title: Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases.
abstract: 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.
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kamei
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nohara
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Fujikawa
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tasaki
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sugahara
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ono
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Matsumoto
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sakaguchi
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Kasumi
authors.initials: K
authors.lastname: Maruta
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Nakashima
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Kawakami
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Ishigami
authors.affiliation: Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takeo
authors.affiliation: Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
authors.forename: Ken-Ichiro
authors.initials: KI
authors.lastname: Tanaka
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.affiliation: University of Yamanashi School of Medicine, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Uchimura
authors.affiliation: University of Yamanashi School of Medicine, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Center for Inflammation, Immunity &Infection, Institute for Biomedical Sciences, Georgia State University, 714 Petit Science Center, 100 Piedmont Ave SE, Atlanta, GA30303, USA.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D008168:Lung / Q000473:pathology; D008173:Lung Diseases, Obstructive / Q000503:physiopathology*; D053858:Metabolic Networks and Pathways; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000096:biosynthesis; D011480:Protease Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D011480:Protease Inhibitors; D010447:Peptide Hydrolases