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

Neuroendocrine lung cancer is among the most common types of lung cancers in smokers. We have recently shown that exposure of hamsters to N-nitrosodiethylamine and hyperoxia causes a high incidence of this tumor type. In this study, we show that the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone also causes neuroendocrine lung tumors in hyperoxic hamsters. Animals maintained in ambient air while being treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone developed pulmonary adenomas composed of Clara cells and alveolar type II cells. Pathogenesis experiments provide evidence for the tumors caused by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in ambient air being derived from Clara cells. In the hyperoxic hamsters, the neuroendocrine carcinogenesis appears to involve two stages: (a) transformation of focal alveolar type II cells into neuroendocrine cells and (b) development of neuroendocrine lung tumors from such foci.
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PMID:Pathobiology of lung tumors induced in hamsters by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and the modulating effect of hyperoxia. 230 45

Toxic effects of ionizing radiation and elevated O2 levels (hyperoxia) are both thought to be mediated by oxidizing free radicals. In view of the reported hypersensitivity of ataxia telangiectasia (A-T) cells to the clastogenic effect of ionizing radiation, the chromosomal sensitivity of A-T cells to hyperoxic culture conditions was investigated in unirradiated and G0-irradiated A-T lymphocyte cultures. Unlike Fanconi's anaemia lymphocytes, which tend to respond to oxygen, especially after treatment with mitomycin C, both non-irradiated and G0-irradiated A-T lymphocytes failed to show an effect. We conclude that the excessive spontaneous and radiation-induced chromosomal breakage in A-T does not result from a deficiency in the cellular defences against the clastogenic effect of hyperoxia.
Carcinogenesis 1987 Feb
PMID:Oxygen toxicity and chromosomal breakage in ataxia telangiectasia. 243 71

The active oxygen species generated by ionizing radiation, hyperoxia, paraquat and hydrogen peroxide induced unscheduled DNA synthesis and DNA synthesis rate inhibition in human fetal lung fibroblast (IMR-90) and transformed cell line derived from Syrian hamster embryo fibroblast (BP6T). The D-glucose and sucrose, which were unable to generate active oxygen species, could induce neither unscheduled DNA synthesis nor DNA synthesis rate inhibition. The indicator of DNA synthesis rate inhibition for active oxygen species was more sensitive than that of unscheduled DNA synthesis. All the enhancing chemicals on active oxygen species aggravated DNA damage, while all the inhibiting chemicals alleviated DNA damage. Results showed that active oxygen species do damage DNA. The active oxygen species mechanism for carcinogenesis, mutation and aging is applicable.
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PMID:DNA damage induced in mammalian cells by active oxygen species. 285 Nov 68

Mice were given i.v. injections of various tumor cell lines and, beginning 24 h later exposed for 3 weeks to 70% oxygen. Hyperoxia reduced the number of lung colonies derived from MT-7 cells (originally a mammary carcinoma) and of the lung-tumor derived cell lines 498 and Line-1 early passage. Lung colonies derived from Line-1 late passage, lines M109, B16-F10 and Lewis lung carcinoma were oxygen resistant. Lung metastases following i.m. injection of MT-7 cells were oxygen-sensitive and metastases derived from B16-F10 cells or Lewis lung carcinoma were oxygen resistant. Pre-exposure of mice for 48 h to 100% oxygen enhanced colony formation for all cell lines examined whereas exposure to 100% oxygen after i.v. injection only curtailed the growth of the cell lines previously shown to be sensitive to 70% oxygen. There was no correlation between oxygen sensitivity or resistance and the levels of total glutathione or activities of superoxide dismutase (SOD), glutathione reductase or peroxidase or glucose 6-phosphate dehydrogenase in the cell lines. However, upon injection in mice a resistant cell line increased its anti-oxidant defense mechanisms while growing in vivo whereas a sensitive cell line failed to show such adaptation.
Carcinogenesis 1988 Mar
PMID:Effects of hyperoxia on growth of experimental lung metastasis. 334 81

The effects of hyperoxia on lung tumor development were examined in mice and rats. In mice, exposure to 70% O2 prevented the development of urethan- or 3-methylcholanthrene-induced lung tumors. Dietary antioxidants [butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA)] were unable to prevent the inhibition of tumor development by oxygen, although BHT retained its capability to enhance tumor development in mouse lung. In visible-size tumors, oxygen did not depress DNA synthesis. Oxygen also reduced the number of pulmonary metastatic nodules after i.v. injection of mammary gland-derived carcinoma cells, but failed to inhibit growth of murine lung carcinoma or murine melanoma-derived cell lines. Rats treated with one single intratracheal instillation of 3-methylcholanthrene developed multiple lung lesions; their growth could be prevented by exposure of the animals to 40 or 70% O2. It is concluded that hyperoxia prevents development of transformed cells in vivo in the lung and may affect adversely the growth of selected cell lines metastatic to the lung.
Carcinogenesis 1986 Sep
PMID:Modification of lung tumor growth by hyperoxia. 374 30

Reactive oxygen species produced by normal cellular metabolism have been considered to play a causative role in spontaneously occurring genomic instability and carcinogenesis. To study the genotoxic consequences of an enhanced flux of metabolically produced reactive oxygen species, cells may be exposed to hyperoxia (elevated concentrations of oxygen), a condition known to generate high levels of microscopically visible chromosomal damage. Here we assess the mutagenic potential of normobaric hyperoxia in several mammalian cells lines (CHO-K1-BH4 and AS52 Chinese hamster cells and TK6 human lymphoblastoid cells) using different target genes, including hprt, xprt and tk. Exposure of cell cultures to hyperoxia to 10-40% clonogenic cell survival, failed to induce mutations at the hprt and xprt loci. In human TK6 cells, hyperoxia failed to induce normal growing tk mutants, but efficiently induced slow growing tk mutants. The latter type of mutant is supposed to result from very large deletions or mutlilocus events. Our results suggest that elevated levels of endogenous activated oxygen species are inefficient in inducing point mutations or small deletions, but tend to generate gross rearrangements. Mammalian cells under oxidative stress thus exhibit a hyper-recombination phenotype. The carcinogenic impact of metabolic oxygen radical fluxes may thus be based on enhanced mitotic recombination rates, leading to tumor suppressor gene inactivation through 'loss of heterozygosity'.
Carcinogenesis 1994 Dec
PMID:Mutagenicity of metabolic oxygen radicals in mammalian cell cultures. 800 Dec 23

A variety of chronic inflammatory conditions are associated with an increased risk for the development of cancer. Because of the numerous links between DNA oxidative damage and carcinogenesis, a potential role for leukocyte-generated oxidants in these processes has been suggested. In the present study, we demonstrate a novel free transition metal ion-independent mechanism for hydroxyl radical ((*)OH)-mediated damage of cellular DNA, RNA, and cytosolic nucleotides by activated neutrophils and eosinophils. The mechanism involves reaction of peroxidase-generated hypohalous acid (HOCl or HOBr) with intracellular superoxide (O(2)(*)(-)) forming (*)OH, a reactive oxidant species implicated in carcinogenesis. Incubation of DNA with either isolated myeloperoxidase (MPO) or eosinophil peroxidase (EPO), plasma levels of halides (Cl(-) and Br(-)), and a cell-free O(2)(*)(-) -generating system resulted in DNA oxidative damage. Formation of 8-hydroxyguanine (8-OHG), a mutagenic base which is a marker for (*)OH-mediated DNA damage, required peroxidase and halides and occurred in the presence of transition metal chelators (DTPA +/- desferrioxamine), and was inhibited by catalase, superoxide dismutase (SOD), and scavengers of hypohalous acids. Similarly, exposure of DNA to either neutrophils or eosinophils activated in media containing metal ion chelators resulted in 8-OHG formation through a pathway that was blocked by peroxidase inhibitors, hypohalous acid scavengers, and catalytically active (but not heat-inactivated) catalase and SOD. Formation of 8-OHG in target cells (HA1 fibroblasts) occurred in all guanyl nucleotide-containing pools examined following exposure to both a low continuous flux of HOCl (at sublethal doses, as assessed by [(14)C]adenine release and clonogenic survival), and hyperoxia (to enhance intracellular O(2)(*)(-) levels). Mitochondrial DNA, poly A RNA, and the cytosolic nucleotide pool were the primary targets for oxidation. Moreover, modest but statistically significant increases in the 8-OHG content of nuclear DNA were also noted. These results suggest that the peroxidase-H(2)O(2)-halide system of leukocytes is a potential mechanism contributing to the well-established link between chronic inflammation, DNA damage, and cancer development.
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PMID:Activated leukocytes oxidatively damage DNA, RNA, and the nucleotide pool through halide-dependent formation of hydroxyl radical. 1082 20

NRF2 is a transcription factor important in the protection against carcinogenesis and oxidative stress through antioxidant response element (ARE)-mediated transcriptional activation of several phase 2 detoxifying and antioxidant enzymes. This study was designed to determine the role of NRF2 in the pathogenesis of hyperoxic lung injury by comparing pulmonary responses to 95-98% oxygen between mice with site-directed mutation of the gene for NRF2 (Nrf2-/-) and wild-type mice (Nrf2+/+). Pulmonary hyperpermeability, macrophage inflammation, and epithelial injury in Nrf2-/- mice were 7.6-fold, 47%, and 43% greater, respectively, compared with Nrf2+/+ mice after 72 h hyperoxia exposure. Hyperoxia markedly elevated the expression of NRF2 mRNA and DNA-binding activity of NRF2 in the lungs of Nrf2+/+ mice. mRNA expression for ARE- responsive lung antioxidant and phase 2 enzymes was evaluated in both genotypes of mice to identify potential downstream molecular mechanisms of NRF2 in hyperoxic lung responses. Hyperoxia-induced mRNA levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione-S-transferase (GST)-Ya and -Yc subunits, UDP glycosyl transferase (UGT), glutathione peroxidase-2 (GPx2), and heme oxygenase-1 (HO-1) were significantly lower in Nrf2-/- mice compared with Nrf2+/+ mice. Consistent with differential mRNA expression, NQO1 and total GST activities were significantly lower in Nrf2-/- mice compared with Nrf2+/+ mice after hyperoxia. Results demonstrated that NRF2 has a significant protective role against pulmonary hyperoxic injury in mice, possibly through transcriptional activation of lung antioxidant defense enzymes.
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PMID:Role of NRF2 in protection against hyperoxic lung injury in mice. 1180 63

Existing systems of classification of carcinogens are a matter of discussion, world-wide. There is agreement that it should be distinguished between genotoxic and non-genotoxic chemicals. The risk assessment approach used for non-genotoxic chemicals is similar among different regulatory bodies: insertion of an uncertainty (safety) factor permits the derivation of permissible exposure levels at which no relevant human cancer risks are anticipated. For genotoxic carcinogens, case studies of chemicals point to a whole array of possibilities. Positive data of chromosomal effects only, in the absence of mutagenicity, may support the characterization of a compound that produces carcinogenic effects only at high, toxic doses. Non-DNA-reactive genotoxins, such as topoisomerase inhibitors or inhibitors of the spindle apparatus are considered in this respect. In such cases, arguments are in favour of the existence of "practical" thresholds. Taking existing concepts together, it is proposed to basically distinguish between "perfect" and "practical" thresholds. There is a wide consensus that for non-DNA-reactive genotoxins such as aneugens (aneuploidy, chromosome loss, non-disjunction) thresholds should be defined. It is being discussed as to whether the identification of possible threshold effects should also include other mechanisms of genotoxicity, in addition to aneugenic effects. Specific mechanisms of clastogenicity have been repeatedly addressed as also having thresholds, such as topoisomerase II poisons or mechanisms based on reactive oxygen. Oxidative stress as an important mechanism is triggered by exposure to exogenous factors such as ultraviolet (UV) and ionizing radiation, anoxia and hyperoxia, and by chemicals producing reactive oxygen species. The idea is receiving increased support that reactive oxygen species (ROS)-mediated processes of carcinogenesis have practical thresholds. Since reactive oxygen species are genotoxic in principle, questions arise whether chemicals that increase ROS production will superimpose to an endogenously produced background level of DNA lesions, related to mechanisms that may result in non-linear dose-effect relationships. The existence of "endogenous" DNA adducts has been generally accepted, and possible regulatory implications of the presence of endogenous carcinogens have been discussed. It is now becoming evident that a diversity of methods of carcinogenic risk extrapolation to low doses must be considered, dependent on the mode of action. Although there is an increasing international awareness of these developments, the system of classification of carcinogens of the European Union still remains static. This should be changed, as the philosophy of separation of a strictly sequential "hazard assessment" and "risk assessment" appears out-of-date.
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PMID:Carcinogenicity categorization of chemicals-new aspects to be considered in a European perspective. 1517 38

Nuclear factor, erythroid 2 related factor 2 (Nrf2) belongs to the Cap'n'collar/basic region leucine zipper (CNC-bZIP) transcription factor family, and is activated by diverse oxidants, pro-oxidants, antioxidants, and chemopreventive agents. After phosphorylation and dissociation from the cytoplasmic inhibitor, Kelch-like ECH-associated protein 1 (Keap1), Nrf2 translocates to the nucleus and binds to an antioxidant response element (ARE). Through transcriptional induction of ARE-bearing genes that encode antioxidant-detoxifying proteins, Nrf2 activates cellular rescue pathways against oxidative injury, inflammation/immunity, apoptosis, and carcinogenesis. ARE-driven genes include direct antioxidants (e.g., GPx), thiol metabolism-associated detoxifying enzymes (e.g., GSTs), stress-response genes (e.g., HO-1), and others (e.g., PSMB5). Application of nrf2 germ-line mutant mice elucidated protective roles for Nrf2 in various models of human disorders in the liver, lung, kidney, brain, and circulation. In the lung, deficiency of nrf2 augmented injury caused by bleomycin and environmental oxidants including hyperoxia, diesel exhaust particles, and cigarette smoke. Microarray analyses of lungs from nrf2-deficient and -sufficient mice identified Nrf2-dependent genes that might be critical in pulmonary protection. Observations from these studies highlight the importance of the Nrf2-antioxidant pathway and may provide new therapeutic strategies for acute respiratory distress syndrome, idiopathic pulmonary fibrosis, cancer, and emphysema in which oxidative stress is implicated.
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PMID:Nrf2 defends the lung from oxidative stress. 1648 40


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