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)

Hyperoxic lung injury is an unfortunate consequence of ventilatory oxygen therapy that is necessary to sustain life in certain clinical situations. The biochemical events that accompany hyperoxia of the lung, and the molecular mechanisms underlying these events, are incompletely understood. To better understand hyperoxic lung injury, our laboratory has cloned a set of genes corresponding to mRNAs that increase in abundance in the lungs of hyperoxic rabbits. In this report, we focus on three hyperoxia-induced cDNA clones, which encode surfactant apoprotein A (SP-A), the tissue inhibitor of metalloproteinases (TIMP), and metallothionein. In situ hybridizations and RNA dot blots of isolated lung cell populations indicate that the abundance of mRNA encoding all three proteins is increased by hyperoxia in specific cell types. SP-A mRNA increases in type II alveolar epithelial cells and in bronchiolar epithelial cells. TIMP mRNA increases in interstitial fibroblasts, in chondrocytes of the cartilage surrounding airways, and in endothelial cells of a specific subset of vessels, probably venules. Metallothionein transcripts also increase in chondrocytes and pulmonary fibroblasts. A comparison of the increase in these mRNAs during hyperoxic exposure in adults and newborns indicates that adults respond faster and to a greater extent than newborns and suggests that the rate and extent of these increases is correlated with the time course and severity of the injury.
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PMID:Cell-specific alterations in expression of hyperoxia-induced mRNAs of lung. 195 78

Preexposure of male Lewis rats to Cd aerosols (1.6 mg Cd/m3, 3 hr/day, 5 days/week, for 4 weeks) has been found to produce a marked degree of tolerance to hyperoxia (greater than 96% O2). Cd-pretreated animals were still alive after 8 days of continuous exposure to oxygen. In contrast, hyperoxia was fatal to all air-preexposed animals within 54-62 hr. Lungs of Cd-pretreated animals were characterized by hyperplasia and/or hypertrophy of the type II alveolar cell compartment which may have enabled them to more rapidly repair oxidant damage resulting from hyperoxia. Cd pretreatment augmented enzymatic antioxidant enzyme activities, including total lung Se-dependent glutathione peroxidase, catalase, glutathione reductase, and Mn-superoxide dismutase, and caused elevations in pulmonary nonprotein thiols and metallothionein (MT). MT, a thiol-rich, low-molecular-weight protein, was 400-fold higher in Cd-pretreated animals and bound more than 80% of the total Cd in the lung. We have hypothesized that MT serves as an expendable yet renewable cellular target for free radical damage during oxygen exposure. A systemic acute-phase response, characterized by alterations in plasma Zn and Cu concentrations and increased ceruloplasmin oxidase activity, was initiated in Cd-pretreated animals by the fourth day of hyperoxia. This response was accompanied by improvement in pulmonary status and extensive pulmonary repair.
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PMID:Cross-tolerance to hyperoxia following cadmium aerosol pretreatment. 233 May 88

Glutathione reductase (GR) protects tissues from oxidant injury by catalysing the reduction of glutathione disulfide (GSSG) to glutathione (GSH). In order to study the effect of GR in protecting cells from oxidant injury, we generated Chinese hamster ovary (CHO) cell lines stably transformed after antisense-oriented gene transfection. The coding region of the human GR was cloned using revere transcription PCR method and selected by transient expression study in mammalian cells. A clone HGR135 showed overexpression of GR in CHO cells and was proved to have no base substitution. This clone, then, was ligated into MEP4 expression vector in an antisense orientation to the human metallothionein promoter and transfected to CHO cells with polybrene. Among 12 cell lines isolated, G17 showed to have the least GR activity (48% of the control), while another four were mildly GR deficient. Southern hybridization of genomic DNA digests and transformation experiment on E. coli revealed that the promoter-antisense coding region component was integrated. Northern hybridization detected reduced amount of GR transcript but no antisense message. Baseline cellular GSH concentrations were lower in G17 than in control (25.7 +/- 2.5 vs. 36.1 +/- 1.9 nmole/mg protein, P < 0.05), while cellular GSSG concentrations were higher (0.61 +/- 0.19 vs. 0.39 +/- 0.09 nmole/mg protein, P < 0.05). After four hours of treatment of G17 and control cells with increasing doses (1 to 10 mM) of t-butylhydroperoxide (t-BuOOH), cellular GSH concentrations in G17 decreased with an elevation of GSSG concentration at 1 mM followed by no further increase at higher t-BuOOH concentration, while GSSG concentrations increased in the control cells without reduction of GSH concentrations at 1-5 mM t-BuOOH treatment. The concentrations of GSH were lower in G17 than in controls at all doses of t-BuOOH. Four hours of exposure to 10 mM t-BuOOH resulted in greater LDH release in G17 than in control (57.3 +/- 4.7 vs. 32.1 +/- 6.5%, P < 0.05). Similarly, G17 cells released more of their LDH to the media than did CHO cells in response to exposure to 95% O2 for 72 hours (19.3 +/- 5.9 vs. 11.9 +/- 5.4%, P < 0.05). The partial GR deficiency in G17 cells impairs their ability to recycle GSSG and this deficiency offers the best explanation for the increased sensitivity of these cells to injury by t-BuOOH or hyperoxia.
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PMID:[Establishment of Chinese hamster ovary cell lines with reduced expression of glutathione reductase after antisense-oriented gene transfection and assessment of the sensitivity to oxidant injury]. 786 64

Acute exposure to hyperoxia results in well-described pathophysiologic responses in the lungs, beginning with subtle, subcellular changes and ending with severe pulmonary inflammation and edema. The biologic events that underlie or accompany this injury are not well understood. Our previous studies in rabbits have shown that hyperoxia induces large increases in the mRNAs encoding metallothionein (MT) and the tissue inhibitor of metalloproteinases (TIMP-I). Here we report studies of hyperoxic lung injury in two strains of mouse that differ in their relative resistance to O2 toxicity. O2-sensitive (C57BL/6J) mice and O2-resistant (C3H/HeJ) mice were exposed to 100% O2 for up to 96 h. Lung mRNAs were assayed by primer extension and slot blot hybridization. By 72 h of hyperoxia, the sensitive strain showed large increases in MT-I, MT-II, and TIMP-I mRNAs. The resistant strain showed similar changes but with a 24-h delay. In situ hybridization demonstrated that hyperoxic lung injury was accompanied by obvious increases in TIMP-I and MT transcripts in cells surrounding arteries and large airways, where many inflammatory cells were localized. With prolonged exposure, hybridization to MT transcripts had spread throughout lung parenchyma. The two strains showed the same patterns of in situ hybridization for TIMP-I and MT transcripts but, as with the whole lung homogenates, followed a different time course. Corresponding increases in MT protein were shown to occur, using a cadmium binding assay and by immunohistochemistry. The strong spatial correlation between the presence of localized inflammation and increased TIMP-I and MT expression further supports the importance of TIMP-I and MT in acute lung injury.
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PMID:Increased expression of tissue inhibitor of metalloproteinases (TIMP-I) and metallothionein in murine lungs after hyperoxic exposure. 811 Apr 67

Alveolar epithelial type II cells (AEIIC) were isolated from male Lewis rats following repeated in vivo cadmium aerosol exposure and were subsequently evaluated for their oxidant resistance in vitro. AEIIC from Cd-adapted animals removed a greater proportion of hydrogen peroxide from the extracellular milieu and incurred less oxidant-induced cytotoxicity than AEIIC from air controls. This altered response to oxidants occurred coincident with changes in cellular resistance factors. A two-fold increase in glutathione peroxidase activity and a 1.5-fold increase in the activities of glutathione reductase and catalase were observed in Cd-adapted AEIIC compared to control cells. These cells also exhibited a dramatic induction of metallothionein (MT), a thiol-rich protein known to scavenge free radicals in vitro. MT concentration increased as a function of exposure number. MT was localized within the nucleus and cytoplasm of AEIIC by immunocytochemical techniques. MT positive cells showed a wide variation of MT content, particularly in the nucleus. The biochemical and physiological features of these AEIIC may explain, in part, why animals pretreated with Cd aerosols develop cross-tolerance to hyperoxia.
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PMID:Increased oxidant resistance of alveolar epithelial type II cells. Isolated from rats following repeated exposure to cadmium aerosols. 855 67

The objective of the present study was to demonstrate an antioxidant function for Zn in vivo by comparing the efficacy of Zn or Vitamin E without additional energy intake for protection of Zn-deficient (ZnDF) or energy-restricted (ER) rats from hyperoxia-induced lung damage. Zn (200 mumol ZnCl2/kg b.wt.) or Vitamin E (100 mg alpha-tocopherol/kg b.wt.) was injected IP before exposure to 85% oxygen or air for 5 d. During the exposure period, all injected ZnDF or ER rats were restricted to 5 g Zn-deficient or Zn-adequate diet/day, respectively, the amount of diet consumed by the untreated ZnDF or ER rats. We clearly demonstrated that injection of Zn without additional energy intake can protect ZnDF and ER rats from hyperoxia-induced lung damage assessed by the histopathological scoring system and magnetic resonance imaging (MRI). Vitamin E was not as effective as Zn in either ZnDF or ER rats for preventing hyperoxia-induced lung damage. Zn injection did not exert its antioxidant effect through increased lung CuZn-superoxide dismutase activity or metallothionein. This difference in the effectiveness of Vitamin E and Zn for hyperoxic protection in lung injury may be due to the specificity of antioxidant function, i.e., vitamin E inhibits oxidation of membrane lipids and Zn protects sulfhydryl groups of proteins.
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PMID:Comparison of Zn and vitamin E for protection against hyperoxia-induced lung damage. 898 Oct 47

Superoxide formation in pulmonary tissue is modulated by cytokines, PO2, shear force, and disease states, and can be stimulated by drugs. Superoxide has diverse actions on pulmonary cells, including smooth muscle contraction, interaction with redox enzymes, cell proliferation, and gene transcription. In the lungs, there is an impressive array of specific defence mechanisms that destroy superoxide, especially superoxide dismutase (SOD) and metallothionein. Superoxide formation is increased in hyperoxia (e.g., oxygen therapy); however, superoxide-forming enzymes also can be up-regulated in hypoxia. Superoxide has been implicated in acute respiratory distress syndrome, lung ischaemia-reperfusion injury, and lung transplantation. Novel approaches to therapy have been explored, including SOD gene therapy and SOD targeting to the lung. In the future, new drugs interacting with superoxide may provide significant advances in the treatment of lung diseases.
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PMID:Superoxide in the pulmonary circulation. 1066 34

Ceruloplasmin, metallothionein, and ferritin are metal-binding proteins with potential antioxidant activity. Despite evidence that they are upregulated in pulmonary tissue after oxidative stress, little is known regarding their influence on trace metal homeostasis. In this study, we have used copper- and zinc-containing superoxide dismutase (Cu/Zn SOD) transgenic-overexpressing and gene knockout mice and hyperoxia to investigate the effects of chronic and acute oxidative stress on the expression of these metalloproteins and to identify their influence on copper, zinc, and iron homeostasis. We found that the oxidative stress-mediated induction of ceruloplasmin and metallothionein in the lung had no effect on tissue levels of copper, iron, or zinc. However, Cu/Zn SOD expression had a marked influence on hepatic copper and iron as well as circulating copper homeostasis. These results suggest that ceruloplasmin and metallothionein may function as antioxidants independent of their role in trace metal homeostasis and that Cu/Zn SOD functions in copper homeostasis via mechanisms distinct from its superoxide scavenging properties.
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PMID:Cellular response of antioxidant metalloproteins in Cu/Zn SOD transgenic mice exposed to hyperoxia. 1140 60

To identify molecular events occurring during the early response to hyperoxia, we measured changes over time in total lung gene expression in C57BL/6 mice during prolonged exposure to > 95% O2. Specifically, differential gene expression of > 8,734 sequence-verified murine complementary DNAs was analyzed after 0, 8, 24, and 48 h of O2 exposure, with additional genes of interest analyzed at 24 h. Of the 385 genes differentially expressed, hyperoxia increased expression of 175 genes (2.0%) and decreased expression of 210 genes (2.3%). The majority of "classic" antioxidant enzymes, including catalase, MnSOD, and Cu-Zn SOD, showed no change in expression during hyperoxia, with a number of other antioxidant enzymes, including glutathione peroxidase, glutathione-S-Transferase (GST) Pi1, GST mu2, and heme oxygenase-1 showing relatively moderate increases. The exception was the heavy metal-binding protein metallothionein, which increased expression over 7-fold after 48 h of O2. We found no change in the expression of a number of known proinflammatory genes after 24 or 48 h of hyperoxia. A large increase in p21 expression was demonstrated, suggesting overall inhibition of cell cycle progression. Increases of the antiapoptotic gene Bcl-XL were counterbalanced by similar increases of the proapoptotic gene BAX. New findings included significant increases in expression of cysteine-rich protein 61(cyr61) at 48 h, suggesting a potential role for this factor in angiogenesis or remodeling of the extra cellular matrix during recovery from hyperoxia. In addition, downregulation of thrombomodulin expression occurred by 24 h and was further decreased at 48 h. Given the importance of thrombomodulin/thrombin interaction in regulating protein C activity, decreases in thrombomodulin may contribute to activation of the coagulation and inflammatory cascades and development of lung injury with hyperoxia.
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PMID:Gene expression profiling of the early pulmonary response to hyperoxia in mice. 1276 Sep 66

Oxidative stress is an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants characterized by arrested alveolar and vascular development of the immature lung. We investigated differential gene expression with DNA microarray analysis in premature rat lungs exposed to prolonged hyperoxia during the saccular stage of development, which closely resembles the development of the lungs of premature infants receiving neonatal intensive care. Expression profiles were largely confirmed by real-time RT-PCR (27 genes) and in line with histopathology and fibrin deposition studied by Western blotting. Oxidative stress affected a complex orchestra of genes involved in inflammation, coagulation, fibrinolysis, extracellular matrix turnover, cell cycle, signal transduction, and alveolar enlargement and explains, at least in part, the pathological alterations that occur in lungs developing BPD. Exciting findings were the magnitude of fibrin deposition; the upregulation of chemokine-induced neutrophilic chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), amphiregulin, plasminogen activator inhibitor-1 (PAI-1), secretory leukocyte proteinase inhibitor (SLPI), matrix metalloproteinase-12 (MMP12), p21, metallothionein, and heme oxygenase (HO); and the downregulation of fibroblast growth factor receptor-4 (FGFR4) and vascular endothelial growth factor (VEGF) receptor-2 (Flk-1). These findings are not only of fundamental importance in the understanding of the pathophysiology of BPD, but also essential for the development of new therapeutic strategies.
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PMID:Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress. 1499 Mar 57


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