Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases
| Autor: | Tsuyoshi Shuto, Yukihiro Tasaki, Akihito Ishigami, Tomomi Ono, Takuya Sugahara, Kenichiro Kitamura, Taisei Kawakami, Shunsuke Kamei, Hirofumi Kai, Mary Ann Suico, Ken Ichiro Tanaka, Jian Dong Li, Chizuru Matsumoto, Yoshitaka Kondo, Yuki Sakaguchi, Toru Takeo, Ryunosuke Nakashima, Hirofumi Nohara, Kasumi Maruta, Haruka Fujikawa, Hiroshi Watanabe, Naomi Nakagata, Kohei Uchimura |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Camostat medicine.medical_treatment Mice Transgenic Oxidative phosphorylation medicine.disease_cause Cystic fibrosis Article Antioxidants 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Protease Inhibitors Lung Diseases Obstructive Lung COPD Multidisciplinary Protease business.industry Gene Expression Profiling medicine.disease Microarray Analysis Pathophysiology Mice Inbred C57BL Disease Models Animal Oxidative Stress 030104 developmental biology medicine.anatomical_structure 030228 respiratory system chemistry Immunology business Oxidative stress Metabolic Networks and Pathways Peptide Hydrolases Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but limited information is available on their direct roles in the regulation of pulmonary phenotypes. Here, we utilized βENaC-transgenic (Tg) mice, the previously established mouse model of severe obstructive lung diseases, to produce lower-mortality but pathophysiologically highly useful mouse model by backcrossing the original line with C57/BL6J mice. C57/BL6J-βENaC-Tg mice showed higher survival rates and key pulmonary abnormalities of COPD/CF, including mucous hypersecretion, inflammatory and emphysematous phenotypes and pulmonary dysfunction. DNA microarray analysis confirmed that protease- and oxidative stress-dependent pathways are activated in the lung tissue of C57/BL6J-βENaC-Tg mice. Treatments of C57/BL6J-βENaC-Tg mice with a serine protease inhibitor ONO-3403, a derivative of camostat methylate (CM), but not CM, and with an anti-oxidant N-acetylcystein significantly improved pulmonary emphysema and dysfunction. Moreover, depletion of a murine endogenous antioxidant vitamin C (VC), by genetic disruption of VC-synthesizing enzyme SMP30 in C57/BL6J-βENaC-Tg mice, exaggerated pulmonary phenotypes. Thus, these assessments clarified that protease-antiprotease imbalance and oxidative stress are critical pathways that exacerbate the pulmonary phenotypes of C57/BL6J-βENaC-Tg mice, consistent with the characteristics of human COPD/CF. |
| Databáze: | OpenAIRE |
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