Lung Extracellular Superoxide Dismutase Overexpression Lessens Bleomycin-Induced Pulmonary Hypertension and Vascular Remodeling
| Autor: | Kurt R. Stenmark, Susan M. Majka, Zachary Van Rheen, Cheryl L. Fattman, Dwight J. Klemm, Eva Nozik-Grayck, Shannon Domarski |
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| Rok vydání: | 2011 |
| Předmět: |
Pulmonary and Respiratory Medicine
Pathology medicine.medical_specialty Nitric Oxide Synthase Type III Hypertension Pulmonary Nitrosation Pulmonary Fibrosis Clinical Biochemistry Mice Transgenic Pulmonary Artery Bleomycin Superoxide dismutase Mice chemistry.chemical_compound Stress Physiological Transforming Growth Factor beta medicine.artery Pulmonary fibrosis medicine Animals Humans Lung Molecular Biology Cell Proliferation Early Growth Response Protein 1 biology Superoxide Dismutase Superoxide Interstitial lung disease Articles Cell Biology respiratory system medicine.disease Pulmonary hypertension Mice Inbred C57BL medicine.anatomical_structure Gene Expression Regulation chemistry Pulmonary artery biology.protein Tyrosine Extracellular Space Oxidation-Reduction |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 44:500-508 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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