, hyperoxia did not stimulate the phosphorylation of Nrf2 in fibroblasts lacking the ERK-1. Collectively, our findings suggest that hyperoxia-induced, ARE-driven, Nrf2-dependent transcription is controlled by NADPH oxidase and ERK-1 signaling.
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PMID:NADPH oxidase and ERK signaling regulates hyperoxia-induced Nrf2-ARE transcriptional response in pulmonary epithelial cells. 1529 79

Inosine, a naturally occurring purine with anti-inflammatory properties, was assessed as a possible modulator of hyperoxic damage to the pulmonary alveolar epithelium. Rats were treated with inosine, 200 mg/kg ip, twice daily during 48-h exposure to >90% oxygen. The alveolar epithelial type 2 cells (AEC2) were then isolated and cultured. AEC2 isolated from inosine-treated hyperoxic rats had less DNA damage and had increased antioxidant status compared with AEC2 from hyperoxic rats. Inosine treatment during hyperoxia also reduced the proportion of AEC2 in S and G2/M phases of the cell cycle and increased levels of the DNA repair enzyme 8-oxoguanine DNA glycosylase. Bronchoalveolar lavage (BAL) recovered from hyperoxic, inosine-treated rats contained threefold higher levels of active transforming growth factor-beta than BAL from rats exposed to hyperoxia alone, and Smad2 was activated in AEC2 isolated from these animals. ERK1/2 was activated both in freshly isolated and 24-h-cultured AEC2 by in vivo inosine treatment, whereas blockade of the MAPK pathway in vitro reduced the protective effect of in the vivo inosine treatment. Together, the data suggest that inosine treatment during hyperoxic exposure results in protective signaling mediated through pathways downstream of MEK. Thus inosine may deserve further evaluation for its potential to reduce hyperoxic damage to the pulmonary alveolar epithelium.
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PMID:In vivo inosine protects alveolar epithelial type 2 cells against hyperoxia-induced DNA damage through MAP kinase signaling. 1557 26

It is unknown whether base excision DNA repair (BER) proteins interact with mitogen-activated protein kinases (MAPK) under oxidation. Here, we explored roles of BER proteins in signaling transduction involving MAPK during hyperoxia. We demonstrated that ERK1/2 phosphorylation in A549 cells was increased in 95% O(2). p38 activity in A549 cells was also increased by exposure to 95% O(2). To evaluate regulatory roles of MAPK, we have transduced A549 cells and primary alveolar epithelial type II cells (AECII) to overexpress 8-oxoguanine DNA glycosylase (hOgg1). Overexpression of hOgg1 reduced hyperoxic toxicity in A549 and AECII cells. Furthermore, protection by BER against hyperoxia appeared to involve an upregulation of ERK1/2 and downregulation of p38. These observations demonstrate, for the first time, that reduction of hyperoxic toxicity by BER proteins may be involved with MAPK activity, thereby impacting cell survival. Furthermore, our studies suggest that modulation of MAPK may be used in combination with BER proteins to counteract hyperoxic toxicity.
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PMID:Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity. 1605 35

Nuclear factor erythroid 2-related factor (Nrf2) confers protection against cell death induced by hyperoxia and other proapoptotic stimuli. Because phosphoinositide-3-kinase (PI3K)/Akt signaling promotes cell survival, the significance of this pathway in mediating reactive oxygen species (ROS)-dependent hyperoxia-induced Nrf2 activation was investigated in the murine pulmonary epithelial cell line, C10. Inhibition of the PI3K pathway markedly attenuated hyperoxia-induced Nrf2 translocation and ARE (antioxidant response element)-mediated transcription. Consistent with this, hyperoxia markedly stimulated the activation of PI3K pathway, while an NADPH oxidase inhibitor and an antioxidant prevented such activation. The inhibition of Akt activity using a pharmacological inhibitor markedly attenuated Nrf2 translocation and ARE-driven expression. Moreover, overexpression of a dominant-negative Akt mutant attenuated the transcription, whereas a constitutively active mutant stimulated it. These results suggest that PI3K/Akt signaling regulates Nrf2 activation by hyperoxia. Inhibition of the PI3K pathway prevented hyperoxia-stimulated Akt and ERK1/2 kinase activation, which is critical for Nrf2-mediated transcription. Likewise, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, blocked hyperoxia-stimulated Akt and ERK1/2 phosphorylation, Nrf2 nuclear accumulation, and ARE-driven transcription. Consistent with this result, an NADPH oxidase inhibitor blocked hyperoxia- stimulated EGFR phosphorylation, which was correlated with the attenuation of Akt and ERK activation. Collectively, our data suggest that EGFR-PI3K signaling through Akt and ERK kinases regulates ROS-dependent, hyperoxia-induced Nrf2 activation in pulmonary epithelial cells.
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PMID:Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. 1648 36

To investigate the protective effect of retinoic acid (RA) on hyperoxic lung injury and the role of RA as a modulator on mitogen-activated protein kinases (MAPKs), gastation 21 d Sprague-Dawley (SD) fetuses (term = 22 d) were delivered by hysterotomy. Within 12-24 h of birth, premature rat pups were randomly divided into 4 groups (n=12 each): air-exposed control group (group I); hyperoxia-exposed group (group II), air-exposed plus RA group (group III), hyperoxia-exposed plus RA group (group IV). Group I, III were kept in room air, and group II, IV were placed in 85 % oxygen. The pups in groups III and IV were intraperitoneally injected with RA (500 microg/kg every day). All lung tissues of premature rat pups were collected at the 4th day after birth. Terminal transferase d-UTP nick end labeling (TUNEL) staining was used for the detection of cell apoptosis. The expression of PCNA was immunohistochemically detected. Western blot analysis was employed for the determination of phosphorylated and total nonphosphorylated ERKs, JNKs or p38. Our results showed that lungs from the pups exposed to hyperoxia for 4 d exhibited TUNEL-positive nuclei increased markedly throughout the parenchyma (P<0.01), and decreased significantly after RA treatment (P<0.01). The index of PCNA-positive cells was significantly decreased (P<0.01), and was significantly increased by RA treatment (P<0.01). The air-space size was significantly enlarged, secondary crests were markedly decreased in hyperoxia-exposed animals. RA treatment improved lung air spaces and secondary crests in air-exposed pups, but had no effect on hyperoxia-exposure pups. Western blotting showed that the amounts of JNK, p38 and ERK proteins in hyperoxia-exposure or RA-treated lung tissues were same as those in untreated lung tissues (P>0.05), whereas activation of these MAPKs was markedly altered by hyperoxia and RA. After hyperoxia exposure, p-ERK1/2, p-JNK1/2 and p-p38 were dramatically increased (P<0.01), whereas p-JNK1/2 and p-p38 were markedly declined and p-ERK1/2 was further elevated by RA treatment (P<0.01). It is concluded that RA could decrease cell apoptosis and stimulate cell proliferation under hyperoxic condition. The protection of RA on hyperoxia-induced lung injury was related to the regulation of MAP kinase activation.
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PMID:Mechanism of retinoic acid and mitogen-activated protein kinases regulating hyperoxia lung injury. 1685 Jul 40

Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the alpha7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the alpha7nAChR and caused influx of Ca(2+), activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the alpha7nAChR was enhanced when cells were maintained in an environment of 10-15% CO(2) similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the alpha7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention.
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PMID:Nitrosamines as nicotinic receptor ligands. 1745 20

Cystic fibrosis (CF) is a lethal disease caused by defective function of the cftr gene product, the CF transmembrane conductance regulator (CFTR) that leads to oxidative damage and excessive inflammatory response in lungs of CF patients. We here report the effects of oxidative stress (hyperoxia, 95% O(2)) on the expression of pro-inflammatory interleukin (IL)-8 and CXCR1/2 receptors in two human CF lung epithelial cell lines (IB3-1, with the heterozygous F508del/W1282X mutation and CFBE41o- with the homozygous F508del/F508del mutation) and two control non-CF lung epithelial cell lines (S9 cell line derived from IB3-1 after correction with wtCFTR and the normal bronchial cell line 16HBE14o-). Under oxidative stress, the expression of IL-8 and CXCR1/2 receptors was increased in CF, corrected and normal lung cell lines. The effects of oxidative stress were also investigated by measuring the transcription nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) activities. Under oxidative stress, no increase of NF-kappaB activation was observed in CF lung cells in contrast to that observed in normal and corrected CF lung cells. The signalling of mitogen-activated protein (MAP) kinases was further studied. We demonstrated that extracellular signal-regulated kinase (ERK1/2) and AP-1 activity was markedly enhanced in CF but not non-CF lung cells under oxidative stress. Consistently, inhibition of ERK1/2 in oxidative stress-exposed CF lung cells strongly decreased both the IL-8 production and CXCR1/2 expression. Therefore, targeting of ERK1/2 MAP kinase may be critical to reduce oxidative stress-mediated inflammation in lungs of CF patients.
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PMID:Oxidative stress induces extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase in cystic fibrosis lung epithelial cells: Potential mechanism for excessive IL-8 expression. 1793 67


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