Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis

• Project/Area Number: 17K09673
• 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: Jikei University School of Medicine
• Principal Investigator: Minagawa Shunsuke 東京慈恵会医科大学, 医学部, 講師 (70468685)
• Co-Investigator(Kenkyū-buntansha): 荒屋 潤 東京慈恵会医科大学, 医学部, 教授 (90468679)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 慢性閉塞性肺疾患 / COPD / 細胞死 / オートファジー / 脂質酸化 / 活性酸素 / フェロトーシス / フェリチノファジー / 鉄

Outline of Final Research Achievements

Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We demonstrated the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.

Academic Significance and Societal Importance of the Research Achievements

COPDの発生機序は、未だ解明されておらず有効な治療法も確立されていないのが現状である。我々の考えるCOPDの発生機序は、遊離鉄、鉄依存性細胞死、フェリチン依存性オートファジーであるフェリチノファジーといったこれまで検討されていなかった全く新しい機序であり、新規薬剤の開発に大いなる前進をもたらす可能性を秘めている。またCOPDは、世界的に見ても死亡率の高い疾患であり、新規治療法が開発されれば、その社会的意義は十分大きいものと考えられる。

Research Products

• [Journal Article] Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. (2019)
  • Author(s): Yoshida M, Minagawa S, Araya J, Sakamoto T, Hara H, Tsubouchi K, Hosaka Y, Ichikawa A, Saito N, Kadota T, Sato N, Kurita Y, Kobayashi K, Ito S, Utsumi H, Wakui H, Numata T, Kaneko Y, Mori S, Asano H, Yamashita M, Odaka M, Morikawa T, Nakayama K, Iwamoto T, Imai H, Kuwano K.
  • Journal Title: Nat Commun. Volume: 10 Issue: 1 Pages: 3145-3145
  • DOI: 10.1038/s41467-019-10991-7
  • Peer Reviewed / Open Access
• [Presentation] NCOA4依存性フェリチノファジーのCOPD病態への関与 (2018)
  • Author(s): 吉田昌弘
  • Organizer: 日本呼吸器学会
• [Presentation] Involvement of cigarette smoke induced ferroptosis via NCOA4-mediated ferritinophagy in COPD pathogensis (2018)
  • Author(s): 吉田昌弘
  • Organizer: ヨーロッパ呼吸器学会
  • Int'l Joint Research
• [Presentation] The role of ferroptosis in COPD pathogenesis (2017)
  • Author(s): 吉田昌弘
  • Organizer: 欧州呼吸器学会
  • Int'l Joint Research