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

2019 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

呼吸器内科学

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。