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)

Here we discuss the morphological features and our current understanding of the pathways involved in non-apoptotic cell death from O2 toxicity. Preliminary data on hyperoxic signaling indicate that NF-kappa B translocation (and presumptive activation) is not a result of the p42/p44 MAPK pathway, but a likely downstream consequence of activation of the JNK pathway. Our observations suggest the existence of multiple signal transduction pathways in hyperoxia-induced cell death: one involved in the stress response which appears to be NF-kappa B-dependent and another in cell death.
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PMID:Hyperoxia in cell culture. A non-apoptotic programmed cell death. 1066 72

Cell injury and cell death of pulmonary epithelium plays an important role in the pathogenesis of acute lung injury in animals exposed to prolonged hyperoxia. The aim of this study was to decipher the molecular mechanisms modulating cell death induced by hyperoxia in lung epithelium. Cell death is thought to be either apoptotic, with shrinking phenotypes and activated caspases, or oncotic, with swelling organelles. Exposure to 95% O2 (hyperoxia) induced cell death of MLE-12 cells with cellular as well as nuclear swelling, cytosolic vacuolation, and loss of mitochondrial structure and enzyme function. Neither elevated caspase-3 activity nor phosphatidylserine translocation were detected, suggesting that in hyperoxia, MLE-12 cells die via oncosis rather than apoptosis. In addition, hyperoxia triggered a sustained activation of the transcription factor AP-1, as well as mitogen-activated protein kinase (MAPK) family members p38 and JNK. Importantly, survival of MLE-12 cells in hyperoxia was significantly enhanced when either AP-1, p38, or JNK activation was inhibited by either specific inhibitors or dominant negative DNA constructs, indicating that in lung epithelial cells hyperoxia induces a program-driven oncosis, involving AP-1, JNK, and p38 MAPK. Interestingly, hydrogen peroxide-induced oxidative apoptosis of MLE-12 cells, with a shrinking nuclear morphology and activated caspase-3 activity, is also mediated by AP-1, JNK, and p38. Therefore, our data indicate that although they have divergent downstream events, oxidative oncosis and apoptosis share upstream JNK/p38 and AP-1 pathways, which could be used as potential targets for reducing hyperoxic inflammatory lung injury.
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PMID:MAPK pathways mediate hyperoxia-induced oncotic cell death in lung epithelial cells. 1455 62

Neonatal rodents are more tolerant to hyperoxia than adults. We determined whether maturational differences in lung NF-kappaB activation could account for the differences. After hyperoxic exposure (O2 > 95%), neonatal (<12 hours old) lung NF-kappaB binding was increased and reached a maximum between 8 and 16 hours, whereas in adults no changes were observed. Additionally, neonatal NF-kappaB/luciferase transgenic mice (incorporating 2 NF-kappaB consensus sequences driving luciferase gene expression) demonstrated enhanced in vivo NF-kappaB activation after hyperoxia in real time. In the lungs of neonates, there was a propensity toward NF-kappaB activation as evidenced by increased lung I-kappaB kinase protein levels, I-kappaBalpha phosphorylation, beta-transducin repeat-containing protein levels, and total I-kappaBalpha degradation. Increased lung p-JNK immunoreactive protein was observed only in the adult lung. Inhibition of pI-kappaBalpha by BAY 11-7085 resulted in decreased Bcl-2 protein levels in neonatal lung homogenates and decreased cell viability in lung primary cultures after hyperoxic exposure. Furthermore, neonatal p50-null mutant (p50(-/-)) mice showed increased lung DNA degradation and decreased survival in hyperoxia compared with WT mice. These data demonstrate that there are maturational differences in lung NF-kappaB activation and that enhanced NF-kappaB may serve to protect the neonatal lung from acute hyperoxic injury via inhibition of apoptosis.
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PMID:Maturational differences in lung NF-kappaB activation and their role in tolerance to hyperoxia. 1534 85

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

IL-6 overexpression protects mice from hyperoxic acute lung injury in vivo, and treatment with IL-6 protects cells from oxidant-mediated death in vitro. The mechanisms of protection, however, are not clear. We characterized the expression, localization, and regulation of Bax, a proapoptotic member of the Bcl-2 family, in wild-type (WT) and IL-6 lung-specific transgenic (Tg(+)) mice exposed to 100% O(2) and in human umbilical vein endothelial cells (HUVEC) treated with H(2)O(2) and IL-6. In control HUVEC treated with H(2)O(2) or in WT mice exposed to 100% O(2), a marked induction of Bax translocation and dimerization was associated with increased JNK and p38 kinase activity. In contrast, specific JNK or p38 kinase inhibitors or treatment with IL-6 inhibited Bax mitochondrial translocation and apoptosis of HUVEC. IL-6 Tg(+) mice exposed to 100% O(2) exhibited enhanced phosphatidylinositol 3-kinase (PI3K)/Akt kinase and increased serine phosphorylation of Bax at Ser(184) compared with WT mice. The PI3K-specific inhibitor LY-2940002 blocked this IL-6-induced Bax phosphorylation and promoted cell death. Furthermore, IL-6 potently blocked hyperoxia- or oxidant-induced Bax insertion into mitochondrial membranes. Thus IL-6 functions in a cytoprotective manner, in part, by suppressing Bax translocation and dimerization through PI3K/Akt-mediated Bax phosphorylation.
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PMID:IL-6 cytoprotection in hyperoxic acute lung injury occurs via PI3K/Akt-mediated Bax phosphorylation. 1937 89

Hyperoxia-induced oxidative stress plays a key role in many pulmonary diseases. In an earlier study we found the protective effect of the neuropeptide substance P (SP) on type II alveolar epithelial cells (AECIIs) after hyperoxia exposure. Then, we investigated c-Jun N-terminal kinase (C-JNK) signal transduction pathways in AECIIs before and after hyperoxia exposure. Primary AECIIs were isolated and purified from premature rats. Subsequently, the cells were treated with air (21% oxygen), hyperoxia (95% oxygen), SP+ air, and SP+ hyperoxia. SP was added in advance to reach a final concentration 1 x 10(-6) mol/l. The cells were then exposed to air and hyperoxia for 12, 24, and 48 h. XTT cell proliferation assay and fluorescence-activated cell sorting (FACS) were employed to detect cell growth and apoptosis. Phosphorylated JNK (p-JNK) levels were measured using Western blot assay. The morphological alteration of AECIIs was observed using a transmission electron microscope (TEM). Compared with the simple hyperoxia treatment, the cell growth and apoptosis percentage was significantly increased and decreased after adding additional SP. Meanwhile, the reduced levels of p-JNKs could be found after adding SP. Furthermore, the morphological damage of AECIIs was greatly improved. These data suggest that SP can promote AECII proliferation and inhibit apoptosis by suppressing JNK signal pathways after hyperoxia exposure, which attenuates hyperoxia-induced oxidative stress damage in AECIIs. It might be a potential therapy for acute pulmonary injury under hyperoxia-induced oxidative stress.
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PMID:Neuropeptide substance P attenuates hyperoxia-induced oxidative stress injury in type II alveolar epithelial cells via suppressing the activation of JNK pathway. 1978 13

This study examined the effects of retinoic acid (RA), PD98059, SP600125 and SB203580 on the hyperoxia-induced expression and regulation of matrix metalloproteinase-2 (MMP-2) and metalloproteinase-2 (TIMP-2) in premature rat lung fibroblasts (LFs). LFs were exposed to hyperoxia or room air for 12 h in the presence of RA and the kinase inhibitors PD98059 (ERK1/2), SP600125 (JNK1/2) and SB203580 (p38) respectively. The expression levels of MMP-2 and TIMP-2 mRNA were detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). MMP-2 activity was measured by zymography. The amount of p-ERK1/2, REK1/2, p-JNK1/2, JNK1/2, p-p38 and p38 was determined by Western blotting. The results showed that: (1) PD98059, SP600125 and SB203580 significantly inhibited p-ERK1/2, p-JNK1/2 and p-p38 respectively in LFs; (2) The expression of MMP-2 mRNA in LFs exposed to hyperoxia was decreased after treatment with RA, SP600125 and SB203580 respectively (P<0.01 or 0.05), but did not change after treatment with PD98059 (P>0.05). Meanwhile, RA, PD98059, SP600125 and SB203580 had no effect on the expression of TIMP-2 mRNA in LFs exposed to room air or hyperoxia (P>0.05); (3) The expression of pro- and active MMP-2 experienced no change after treatment with RA or SP600125 in LFs exposed to room air (P>0.05), but decreased remarkably after hyperoxia (P<0.01 or 0.05). SB203580 inhibited the expression of pro- and active MMP-2 either in room air or under hyperoxia (P<0.01). PD98059 exerted no effect on the expression of pro- and active MMP-2 (P<0.05). It was suggested that RA had a protective effect on hyperoxia-induced lung injury by down-regulating the expression of MMP-2 through decreasing the JNK and p38 activation in hyperoxia.
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PMID:Retinoic acid diminished the expression of MMP-2 in hyperoxia-exposed premature rat lung fibroblasts through regulating mitogen-activated protein kinases. 2150 95

Both prolonged exposure to hyperoxia and large tidal volume mechanical ventilation can each independently cause lung injury. However, the combined impact of these insults is poorly understood. We recently reported that preexposure to hyperoxia for 12 h, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone (Makena et al. Am J Physiol Lung Cell Mol Physiol 299: L711-L719, 2010). The upstream mechanisms of this lung injury and apoptosis have not been clearly elucidated. We hypothesized that lung injury in this model was dependent on oxidative signaling via the c-Jun NH(2)-terminal kinases (JNK). We, therefore, evaluated lung injury and apoptosis in the presence of N-acetyl-cysteine (NAC) in both mouse and cell culture models, and we provide evidence that NAC significantly inhibited lung injury and apoptosis by reducing the production of ROS, activation of JNK, and apoptosis. To confirm JNK involvement in apoptosis, cells treated with a specific JNK inhibitor, SP600125, and subjected to preexposure to hyperoxia, followed by mechanical stretch, exhibited significantly reduced evidence of apoptosis. In conclusion, lung injury and apoptosis caused by preexposure to hyperoxia, followed by high tidal volume mechanical ventilation, induces ROS-mediated activation of JNK and mitochondrial-mediated apoptosis. NAC protects lung injury and apoptosis by inhibiting ROS-mediated activation of JNK and downstream proapoptotic signaling.
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PMID:Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent on oxidant-mediated c-Jun NH2-terminal kinase activation. 2179 26

MRP4 (multidrug resistance-associated protein 4) is a member of the MRP/ABCC subfamily of ATP-binding cassette (ABC) transporters that are essential for many cellular processes requiring the transport of substrates across cell membranes. Although MRP4 has been implicated as a detoxification protein by transport of structurally diverse endogenous and xenobiotic compounds, including antivirus and anticancer drugs, that usually induce oxidative stress in cells, its in vivo biological function remains unknown. In this study, we investigate the biological functions of a Drosophila homolog of human MRP4, dMRP4. We show that dMRP4 expression is elevated in response to oxidative stress (paraquat, hydrogen peroxide and hyperoxia) in Drosophila. Flies lacking dMRP4 have a shortened lifespan under both oxidative and normal conditions. Overexpression of dMRP4, on the other hand, is sufficient to increase oxidative stress resistance and extend lifespan. By genetic manipulations, we demonstrate that dMRP4 is required for JNK (c-Jun NH2-terminal kinase) activation during paraquat challenge and for basal transcription of some JNK target genes under normal condition. We show that impaired JNK signaling is an important cause for major defects associated with dMRP4 mutations, suggesting that dMRP4 regulates lifespan by modulating the expression of a set of genes related to both oxidative resistance and aging, at least in part, through JNK signaling.
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PMID:A Drosophila ABC transporter regulates lifespan. 2547 22

Exposure to supraphysiological concentrations of oxygen is often applied in clinical practice to enhance oxygenation in acute or chronic lung injury. However, hyperoxic exposure is associated with increased reactive oxygen species production, which can be toxic to pulmonary endothelial and alveolar epithelial cells. Oxidative stress activates the pathways of the mitogen-activated protein kinases family: extracellular signal-regulated kinase (ERK1/2), C-Jun-terminal protein kinase (JNK1/2), and p38 kinase. Several studies have suggested that ERK activation in lung cells has a protective effect in response to hyperoxia, through stimulation of DNA repair and antioxidant mechanisms, and prolonged cell survival. Conversely, JNK1/2 and p38 kinase have been most frequently reported to have roles in induction of apoptotic responses. Moreover, exogenous factors, such as ATP, retinoic acid, substance P, thioredoxin, inosine and laminin, can have cytoprotective effects against hyperoxia-induced cell damage, through promotion of ERK activation and/or limiting JNK and p38 involvement.
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PMID:Effects of hyperoxic exposure on signal transduction pathways in the lung. 2548 98


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