The role and regulatory mechanisms of ROS signaling in the pathogensis of pulmonary fibrosis

• Project/Area Number: 16K09571
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: University of Tsukuba
• Principal Investigator: Matsuno Yosuke 筑波大学, 医学医療系, 講師 (30633177)
• Co-Investigator(Kenkyū-buntansha): 石井 幸雄 筑波大学, 医学医療系, 教授 (80272194)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肺線維症 / 活性酸素 / Notchシグナリング / 上皮間葉移行 / アポトーシス / Nrf2 / 肺胞上皮細胞 / 線維芽細胞 / ROS / EMT / Notch / IL-6 / STAT3 / apoptosis / TGF-β1 / Notch経路

Outline of Final Research Achievements

We explored the role of ROS signaling in the pathogenesis of pulmonary fibrosis. In TGF-beta1-induced EMT of alveolar epithelial cells, TGF-beta1 production of ROS induced EMT through Nrf2-mediated Notch signaling activation. In cell density-dependent apoptosis of fibroblasts, while the involvement of ROS was not clear, cell density-dependent activation of Notch signaling regulated apoptosis via transcriptional activation of IL-6. ROS and its related signaling pathways are suggested to play a pivotal role in the development of pulmonary fibrosis.

Academic Significance and Societal Importance of the Research Achievements

本研究は、ROSが細胞・組織障害を引き起こすだけでなく、シグナル伝達物質として機能し、Notch経路の活性化を通してEMTを誘導することを明らかにした。またNotch経路は、線維芽細胞のアポトーシス制御にも関与していた。ROSシグナリングとNotch経路は、肺の細胞の分化・運命決定の調節を通して、肺線維症の進展において重要な役割を担うことが示唆された。今後これらのシグナル経路について、肺線維症で担う役割の解明が進み、新規治療標的となりうるかどうか検証されることが期待される。

Research Products

• [Journal Article] Notch signaling regulates cell density-dependent apoptosis of NIH 3T3 through an IL-6/STAT3 dependent mechanism (2018)
  • Author(s): Matsuno Yosuke、Kiwamoto Takumi、Morishima Yuko、Ishii Yukio、Hizawa Nobuyuki、Hogaboam Cory M.
  • Journal Title: European Journal of Cell Biology Volume: 97 Issue: 7 Pages: 512-522
  • DOI: 10.1016/j.ejcb.2018.09.001
  • Peer Reviewed / Open Access
• [Journal Article] Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice (2018)
  • Author(s): Sakurai Hirofumi、Morishima Yuko、Ishii Yukio、Yoshida Kazufumi、Nakajima Masayuki、Tsunoda Yoshiya、Hayashi Shih-Yuan、Kiwamoto Takumi、Matsuno Yosuke、Kawaguchi Mio、Yamamoto Masayuki、Hizawa Nobuyuki
  • Journal Title: Free Radical Biology and Medicine Volume: 129 Pages: 473-485
  • DOI: 10.1016/j.freeradbiomed.2018.10.400
  • Peer Reviewed
• [Presentation] ROS-Nrf2 Pathway Mediates the Development of TGF-b1-Induced Epithelial-Mesenchymal Transition Through the Interaction with Notch Signaling (2018)
  • Author(s): Yosuke Matsuno, Masashi Matsuyama, Takumi Kiwamoto, Yuko Morishima, Yukio Ishii, Nobuyuki Hizawa
  • Organizer: American Thoracic Society Conference
  • Int'l Joint Research
• [Presentation] The Role of T-bet in Emphysema (2017)
  • Author(s): Shigen Hayashi , Yousuke Matsuno , Yoshiya Tsunoda , Hirofumi Sakurai , Takumi Kiwamoto , Miou Kawaguchi , Yuko Morishima , Yukio Ishii , Nobuyuki Hizawa
  • Organizer: American Thoracic Society 2017 International Conference
  • Int'l Joint Research