Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Asbestos resembles the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), in its ability to elicit release of superoxide (O2-.) from rodent alveolar macrophages (AM) in vitro. In addition, superoxide dismutase (SOD), the antioxidant enzyme scavenging O2-, is increased in cultures of tracheobronchial epithelial cells and lung fibroblasts after exposure to either crocidolite or chrysotile asbestos. Our objectives here were to determine: (1) the chemical and physical properties of asbestos important in the generation of O2- from rat AM; and (2) the effects of O2- in comparison with asbestos on biosyntheses of collagen and non-collagen protein in rat lung fibroblasts in vitro. We were also interested in whether increased production of SOD occurred in the lungs of rats after inhalation of crocidolite asbestos. To determine whether O2- was elicited in response to a variety of asbestiform fibres, AM lavaged from Fischer 344 rat lungs were exposed in vitro to equivalent non-toxic amounts of crocidolite asbestos, erionite, Code 100 fibreglass, sepiolite, and their non-fibrous analogues, riebeckite, mordenite and glass particles. In addition, sized preparations of long (greater than 10 microns) and short (less than 2 microns) asbestos were introduced at identical concentrations to determine whether length of fibres is critical in O2- release. The amount of O2- released from AM in response to dusts was then determined by measuring SOD-inhibitable reduction of cytochrome C. All asbestiform fibres caused a significant (p less than 0.05) increase in generation of O2- from epithelial cells, whereas non-fibrous particles were less active at comparable concentrations. Experiments with long (greater than 10 microns) versus short (less than 2 microns) chrysotile showed that long fibres caused a more striking, dosage-dependent release of O2-. To determine whether O2- plays a role in the causation of fibrotic lung disease, rat lung fibroblasts were exposed to a biochemical generation system (xanthine-xanthine oxidase) for O2- before quantitation of cell-associated collagen and non-collagen protein at 24, 48 and 72 h thereafter. At the latter time periods, significant increases in total collagen per ng DNA were observed. In comparison with controls, the generation system for O2- also caused an initial decrease in synthesis of non-collagen protein followed by increases in synthesis of non-collagen protein at 48 and 72 h.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of fibre-induced superoxide release from alveolar macrophages and induction of superoxide dismutase in the lungs of rats inhaling crocidolite. 254 20

Asbestos exposure in humans is associated with inflammatory, fibrotic, and malignant diseases in the lung. Increasing evidence supports the hypothesis that the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNFalpha) is an important mediator of the pathologic responses of asbestosis. In this study, we examine the role of nuclear transcription factor-kappaB (NF-kappaB) and free oxygen radicals in asbestos-induced TNFalpha gene and protein expression in lung macrophages. Exposure of the cells to crocidolite asbestos caused a parallel increase in TNFalpha production and NF-kappaB activation, as analyzed by enzyme-linked immunosorbent assay and electrophoretic mobility shift assay. Inhibition of NF-kappaB by SN50, an inhibitor of NF-kappaB nuclear translocation, or by sequence-specific oligonucleotides directed against the NF-kappaB binding site of TNFalpha promoter attenuated the asbestos effect on TNFalpha production. Gene transfection assays using an expression plasmid containing a luciferase reporter gene and a TNFalpha-derived NF-kappaB gene promoter further indicated the dependence of NF-kappaB activation on asbestos-induced gene expression. The effects of asbestos on NF-kappaB and TNFalpha activation were inhibited by oxygen radical scavengers and were enhanced by antioxidant enzyme inhibitors. These results indicate that asbestos-induced TNFalpha gene expression is mediated through a process that involves NF-kappaB activation and free radical reactions.
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PMID:Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages. 1048 38

Results are presented which support the hypothesis that adequate steady-state levels of hydrogen peroxide (H2O2) are required to overcome the effects of high catalase and glutathione peroxidase (GPx) expression for p38 mitogen-activated protein (MAP) kinase activation and tumor necrosis factor (TNF)-alpha gene expression in human alveolar macrophages stimulated with asbestos. We found significant differences in the types and amounts of reactive oxygen species generated in human blood monocytes compared with human alveolar macrophages. This difference in reactive oxygen species production is related, in part, to the differences in antioxidant enzyme expression and activity. Most importantly, catalase and GPx activities were significantly increased in alveolar macrophages compared with blood monocytes. Asbestos activated the p38 MAP kinase and induced TNF-alpha gene expression only in blood monocytes. Increasing the steady-state levels of H2O2 by using polyethylene glycol superoxide dismutase, an antioxidant that crosses the cell membrane, or aminotriazole, an irreversible inhibitor of catalase, allowed the p38 MAP kinase to be activated in alveolar macrophages. In addition, asbestos-stimulated macrophages cultured with polyethylene glycol superoxide dismutase had a significant increase in gene expression mediated by the TNF-alpha promoter. These results demonstrate that high catalase and GPx activity in human alveolar macrophages limits the effectiveness of H2O2 to act as a mediator of inflammatory gene expression.
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PMID:High levels of catalase and glutathione peroxidase activity dampen H2O2 signaling in human alveolar macrophages. 1496 75

The release of H(2)O(2) from alveolar macrophages has been linked to the development of pulmonary fibrosis, but little is known about its source or mechanism of production. We found that alveolar macrophages from asbestosis patients spontaneously produce high levels of H(2)O(2) and have high expression of Cu,Zn-superoxide dismutase (SOD). Because Cu,Zn-SOD is found in the mitochondrial intermembrane space (IMS), we hypothesized that mitochondrial Cu,Zn-SOD-mediated H(2)O(2) generation contributed to pulmonary fibrosis. Asbestos-induced translocation of Cu,Zn-SOD to the IMS was unique to macrophages and dependent on functional mitochondrial respiration and the presence of at least one of the conserved cysteines required for disulfide bond formation. These conserved cysteine residues were also necessary for enzyme activation and H(2)O(2) generation. Cu,Zn-SOD-mediated H(2)O(2) generation was inhibited by knockdown of the iron-sulfur protein, Rieske, in complex III. The role of Cu,Zn-SOD was biologically relevant in that Cu,Zn-SOD(-/-) mice generated significantly less H(2)O(2) and had less oxidant stress in bronchoalveolar lavage fluid and lung parenchyma. Furthermore, Cu,Zn-SOD(-/-) mice did not develop pulmonary fibrosis, and knockdown of Cu,Zn-SOD in monocytes attenuated collagen I deposition by lung fibroblasts. Our findings demonstrate a novel mechanism for the pathogenesis of pulmonary fibrosis where the antioxidant enzyme Cu,Zn-SOD translocates to the mitochondrial IMS to increase H(2)O(2) generation in alveolar macrophages.
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PMID:Mitochondrial Cu,Zn-superoxide dismutase mediates pulmonary fibrosis by augmenting H2O2 generation. 2139 38