Chaperone-mediated autophagy modulates epithelial cell apoptosis in COPD pathogenesis

• Project/Area Number: 17K09672
• 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: Numata Takanori 東京慈恵会医科大学, 医学部, 講師 (30366257)
• 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: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: シャペロン介在性オートファジー / LAMP2A / 慢性閉塞性肺疾患 / ヒト気道上皮細胞 / 細胞死 / アポトーシス / 細胞老化 / 活性酸素種 / 分子細胞呼吸器病 / オートファジー

Outline of Final Research Achievements

Chaperon-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins. CMA has been implicated in maintaining nutritional homeostasis. We sought to examine the role of CMA in regulating cigarette smoke(CS)-induced apoptosis linked to UPR during COPD pathogenesis by using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through Nrf2 dependent manner in HBEC. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD and LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest impaired CMA during CSE exposure may be causally associated with COPD pathogenes is through enhanced UPR-mediated apoptosis in epithelial cells.

Academic Significance and Societal Importance of the Research Achievements

慢性閉塞性肺疾患(COPD)は喫煙を原因とし, 酸化ストレス増加に関連した細胞老化や細胞死の亢進が重要な役割を果たす。COPD病態におけるシャペロン介在性オートファジー(CMA)の蛋白質恒常性維持機構としての役割解明を目的に検討を行った。
Nrf2-LAMP2A axisがUPRとアポトーシス制御によりCOPD病態進展に関与する可能性が示された。また、LAMP2A発現量は呼吸機能検査結果と相関した点から、CMAのCOPD病態の気道閉塞への関与の可能性が強く示唆され、今後CMA活性化を標的としたCOPD治療法開発が重要な検討課題と考えられた。

Research Products

• [Presentation] COPD病態におけるシャペロン介在性オートファジー（chaperon-mediated autophagy；CMA）の役割の検討 (2019)
  • Author(s): 保坂悠介，荒屋潤，皆川俊介，原 弘道，伊藤晶彦，中野貴之，市川晶博，斉藤那由多，吉田昌弘，橋本典生，沼田尊功，金子由美，浅野久敏，松平秀樹，大塚 崇，桑野和善
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] Chaperone-mediated autophagy modulates epithelial cell apoptosis in COPD pathogenesis (2019)
  • Author(s): Hosaka Y, Araya J, Fujita Y, Tsubouchi K, Minagawa S, Hara H, Nakano T, Ito A, Ichikawa A, Saito N, Kadota T, Yoshida M, Hashimoto M, Numata N, Kaneko Y, Kuwano K
  • Organizer: The European Respiratory Society International Congress
  • Int'l Joint Research
• [Presentation] COPD病態におけるシャペロン介在性オートファジーの役割の検討 (2019)
  • Author(s): 保坂悠介、荒屋潤、皆川俊介、原弘道、伊藤晶彦、中野貴之、市川晶博、斉藤那由多、吉田昌弘、橋本典生、沼田尊功、金子由美、浅野久敏、松平秀樹、大塚崇、桑野和善
  • Organizer: 日本呼吸器学会学術講演会
• [Presentation] Role of chaperone-mediated autophagy in COPD pathogenesis (2018)
  • Author(s): Yusuke Hosaka, Jun Araya, Kazuya Tsubouchi, Shunsuke Minagawa, Hiromichi Hara, Akihiro Ichikawa, Nayuta Saito, Tsukasa Kadota, Masahiro Yoshida, Takeo Ishikawa, Takanori Numata, Yumi Kaneko, Katsutoshi Nakayama, Kazuyoshi Kuwano
  • Organizer: 欧州呼吸器学会
  • Int'l Joint Research