Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Activated leukocytes oxidatively damage DNA, RNA, and the nucleotide pool through halide-dependent formation of hydroxyl radical. 1082 20

In many models, a protective role for heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, has been demonstrated. Also, HO-1 null mice (KO) are more susceptible to inflammation and hypoxia and transplant rejection. Nonetheless, their response to hyperoxia (> 95% O(2)) has not yet been evaluated. Surprisingly, after acute hyperoxic exposure, KO had significantly decreased markers of lung oxidative injury and survived chronic hyperoxia as well as wild-type (WT) controls. Disrupted HO-1 expression was associated with decreased lung reactive iron and iron-associated proteins, decreased NADPH cytochrome cp450 reductase activity, and decreased lung peroxidase activity compared to WT. Injection of tin protoporphyrin, an inhibitor of HO, in the WT decreased acute hyperoxic lung injury, whereas transduction of human HO-1 in the KO reversed the relative protection of the KO to acute injury and worsened hyperoxic survival. This suggests that disruption of HO-1 protects against hyperoxia by diminishing the generation of toxic reactive intermediates in the lung via iron and H(2)O(2).
 ...
PMID:Resistance to hyperoxia with heme oxygenase-1 disruption: role of iron. 1249 87

1-Cys peroxiredoxin (1-cysPrx), a member of the peroxiredoxin family that contains a single conserved cysteine residue, reduces a broad spectrum of hydroperoxides. We studied changes in 1-cysPrx expression in rat lungs and lung cell lines in response to oxidative stress due to hyperoxia, H2O2, or paraquat. After 60 h of hyperoxia (>95% O2), mRNA and protein levels of 1-cysPrx and peroxidase activity were significantly elevated in rat lungs by approximately 1.5- to 2-fold compared with the control (P < 0.05). A similar induction of 1-cysPrx was observed in mouse lungs following exposure to O2 for 63 or 72 h; enzyme induction in mouse lungs was similar for wild-type and glutathione peroxidase 1 gene-targeted mice. H2O2 and paraquat treatment induced 1-cysPrx gene expression in L2 cells. Enzyme induction was attenuated by pretreatment with Trolox or N-acetylcysteine. Actinomycin D treatment showed that stability of 1-cysPrx mRNA was not altered in the presence of H2O2 or paraquat, indicating that increased expression with oxidative stress is regulated at the transcriptional level. These data indicate that the antioxidant enzyme 1-cysPrx is induced in lung cells by oxidative stress.
 ...
PMID:Induction of 1-cys peroxiredoxin expression by oxidative stress in lung epithelial cells. 1285 Dec 11

Peroxiredoxin 6 (Prd x 6) is a novel peroxidase enzyme that is expressed at a high level in the lung. We tested the hypothesis that transgenic (Tg) mice overexpressing Prd x 6 would exhibit increased resistance to hyperoxia-induced lung injury. Wild-type and Tg mice were exposed to 100% O(2) and evaluated for survival, lung histopathology, total protein, and nucleated cells in bronchoalveolar lavage fluid (BALF), and oxidation of lung protein and lipids. Prd x 6 protein expression and enzyme activity were approximately 3-fold higher in Tg lungs compared with wild-type. Tg mice survived longer during exposure to 100% O(2) (LT(50) 104+/-2.8 h in Tg versus 88.9+/-1.1 h for wild-type). Lung wet/dry weight ratio and total protein and nucleated cell count in lung lavage fluid were significantly greater in wild-type mice at 72 and 96 h of hyperoxia compared with Tg mice. At 96 h of hyperoxia, Tg mice had less epithelial cell necrosis, perivascular edema, and inflammatory cell recruitment by light microscopy, and lower TBARS and protein carbonyls in lung homogenate (P<0.05). These results show that Tg mice have increased defense against lung injury in hyperoxia, providing evidence that Prd x 6 functions as a lung antioxidant enzyme.
 ...
PMID:Transgenic mice overexpressing peroxiredoxin 6 show increased resistance to lung injury in hyperoxia. 1639 55

The cysteine residue at the active site of peroxiredoxin (Prx) I, Prx II, or Prx III is reversibly hyperoxidized to cysteine sulfinic acid, with concomitant loss of peroxidase activity, during normal catalysis. Sulfiredoxin (Srx) is the enzyme responsible for reversing this hyperoxidation. We now show that the expression of Srx at both the mRNA and protein levels is increased markedly in the lungs of mice exposed to hyperoxia. This hyperoxia-induced expression of Srx was not evident in mice deficient in the transcription factor Nrf2, indicating an essential role for an Nrf2 signaling pathway in this effect. Hyperoxia also elicited the accumulation of the sulfinic form of the mitochondrial enzyme Prx III, but not that of the cytosolic enzymes Prx I or Prx II, in lung tissue. This selective hyperoxidation of Prx III is likely due either to mitochondria being the major site of the hyperoxia-induced production of reactive oxygen species or to the translocation of Srx from the cytosol into mitochondria being rate limiting for the reduction of sulfinic Prx III. Hyperoxia induced the degradation of Prx III in Nrf2-deficient mice but not in wild-type animals, suggesting that, in the absence of a sufficient amount of Srx, sulfinic Prx III is converted to a form that is susceptible to proteolysis.
 ...
PMID:Induction of sulfiredoxin via an Nrf2-dependent pathway and hyperoxidation of peroxiredoxin III in the lungs of mice exposed to hyperoxia. 1908 7

Phospholipids are a major structural component of all cell membranes; their peroxidation represents a severe threat to cellular integrity and their repair is important to prevent cell death. Peroxiredoxin 6 (Prdx6), a protein with both GSH peroxidase and phospholipase A(2) (PLA(2)) activity, plays a critical role in antioxidant defense of the lung and other organs. We investigated the role of Prdx6 in the repair of peroxidized cell membranes in pulmonary microvascular endothelial cells (PMVEC) and isolated mouse lungs treated with tert-butyl hydroperoxide and lungs from mice exposed to hyperoxia (100% O(2)). Lipid peroxidation was evaluated by measurement of thiobarbituric acid reactive substances, oxidation of diphenyl-1-pyrenylphosphine, or ferrous xylenol orange assay. The exposure dose was varied to give a similar degree of lipid peroxidation at the end of exposure in the different models. Values for lipid peroxidation returned to control levels within 2 h after oxidant removal in wild-type PMVEC and perfused lungs but were unchanged in Pxdx6 null preparations. An intermediate degree of repair was observed with PMVEC and lungs that expressed only C47S or D140A mutant Prdx6; the former mutant does not have peroxidase activity, while the latter loses its PLA(2) activity. Prdx6 null mice showed markedly delayed recovery from lipid peroxidation during 20 h observation following exposure to hyperoxia. Thus, Prdx6 plays a critical role in the repair of peroxidized phospholipids in cell membranes and the recovery of lung cells from peroxidative stress; the peroxidase and PLA(2) activity each contribute to the recovery process.
 ...
PMID:Critical role of peroxiredoxin 6 in the repair of peroxidized cell membranes following oxidative stress. 2611 27

Although lipid peroxidation associated with oxidative stress can result in cellular death, sub-lethal lipid peroxidation can gradually resolve with return to the pre-exposure state. We have shown that resolution of lipid peroxidation is greatly delayed in lungs or cells that are null for peroxiredoxin 6 (Prdx6) and that both the phospholipase A2 and the GSH peroxidase activities of Prdx6 are required for a maximal rate of recovery. Like other peroxiredoxins, Prdx6 can reduce H2O2 and short chain hydroperoxides, but in addition can directly reduce phospholipid hydroperoxides. This study evaluated the relative role of these two different peroxidase activities of Prdx6 in the repair of peroxidized cell membranes. The His26 residue in Prdx6 is an important component of the binding site for phospholipids. Thus, we evaluated the lungs from H26A-Prdx6 expressing mice and generated H26A-Prdx6 expressing pulmonary microvascular endothelial cells (PMVEC) by lentiviral infection of Prdx6 null cells to compare with wild type in the repair of lipid peroxidation. Isolated lungs and PMVEC were exposed to tert-butyl hydroperoxide and mice were exposed to hyperoxia (> 95% O2). Assays for lipid peroxidation in wild type control and mutant lungs and cells showed ~4-fold increase at end-exposure. Control lungs and cells showed gradual resolution during a post-exposure recovery period. However, there was no recovery from lipid peroxidation by H26A-Prdx6 lungs or PMVEC. These studies confirm an important role for Prdx6 in recovery from membrane lipid peroxidation and indicate that reduction of H2O2 or short chain hydroperoxides does not play a role in the recovery process.
 ...
PMID:Peroxiredoxin 6 phospholipid hydroperoxidase activity in the repair of peroxidized cell membranes. 2886 96


<< Previous 1 2