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)

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

Hyperoxia may contribute to lung disease in newborns through effects on alveolar neutrophils which predominate in respiratory distress syndrome and other acute lung injuries. Neutrophil chemokines such as interleukin-8 (IL-8) regulate chemoattraction, and are elevated in tracheal aspirates of newborns who develop bronchopulmonary dysplasia (BPD). Blockade of neutrophil chemokines may reduce hyperoxia-induced inflammatory lung injury and BPD. We therefore tested the hypothesis that hyperoxia contributes to elevations of rat neutrophil chemokines, cytokine-induced neutrophil chemoattractant-1 (CINC-1), and macrophage inflammatory protein-2 (MIP-2) in newborn rat lung. Newborn rats were exposed to air or 95% O(2) for 8 d. CINC-1 and MIP-2 were measured in whole lung homogenates by ELISA. Newborn 95% O(2)-exposed animals were given anti-CINC-1 or anti-MIP-2, 1, 5, or 10 microg on Days 3 and 4 of 95% O(2) exposure. Bronchoalveolar lavage (BAL) was performed after perfusion on day 6 to evaluate airway neutrophils, and myeloperoxidase (MPO) was measured in perfused whole lung. Lungs were examined histologically and immunohistochemically for effects of 95% O(2) +/- antichemokine. CINC-1 and MIP-2 increased nearly tenfold by Day 8 95% O(2) treatment versus air control. CINC-1 and MIP-2 immunolabeling was increased in alveolar macrophages and alveolar epithelium in 95% O(2). Anti-CINC-1 and anti-MIP-2 treatment at every dose reduced neutrophil number > 90% in BAL. Anti-CINC-1 10 microg reduced tissue MPO by 50%. Antichemokine treatment on days 3 and 4 prevented alveolar septal thickening and reduced chemokine immunolabeling on Day 6. Hyperoxia-induced neutrophil influx is mediated in part by CINC-1 and MIP-2 in newborn rats and can be partially prevented by treatment with anti-CINC-1 and anti-MIP-2.
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PMID:Lung inflammation in hyperoxia can be prevented by antichemokine treatment in newborn rats. 1111 57

Neutrophil influx in lung injury is controlled in part by chemokines acting through the receptor, CXCR2. To avoid adverse effects of steroids typically used to modify inflammation, we evaluated the effects of competitive blockade of CXCR2 in rats on neutrophil function in vitro and on neutrophil influx in vivo in hyperoxia-induced newborn lung injury, a model of bronchopulmonary dysplasia. In vitro, SB-265610 antagonizes rat cytokine-induced neutrophil chemoattractant-1 (CINC-1)-induced calcium mobilization, IC50 = 3.7 nM, and rat neutrophil chemotaxis in a concentration-dependent manner, IC50 = 70 nM. In vivo, newborn rats exposed to 95% O2 for 8 days had increased lung neutrophil content. Injection with 1 to 3 mg/kg SB-265610 on days 3 to 5 reduced hyperoxia-induced neutrophil accumulation in bronchoalveolar lavage and whole lung myeloperoxidase accumulation at the highest doses. To determine whether these effects might be due in part to increased neutrophil apoptosis, peripheral neutrophils were cultured with and without SB-265610. Apoptosis was assessed by morphology, viability, and terminal transferase deoxyuridine triphosphatidyl nucleotide nick-end labeling. Treatment of neutrophils with CINC-1 reduced apoptosis compared with untreated neutrophils. SB-265610 reduced the antiapoptotic effect of CINC-1 to the levels of those untreated with CINC-1. A selective CXCR2 antagonist may be useful in diseases where neutrophil-mediated exacerbation is present.
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PMID:Nonpeptide CXCR2 antagonist prevents neutrophil accumulation in hyperoxia-exposed newborn rats. 1156 Oct 67

The mechanisms by which sublethal doses of endotoxin protect against hyperoxic lung injury are not completely understood. We hypothesized that endotoxin treatment would result in a decreased inflammatory response to hyperoxia and that this would be accompanied by activation of neutrophils (as evidenced by loss of L-selectin) in the peripheral circulation. Adult rats were injected with endotoxin 0.5 mg/kg prior to and 24 hr after onset of exposure to > or = 98% O2. After 56 hr of hyperoxia, pulmonary neutrophils were lower in the O2/endotoxin group compared to O2 controls as measured by myeloperoxidase in lung homogenates and neutrophil counts in bronchoalveolar lavage fluid. Circulating neutrophils were also significantly lower in the O2/endotoxin group compared to O2 controls at 56 hr. Expression of the neutrophil adhesion molecule, L-selectin, was lower at 4 and 24 hr in the endotoxin-treated rats compared to O2 controls. There were no differences at 48 hr. Expression of CD18 rose significantly in the O2/endotoxin group after 4 hr, but thereafter did not differ from O2 controls. In summary, endotoxin protection from O2 toxicity was associated with reduced neutrophils in the lung and a loss of L-selectin from peripheral blood neutrophils.
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PMID:Endotoxin protection from oxygen toxicity: effect on pulmonary neutrophils and L-selectin. 1223 67

We tested the hypothesis that targeted transgenic overexpression of human extracellular superoxide dismutase (EC-SOD) would preserve alveolar development in hyperoxia-exposed newborn mice. We exposed newborn transgenic and wild-type mice to 95% oxygen (O2) or air x 7 days and measured bronchoalveolar lavage cell counts, and lung homogenate EC-SOD, oxidized and reduced glutathione, and myeloperoxidase. We found that total EC-SOD activity in transgenic newborn mice was approximately 2.5x the wild-type activity. Hyperoxia-exposed transgenic mice had less pulmonary neutrophil influx and oxidized glutathione than wild-type littermates at 7 days. We measured alveolar surface and volume density in animals exposed to 14 days more of air or 60% O2. Hyperoxia-exposed transgenic EC-SOD mice had significant preservation of alveolar surface and volume density compared with wild-type littermates. After 7 days 95% O2 + 14 days 60% O2, lung inflammation measured as myeloperoxidase activity was reduced to control levels in all treatment groups.
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PMID:Extracellular superoxide dismutase protects lung development in hyperoxia-exposed newborn mice. 1240 46

Hyperoxia generates an oxidative stress in the mouse lung, which activates the major stress-inducible kinase pathways, including c-Jun NH2-terminal kinase (JNK). We examined the effect of Jnk1 gene deletion on in vivo responses to hyperoxia in mice. The survival of Jnk1-/- mice was reduced relative to wild-type mice after exposure to continuous hyperoxia. Jnk1-/- mice displayed higher protein concentration in bronchoalveolar lavage (BAL) fluid and increased expression of heme oxygenase-1, a stress-inducible gene, after 65 h of hyperoxia. Contrary to other markers of injury, the leukocyte count in BAL fluid of Jnk1-/- mice was markedly diminished relative to that of wild-type mice. The decrease in BAL leukocyte count was not associated with any decrease in lung myeloperoxidase activity at baseline or after hyperoxia treatment. Pretreatment with inhaled lipopolysaccharide increased BAL neutrophil content and extended hyperoxia survival time to a similar extent in Jnk1-/- and wild-type mice. Associated with increased mortality, Jnk1-/- mice had increased pulmonary epithelial cell apoptosis after exposure to hyperoxia compared with wild-type mice. These results indicate that JNK pathways participate in adaptive responses to hyperoxia in mice.
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PMID:Deficiency in the c-Jun NH2-terminal kinase signaling pathway confers susceptibility to hyperoxic lung injury in mice. 1265 33

Several studies have suggested that exposure to hyperoxia causes lung injury through increased generation of reactive oxygen and nitrogen species. The present study was aimed to investigate the effects of hyperoxia exposure on protein nitration in lungs. Rats were exposed to hyperoxia (>95%) for 48, 60, and 72 h. Histopathological analysis showed a dramatic change in the severity of lung injury in terms of edema and hemorrhage between 48- and 60-h exposure times. Western blot for nitrotyrosine showed that several proteins with molecular masses of 29-66 kDa were nitrated in hyperoxic lung tissues. Immunohistochemical analyses indicate nitrotyrosine staining of alveolar epithelial and interstitial regions. Furthermore, immunoprecipitation followed by Western blot revealed the nitration of surfactant protein A and t1alpha, proteins specific for alveolar epithelial type II and type I cells, respectively. The increased myeloperoxidase (MPO) activity and total nitrite levels in bronchoalveolar lavage and lung tissue homogenates were observed in hyperoxic lungs. Neutrophils and macrophages isolated from the hyperoxia-exposed rats, when cocultured with a rat lung epithelial L2 cell line, caused a significant protein nitration in L2 cells. Inclusion of nitrite further increased the protein nitration. These studies suggest that protein nitration during hyperoxia may be mediated in part by MPO generated from activated phagocytic cells, and such protein modifications may contribute to hyperoxia-mediated lung injury.
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PMID:Protein nitration in rat lungs during hyperoxia exposure: a possible role of myeloperoxidase. 1292 78

We investigated the effect of timing of early postnatal dexamethasone on survival of hyperoxia-exposed neonatal rats. Pups <24 h old were treated with a tapering course of dexamethasone or saline beginning either prior to exposure (day 0), or after 2, 4, or 6 days of > or =98% O2 (n=11-14) or air (n=8-11). Exposures were continued for 14 days. By day 14, day 0 pups had poor survival regardless of the exposure (14% in O2, 13% in air). Survival of pups treated with dexamethasone after 2, 4 and 6 days of O2 exposure was significantly higher at 14 days (50, 86 and 79%, respectively) compared to saline O2 controls (9%, p < 0.001 for each). Pulmonary biochemical analyses were conducted after exposure for 7 days in rat pups treated with dexamethasone or saline beginning after 4 days of exposure to air or O2 (n=11-12 for each group). While pups treated with dexamethasone showed greatly improved survival compared to O2 controls, there was no decrease in neutrophil influx into the lung as measured by lung myeloperoxidase and neutrophil counts in histologic specimens and lavage fluid. Catalase, glutathione peroxidase, total and manganese superoxide dismutase activities as well as manganese superoxide dismutase (MnSOD) mRNA expression were elevated in both O2 groups after 7 days compared to the air groups (p < 0.05) and MnSOD mRNA expression was elevated in the O2/dexamethasone group, but there were no differences between dexamethasone and saline groups in O2. Thus, this study indicates that the timing of dexamethasone administration is crucial. Mechanisms other than increases in antioxidant enzymes or decreases in lung neutrophils underlie the ability of dexamethasone to improve survival of these neonatal rats.
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PMID:Effects of postnatal dexamethasone on oxygen toxicity in neonatal rats. 1520 72

Acute lung injury after acid aspiration and increased ambient oxygen result in significant oxidative damage to the lungs. Lung antioxidant levels are also reduced. Because levels of serine proteinases in the airspaces are also dramatically increased, we hypothesized that these enzymes play a role in degrading lung antioxidants. Rats were treated with a serine proteinase inhibitor, aprotinin, before pulmonary aspiration of acid in the presence of increased ambient oxygen (hyperoxia). Lung Cu/Zn and Mn superoxide dismutase (SOD) activity (by colorimetric assay) and Cu/Zn SOD immune reactive protein (enzyme-linked immunosorbent assay) were assayed. The effects of antiproteinase treatment on acute lung injury were also assessed. Total SOD, Cu/Zn SOD, and Cu/Zn SOD antigenic protein levels were decreased in animals after acid aspiration and hyperoxia. However, Mn SOD activity was unchanged. The decrease in Cu/Zn SOD was attenuated in animals, where serine proteinase activity was inhibited. However, antiproteinase treatment did not decrease acute pulmonary injury, as assessed by leakage of radiolabeled albumin into the lung (permeability index), arterial blood gases, and markers of acute inflammation (pulmonary myeloperoxidase activity, a surrogate neutrophilic marker, and inflammatory cytokine profiles). We conclude that production of serine proteinases play a major role in degrading Cu/Zn SOD, thereby decreasing pulmonary antioxidant capacity. However, the role this plays in the pathogenesis of the acute lung injury is not clear.
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PMID:Serine antiproteinase administration preserves innate superoxide dismutase levels after acid aspiration and hyperoxia but does not decrease lung injury. 1597 34

Glutamate (Glu) N-methyl-D-aspartate (NMDA) receptor is present in the lungs, and NMDA receptor antagonist MK-801 attenuates oxidant lung injury. We hypothesized that Glu excitotoxicity may participate in the pathogenesis of hyperoxia-induced lung injury. To determine possible pulmonary protective effects, we administered 0.05 ml/kg MK-801 or saline intraperitoneally daily to neonatal rats exposed to more than 95% oxygen in air. After 7 days, MK-801 decreased the hyperoxia-associated elevation of wet-to-dry lung weight, total leukocyte and neutrophil counts, total protein and lactate dehydroase in BAL fluid, total myeloperoxidase activity, and lung pathological injury. MK-801 inhibited hyperoxia-associated increments in reactive oxygen species production and NF-kappaB production. Hence, NMDA receptor antagonist MK-801 ameliorates hyperoxia-induced lung injury in neonatal rats, and is associated with decreased reactive oxygen species and NF-kappaB. We conclude that Glu may play an important role in hyperoxia-induced lung injury by activation of NMDA receptor.
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PMID:Role of N-methyl-D-aspartate receptor in hyperoxia-induced lung injury. 1616 26


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