UMLS:C0242706 - FACTA Search

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

Fanconi's anaemia (FA) is characterized by increased spontaneous and induced chromosome fragility. This has been widely regarded to be due to a defect in DNA crosslink repair, because of the sensitivity of cells to known DNA crosslinking agents such as mitomycin C (MMC) and diepoxybutane (DEB). Although Fanconi cells are also sensitive to molecular oxygen, and may be protected by antioxidants, this has generally been considered to be a secondary phenomenon. However, it has recently been demonstrated that the FAC protein, coded for by the Fanconi anaemia gene for complementation group C, is strictly cytoplasmic and does not enter the nucleus even after DNA damage, which seems inconsistent with a role in DNA repair. We have studied the effects of MMC and oxygen on apoptotic cell death in FA group C (FA-C) and normal lymphoblastoid cell lines. Hyperoxia alone failed to induce apoptosis in either FA-C or normal cells. At ambient oxygen, MMC is known to generate oxygen free radicals, whereas decreased oxygen tension facilitates the metabolic activation of MMC for DNA crosslinking. We therefore studied the effects of MMC at 20% and 5% oxygen to favour oxygen radical generation or DNA crosslinking respectively. FA-C cells showed increased sensitivity compared to normal cells for the induction of apoptosis by MMC at 20% oxygen. When cells were treated with MMC at 5% oxygen we found no increased sensitivity of Fanconi cells to MMC when compared to normal cells. These results imply a role for oxygen free radicals, but not for DNA crosslinking, in the sensitivity of FA cells to MMC.
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PMID:The sensitivity of Fanconi anaemia group C cells to apoptosis induced by mitomycin C is due to oxygen radical generation, not DNA crosslinking. 902 6

Pulmonary oxygen injury is classified by the development of tissue and alveolar edema, surfactant dysfunction, lung inflammation, and decreased pulmonary compliance. In neonates prolonged oxygen therapy is associated with the development of bronchopulmonary dysplasia. Recombinant DNA technology makes it possible to experimentally explore the role of specific proteins in the development of pulmonary oxygen injury. However, in vivo experiments require sensitive ways of identifying pulmonary oxygen injury early in its development. We therefore compared the sensitivities of several experimental assays used to assess pulmonary injury. We found that changes in pulmonary compliance were the most sensitive and showed significant differences after 72 hr of exposure to normobaric hyperoxia (FiO2 = 0.95), which correlated with a small change in the histology of the mice lungs. The concentration of protein in the bronchoalveolar lavage fluid was less sensitive and did not differ significantly until after 96 hr of exposure. The survival in hyperoxia also did not worsen until after 96 hr. The lung wet/ dry weight ratios was the least sensitive assay and did not increase until after 5 days of exposure to normobaric hyperoxia. We conclude that a decrease in pulmonary compliance is an early indicator of pulmonary oxygen injury and may be a better way to study the mechanisms and mediators of pulmonary oxygen injury.
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PMID:Decreased pulmonary compliance is an early indicator of pulmonary oxygen injury. 907 67

Hyperoxia leads to excessive formation of reactive oxygen species (ROS). ROS cause damage to many cellular components, including DNA. Exposure of bovine cerebral endothelial cells to 95 or 100% oxygen resulted in an increase in DNA fragmentation, the appearance of DNA ladders, and cell death with morphological features suggestive of apoptosis. Melatonin, an antioxidant, reduced hyperoxia-induced DNA fragmentation and cell death in a dose-dependent manner. Results from the present study support the contention that ROS play a major role in DNA damage and apoptotic death. Melatonin is an effective agent in reducing ROS-mediated DNA fragmentation and death in bovine cerebral endothelial cells.
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PMID:Melatonin protects bovine cerebral endothelial cells from hyperoxia-induced DNA damage and death. 923 91

Epithelial cells are prone to oxidant injury, which could change epithelial cell homeostasis and lead to degenerative diseases. We examined the effects of hyperoxia on death and proliferation off Madin-Darby canine kidney (MDCK) epithelial cells and antioxidant vitamin protection. Subconfluent and near-confluent MDCK cells were cultured under normoxia or hyperoxia for two days. We measured cell number and viability, mitochondria enzymatic activity, thymidine incorporation, necrosis [lactate dehydrogenase (LDH) release], and apoptosis (DNA fragmentation and morphological changes). When the cells were subconfluent, hyperoxia decreased the number of adherent cells, mitochondrial enzymatic activity, and thymidine incorporation, but neither LDH release nor apoptotic changes increased compared with normoxic controls. In normoxia, near-confluent cells had lower nonadherent cell numbers, mitochondrial enzymatic activity, and thymidine incorporation than subconfluent cells; hyperoxia further decreased the latter two parameters and increased apoptotic changes and LDH release in near-confluent cells. Vitamin E protected mitochondrial enzymatic activity, apoptotic changes, and LDH release against hyperoxic injury but did not affect changes in thymidine incorporation with hyperoxia. Vitamin C partially protected the mitochondrial enzymatic activity and thymidine incorporation in subconfluence, but not in near confluence. These results indicate that cell density is a major determinant of the effects of hyperoxic injury and the profile of antioxidant vitamin protection.
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PMID:Cell density and antioxidant vitamins determine the effects of hyperoxia on proliferation and death of MDCK epithelial cells. 929 Jan 15

The rat pheochromocytoma cell line PC12 is useful for studying neuronal cell differentiation since this cell line differentiates into neuron-like cells in response to nerve growth factor (NGF). We demonstrated that PC12h cells, a subclone of PC12 cells, died under hyperoxia (50% O2). This cell death did not occur in the presence of antioxidant reagents. In the dead cells, DNA fragmentation and chromatin condensation were observed, suggesting that hyperoxia-induced apoptosis via reactive oxygen species (ROS). NGF effectively suppressed this hyperoxia-induced apoptosis. Accordingly, the amounts of bcl-2, a proto-oncogene product, increased in the cells rescued from apoptosis by NGF. Furthermore, bcl-2 antisense oligonucleotide canceled this rescuing effect of NGF. The present findings indicate that NGF rescues PC12h cells from hyperoxia-induced apoptosis via up-regulation of bcl-2.
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PMID:The rescuing effect of nerve growth factor is the result of up-regulation of bcl-2 in hyperoxia-induced apoptosis of a subclone of pheochromocytoma cells, PC12h. 930 89

Telomere loss has been proposed as a mechanism for counting cell divisions during aging in normal somatic cells. How such a mitotic clock initiates the intracellular signalling events that culminate in G1 cell cycle arrest and senescence to restrict the lifespan of normal human cells is not known. We investigated the possibility that critically short telomere length activates a DNA damage response pathway involving p53 and p21(WAF1) in aging cells. We show that the DNA binding and transcriptional activity of p53 protein increases with cell age in the absence of any marked increase in the level of p53 protein, and that p21(WAF1) promoter activity in senescent cells is dependent on both p53 and the transcriptional co-activator p300. Moreover, we detected increased specific activity of p53 protein in AT fibroblasts, which exhibit accelerated telomere loss and undergo premature senescence, compared with normal fibroblasts. We investigated the possibility that poly(ADP-ribose) polymerase is involved in the post-translational activation of p53 protein in aging cells. We show that p53 protein can associate with PARP and inhibition of PARP activity leads to abrogation of p21 and mdm2 expression in response to DNA damage. Moreover, inhibition of PARP activity leads to extension of cellular lifespan. In contrast, hyperoxia, an activator of PARP, is associated with accelerated telomere loss, activation of p53 and premature senescence. We propose that p53 is post-translationally activated not only in response to DNA damage but also in response to the critical shortening of telomeres that occurs during cellular aging.
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PMID:ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. 931 59

Although the antioxidant properties of N-acetylcysteine (NAC) in vitro are widely accepted, the efficacy of NAC in the prevention of O2 toxicity in vivo is poorly documented. The aim of our study was to investigate the presumed protective effect of NAC on hyperoxic lung injury, focusing on gamma-glutamyltransferase (gamma-GT) activity and glutathione (GSH) levels in lung tissue, epithelial lining fluid (ELF), and isolated rat type II cells immediately after their isolation and 48 h later when kept in culture in normoxia. Thirty-four male Wistar rats were divided in three groups (n = 10-14) and were exposed to air or to 60 or 85% O2 for 7 days. One-half of the rats in each group received 200 mg/kg NAC intraperitoneally one time per day from 3 days before exposure until the end of the experiment, and the other one-half received the vehicle. In the 85% O2-exposed animals, NAC led to more respiratory distress and weight loss. NAC did not prevent the rise in bronchoalveolar lavage lactate dehydrogenase and alkaline phosphatase, but it did prevent the rise in calculated ELF volume. NAC decreased GSH levels (1.4-fold) and gamma-GT activity (1.8-fold) in the air-exposed type II cells. In the 60% O2-exposed group, no effects of NAC were seen (except for a decrease in gamma-GT mRNA expression), but, in the 85% O2-exposed group, NAC gave rise to higher GSH (2.6-fold) and higher gamma-GT activity (2.9-fold) in the ELF and lower GSH (6.9-fold) and higher gamma-GT activity (3.6-fold) in the type II cells. Even in culture, GSH levels remained 1.5-fold lower than in the cells from the air-exposed animals and 2-fold lower than in the cells from the 85% O2-exposed animals. There was increased DNA damage (as assessed by thymidine incorporation) and apoptosis after hyperoxia, especially after 60% O2, and this effect was amplified after NAC treatment. Although protective at the endothelial side, NAC treatment led to adverse effects at the epithelial side, despite, or probably because of, restoration of the ELF GSH levels in the presence of high O2 levels. Because NAC is rapidly metabolized to cysteine, it is plausible that the effects of NAC are manifested through the toxic effects of cysteine.
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PMID:N-acetylcysteine does not protect against type II cell injury after prolonged exposure to hyperoxia in rats. 931 88

Human selenium-dependent glutathione peroxidase (GP) is implicated as a mechanism of resistance against oxygen free radicals. The 5' flanking sequence upstream from the coding region of GP contained an oxygen-responsive element termed ORE1 that is responsive to hypoxia, as well as several copies of the activator protein-1 (AP-1)- and AP-1-like-binding sites. In this study, we sought to define the molecular events that lead to GP gene transcription in response to hyperoxia in human umbilical-vein endothelial cells, and asked whether such induction is mimicked and sustained by activation of protein kinase C (PKC) by phorbol esters. Treatment of cells with 100 nM phorbol 12,13-dibutyrate (PdBu) induced a delayed (24-48 h) but significant (2-fold) increase in steady-state GP mRNA levels. Steady-state GP mRNA levels also rose after exposure to 95% O2, again after considerable delay (48-72 h). For both PdBu and oxygen, induction was transcriptionally regulated, as demonstrated by nuclear run-on experiments. The simulations by PdBu and oxygen were additive. In contrast with PdBu, hyperoxia did not stimulate translocation of PKC from the cytosol to the particulate fraction, although the specific activity of both cytosolic and particulate-associated PKC was increased 2-fold in cells exposed to 95% O2 for 5 days. In addition, gel mobility-shift assays using double-stranded tumour-promoting-agent-responsive element (TRE) and nuclear extracts derived from phorbol- and oxygen-treated cells revealed that PdBu, but not hyperoxia, increased AP-1 DNA-binding activity. On the other hand, the up-regulation of GP expression by oxygen could not be accounted for by the ORE1 core sequence, since no specific protein-DNA binding activity could be detected using nuclear extracts from hyperoxic cells and ORE1. Taken together, these results suggest that there may be different molecular mechanisms controlling GP expression. After exposure to PdBu, GP undergoes transcriptional activation via a process that can be readily explained by a classic AP-1 interaction with the TRE sites in the GP promoter. During hyperoxia, GP also undergoes transcriptional activity, but via a process that appears to involve neither TRE nor ORE1.
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PMID:Hyperoxia, unlike phorbol ester, induces glutathione peroxidase through a protein kinase C-independent mechanism. 933 58

The oxygen partial pressure of middle ear gas increases more than 3-fold upon insertion of ventilation tubes, while the carbon dioxide partial pressure decreases. Whereas the middle ear gas is normally equilibrated to venous gases and has an oxygen partial pressure of 43 mmHg, 138 mmHg is measured in ventilated ears. The present study was undertaken to compare the effects of these oxygen tensions on in vitro growth and glycoprotein secretion of rabbit middle ear epithelium and for comparison auditory meatal epithelium. Cultures were incubated in atmospheres of 7, 21 or 75% O2 in 5% CO2 and the remnant N2. The cell layer protein mass, [3H]thymidine-incorporation, DNA content and [3H]glucosamine-incorporation was measured in identical subcultures every third day during a 15-day period. In middle ear epithelium the DNA content, DNA synthesis and cell layer protein mass were significantly higher at 7% oxygen compared to 21% and 75%. In conclusion hyperoxia leads to decreased growth of middle ear epithelium in vitro. If applicable to in vivo conditions, this might contribute to the mechanism of action of ventilation tubes. Moreover the proliferation rate of auditory meatal epithelium exceeds that of middle ear epithelium both at 7 and 21% oxygen, an interesting point with regards to cholesteatoma pathogenesis.
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PMID:Influence of hyperoxia on in vitro growth of rabbit middle ear epithelium and auditory meatal epithelium. 935 Apr 87

Hyperoxia-exposure results in neutrophil accumulation and edema in the exposed lung. Intercellular adhesion molecule-1 (ICAM-1), a ligand for neutrophil beta 2 integrins, is upregulated in hyperoxia-exposed lungs and enhances neutrophil-mediated injury. Because tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) are potent inducers of ICAM-1, we investigated whether TNF-alpha and IL-1 beta mRNA increase prior to the increase in ICAM-1 mRNA in hyperoxia-exposed mouse lungs. We exposed mice to > 95% oxygen for up to 96 h, isolated lung RNA, and assessed ICAM-1, TNF-alpha, and IL-1 beta mRNA by Northern blotting. We found that neither, TNF-alpha nor IL-1 beta mRNA was detectable prior to 96 h, while ICAM-1 mRNA increased by 48 h. To further assess TNF-alpha and IL-1 beta mRNA, we employed quantitative reverse-transcriptase polymerase chain reaction (RTPCR) using a mimic DNA (mimic) species as an internal control for PCR. Mimic DNA was identical to reverse-transcribed cDNA (wild type), except for 147 bp of irrelevant DNA ligated into the original cDNA. For each lung RNA sample we reverse transcribed total lung RNA and coamplified the resulting wild-type cDNA with serial dilutions of mimic DNA in a PCR containing [32P] dCTP. After PCR, we electrophoresed the samples and determined the concentration of TNF-alpha and IL-1 beta wild-type cDNAs by the ratios of wild type to mimic counts. We found no increase in TNF-alpha or IL-1 beta mRNA through 72 h of hyperoxia exposure, while there was an approximately 10-fold increase in TNF-alpha mRNA and a 35-fold increase in IL-1 beta mRNA within 2 h in the lungs of animals exposed to endotoxin. In conclusion, our data suggest that TNF-alpha and IL-1 beta are not responsible for the upregulation of ICAM-1 in hyperoxia-exposed mouse lungs.
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PMID:Hyperoxic increases in lung ICAM-1 mRNA are independent of TNF-alpha and IL-1 beta mRNA. 937 69

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