Identification and application of therapeutic targets and diagnostic markers of obstructive pulmonary diseases based on global expression analysis

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460102
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: Shuto Tsuyoshi 熊本大学, 生命科学研究部(薬), 准教授 (80333524)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 閉塞性肺疾患 / プロテアーゼ / 参加ストレス / ビタミンC

Outline of Final Research Achievements

Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but their role in the regulation of pulmonary emphysema and dysfunction of βENaC-transgenic (Tg) mice, a murine model of COPD/CF, is unknown. DNA microarray analysis revealed that protease- and oxidative stress-dependent pathways are activated in the lung tissue of βENaC-Tg mice. Here, treatments of βENaC-Tg mice with a serine protease inhibitor ONO3403 and an antioxidant 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 βENaC-Tg mice, increased inflammatory status in lung tissue and exaggerated pulmonary emphysema with a significant decrease in pulmonary function, possibly due to an increased oxidative stress.

Free Research Field

薬理学、細胞生物学