Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases

Tsuyoshi Shuto, Shunsuke Kamei, Hirofumi Nohara, Haruka Fujikawa, Yukihiro Tasaki, Takuya Sugahara, Tomomi Ono, Chizuru Matsumoto, Yuki Sakaguchi, Kasumi Maruta, Ryunosuke Nakashima, Taisei Kawakami, Mary Ann Suico, Yoshitaka Kondo, Akihito Ishigami, Toru Takeo, Ken Ichiro Tanaka, Hiroshi Watanabe, Naomi Nakagata, Kohei UchimuraKenichiro Kitamura, Jian Dong Li, Hirofumi Kai

研究成果: Article査読

11 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号39305
ジャーナルScientific reports
6
DOI
出版ステータスPublished - 2016 12 16
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