Chaperone-mediated autophagy modulates epithelial cell apoptosis in COPD pathogenesis

2019 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

呼吸器

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。