Elucidation of the molecular mechanism of preferential suppression of fibroblast activity and its application to the treatment of pulmonary fibrosis

• Project/Area Number: 18K06691
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Musashino University
• Principal Investigator: Tanaka Ken-ichiro 武蔵野大学, 薬学部, 講師 (30555777)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肺線維症 / 線維芽細胞 / 線維化 / 既存薬 / IPF / 呼吸器 / 肺線維芽細胞 / スクリーニング / 細胞死 / ライブラリー / ドラッグリポジショニング

Outline of Final Research Achievements

The onset and exacerbation of idiopathic pulmonary fibrosis (IPF), an intractable disease, involves abnormal proliferation and activation of lung fibroblasts (e.g., collagen overproduction) triggered by alveolar epithelial cell injury caused by reactive oxygen species (ROS). In this study, we aimed to apply compounds (approved drug) that preferentially induce cell death in fibroblasts without damaging alveolar epithelial cells as a therapeutic agent for IPF. As a result, we found that the candidate compound showed efficacy against a mouse model of pulmonary fibrosis. We also found that the efficacy was superior to that of existing drugs such as pirfenidone, and that the candidate compound did not induce side effects in the gastrointestinal tract or liver.

Academic Significance and Societal Importance of the Research Achievements

ピルフェニドンやニンテダニブなどの治療薬は存在するが、有効性を示さない患者が存在することや副作用を誘発することなどから、IPFに対する新規治療薬の開発が望まれている。本研究で用いた候補化合物は、肺線維症に対して既存治療薬より優れた有効性を発揮し、副作用を起こしにくいことを動物モデルを用いて明らかにした。このように本研究では、難病であるIPF対して安全で有効な候補化合物を発見しており、臨床的な意義が大きいと考えている。また、本研究では、候補化合物が線維芽細胞選択的に作用するターゲット候補を発見しているので、今後のIPF治療薬開発における一助となるのではないかと考えている。

Research Products

• [Journal Article] Thioredoxin-albumin fusion protein prevents urban aerosol-induced lung injury via suppressing oxidative stress-related neutrophil extracellular trap formation. (2021)
  • Author(s): Tanaka KI, Kubota M, Shimoda M, Hayase T, Miyaguchi M, Kobayashi N, Ikeda M, Ishima Y, Kawahara M.
  • Journal Title: Environ Pollut. Volume: 268(Pt A) Pages: 115787-115787
  • DOI: 10.1016/j.envpol.2020.115787
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Carnosine and Lung Disease (2020)
  • Author(s): Tanaka KI, Kawahara M.
  • Journal Title: Curr Med Chem Volume: 27 Issue: 11 Pages: 1714-1725
  • DOI: 10.2174/0929867326666190712140545
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Idebenone has preventative and therapeutic effects on pulmonary fibrosis via preferential suppression of fibroblast activity (2019)
  • Author(s): Tanaka Ken-ichiro、Shimoda Mikako、Takafuji Ayaka、Hino Yuuki、Sugizaki Toshifumi、Kawahara Masahiro
  • Journal Title: Proceedings for Annual Meeting of The Japanese Pharmacological Society Volume: 92 Issue: 0 Pages: 3-P-084
  • DOI: 10.1254/jpssuppl.92.0_3-P-084
  • NAID: 130007813267
  • ISSN: 2435-4953
  • Peer Reviewed / Open Access
• [Presentation] 線維芽細胞選択的に作用する薬の探索と特発性肺線維症治療薬への応用 (2019)
  • Author(s): 田中 健一郎、下田 実可子、高藤 綾香、日野 優生、杉崎 俊文、川原 正博
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Therapeutic effect of idebenone on pulmonary fibrosis via preferential suppression of fibroblast activity (2019)
  • Author(s): Ken-ichiro Tanaka, Mikako Shimoda, Ayaka Takafuji, Yuki hino, Toshifumi Sugizaki, and Masahiro Kawahara
  • Organizer: CHEST Congress 2019
  • Int'l Joint Research