Studies on intracellular and extracellular pathways involved in drug-induced pulmonary fibrosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06749
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Hiroshima University
• Principal Investigator: Yumoto Ryoko 広島大学, 医系科学研究科(薬), 准教授 (70379915)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 薬剤誘発性肺線維症 / 上皮間葉転換(EMT) / 肺胞上皮Ⅱ型細胞 / 細胞周期の停止 / 細胞外分泌因子(PAI-1) / 肺線維症モデル動物

Outline of Final Research Achievements

Several anticancer drugs including methotrexate (MTX) cause serious lung diseases such as pulmonary fibrosis. Although evidences showing the association of epithelial-mesenchymal transition (EMT) with pulmonary fibrosis are increasing, the mechanism underlying anticancer drug-induced EMT has been poorly understood.
In this research, we indicated that MTX-induced EMT may be related to cell cycle arrest in human alveolar epithelial cell line, A549. It was also suggested that the transforming growth factor (TGF)-β-related signaling pathway may partly be involved in MTX-induced EMT, and MTX may induce EMT via upregulation of ATF3 expression and increase of PAI-1 secretion followed by interaction of PAI-1 with uPAR

Free Research Field

医療薬剤学

Academic Significance and Societal Importance of the Research Achievements

薬剤性肺障害のうち、肺線維症は非常に重篤な障害であるが、その発症機構を細胞・分子レベルで解析した報告は乏しく、また有効な予防方法・治療方法はない。
本研究では薬剤誘発性EMTによる肺線維症に関わる分子機構を細胞内経路、細胞外経路の両面から解明することによって、肺線維症に対する新たな予防法や治療戦略を考案し得るところに学術的・社会的意義があると考える。