| Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling. | |
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MedLine Citation:
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PMID: 20539010 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Interstitial lung disease is a devastating disease in humans that can be further complicated by the development of secondary pulmonary hypertension. Accumulating evidence indicates that the oxidant superoxide can contribute to the pathogenesis of both interstitial lung disease and pulmonary hypertension. We used a model of pulmonary hypertension secondary to bleomycin-induced pulmonary fibrosis to test the hypothesis that an imbalance in extracellular superoxide and its antioxidant defense, extracellular superoxide dismutase, will promote pulmonary vascular remodeling and pulmonary hypertension. We exposed transgenic mice overexpressing lung extracellular superoxide dismutase and wild-type littermates to a single dose of intratracheal bleomycin, and evaluated the mice weekly for up to 35 days. We assessed pulmonary vascular remodeling and the expression of several genes critical to lung fibrosis, as well as pulmonary hypertension and mortality. The overexpression of extracellular superoxide dismutase protected against late remodeling within the medial, adventitial, and intimal layers of the vessel wall after the administration of bleomycin, and attenuated pulmonary hypertension at the same late time point. The overexpression of extracellular superoxide dismutase also blocked the early up-regulation of two key genes in the lung known to be critical in pulmonary fibrosis and vascular remodeling, the transcription factor early growth response-1 and transforming growth factor-β. The overexpression of extracellular superoxide dismutase attenuated late pulmonary hypertension and significantly improved survival after exposure to bleomycin. These data indicate an important role for an extracellular oxidant/antioxidant imbalance in the pathogenesis of pulmonary vascular remodeling associated with secondary pulmonary hypertension attributable to bleomycin-induced lung fibrosis. |
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Authors:
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Zachary Van Rheen; Cheryl Fattman; Shannon Domarski; Susan Majka; Dwight Klemm; Kurt R Stenmark; Eva Nozik-Grayck |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-06-10 |
Journal Detail:
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Title: American journal of respiratory cell and molecular biology Volume: 44 ISSN: 1535-4989 ISO Abbreviation: Am. J. Respir. Cell Mol. Biol. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-06 Completed Date: 2011-06-07 Revised Date: 2012-04-02 |
Medline Journal Info:
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Nlm Unique ID: 8917225 Medline TA: Am J Respir Cell Mol Biol Country: United States |
Other Details:
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Languages: eng Pagination: 500-8 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bleomycin Cell Proliferation Early Growth Response Protein 1 / genetics, metabolism Extracellular Space / enzymology* Gene Expression Regulation Humans Hypertension, Pulmonary / complications, enzymology*, mortality, physiopathology* Lung / blood supply*, enzymology*, physiopathology Mice Mice, Inbred C57BL Mice, Transgenic Nitric Oxide Synthase Type III / metabolism Nitrosation Oxidation-Reduction Pulmonary Artery / pathology, physiopathology Pulmonary Fibrosis / complications, genetics, pathology Stress, Physiological Superoxide Dismutase / metabolism* Transforming Growth Factor beta / genetics, metabolism Tyrosine / analogs & derivatives, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HL086680/HL/NHLBI NIH HHS; R01 HL086680-04/HL/NHLBI NIH HHS; R01 HL086680-05/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Early Growth Response Protein 1; 0/Transforming Growth Factor beta; 11056-06-7/Bleomycin; 3604-79-3/3-nitrotyrosine; 55520-40-6/Tyrosine; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.15.1.1/Superoxide Dismutase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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