Does homocysteine-induced endoplasmic reticulum stress contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD)?

• Project/Area Number: 19K08658
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Shibata Yoko 福島県立医科大学, 医学部, 教授 (60333978)
• Co-Investigator(Kenkyū-buntansha): 黒谷 玲子 山形大学, 大学院理工学研究科, 准教授 (00453043) ; 井上 純人 山形大学, 医学部, 講師 (70466621)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: COPD / 喫煙 / ホモシステイン / 小胞体ストレス / ＣＯＰＤ / 慢性閉塞性肺疾患

Outline of Research at the Start

本研究はタバコ煙長期曝露による生活習慣病である慢性閉塞性肺疾患（COPD）の病態には、高ホモシステイン血症によりもたらされる過剰な小胞体ストレスが関連していることをマウスや肺胞上皮細胞株を用いて基礎的に検討し、高ホモシステイン血症に対する治療介入がCOPD進展の予防になるかどうかを検討する。

Outline of Final Research Achievements

A549 cells (human alveolar epithelial cell line) were cultured with homocysteine and exposed to cigarette smoke extract (CSE). The treatment induced apoptosis, which was further enhanced by CSE. The expression levels of endoplasmic reticulum (ER) stress markers also significantly increased. Supplementation of vitamin B12 and folic acid to reduce homocysteine levels resulted in an improvement of ER stress markers. In animal experiments, exposing mice with high homocysteine levels to cigarette smoke exacerbates pulmonary emphysema. These findings suggest that enhanced ER stress mediated by high homocysteine levels is implicated in the development of cigarette smoke-induced pulmonary emphysema. doi: 10.1038/s41598-022-16767-2

Academic Significance and Societal Importance of the Research Achievements

本研究によって喫煙曝露によるCOPD（肺気腫）の形成には、高ホモシステイン血症に起因する小胞体ストレスが重要であることが示された。葉酸やビタミンB12はホモシステイン血症を改善させることが知られており、これらはCOPDの進展を抑制する効果も期待される。また、さらに強力な小胞体ストレス阻害剤の開発はCOPDに対する新たな創薬に発展する可能性がある。本研究の成果は、その足掛かりになるものと言えるだろう。

Research Products

• [Journal Article] Secretoglobin 3A2 suppresses cigarette smoke-induced pulmonary emphysema. (2023)
  • Author(s): Kurotani R, Ono S, Miyano Y, Nakayama S, Liu H, Aibara D, Sakahara S, Sato M, Sato K, Inoue S, Shibata Y, Lee MP, Abe H, Kimura S.
  • Journal Title: Journal of Int J Biochem Cell Biol. Volume: 157 Pages: 106390-106390
  • DOI: 10.1016/j.biocel.2023.106390
  • Peer Reviewed
• [Journal Article] Effect of hyperhomocysteinemia on a murine model of smoke-induced pulmonary emphysema. (2022)
  • Author(s): Nakano H, Inoue S, Minegishi Y, Igarashi A, Tokairin Y, Yamauchi K, Kimura T, Nishiwaki M, Nemoto T, Otaki Y, Sato M, Sato K, Machida H, Yang S, Murano H, Watanabe M, and Shibata Y.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 12968-12968
  • DOI: 10.1038/s41598-022-16767-2
  • Peer Reviewed / Open Access
• [Journal Article] Role of CC Chemokine Ligand 17 in Mouse Models of Chronic Obstructive Pulmonary Disease (2022)
  • Author(s): Machida Hiroyoshi、Inoue Sumito、Igarashi Akira、Saitoh Shinichi、Yamauchi Keiko、Nishiwaki Michiko、Nemoto Takako、Otaki Yoichiro、Sato Masamichi、Sato Kento、Nakano Hiroshi、Yang Sujeong、Furuyama Kodai、Murano Hiroaki、Ishibashi Yu、Ota Takahito、Nakayama Takashi、Shibata Yoko、Watanabe Masafumi
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 66 Issue: 4 Pages: 428-438
  • DOI: 10.1165/rcmb.2021-0069oc
  • Peer Reviewed / Open Access
• [Journal Article] Thymus and activation-regulated chemokine (TARC/CCL17) predicts decline of pulmonary function in patients with chronic obstructive pulmonary disease (2021)
  • Author(s): Machida Hiroyoshi、Inoue Sumito、Shibata Yoko、Kimura Tomomi、Sato Kento、Abe Koya、Murano Hiroaki、Yang Sujeong、Nakano Hiroshi、Sato Masamichi、Nemoto Takako、Sato Chisa、Nishiwaki Michiko、Yamauchi Keiko、Igarashi Akira、Tokairin Yoshikane、Watanabe Masafumi
  • Journal Title: Allergology International Volume: 70 Issue: 1 Pages: 81-88
  • DOI: 10.1016/j.alit.2020.04.004
  • NAID: 130007966761
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Effect of Hyperhomocysteinemia on a Murine Model of Smoke-Induced Pulmonary Emphysema. (2021)
  • Author(s): Nakano Hiroshi、Inoue Sumito、Igarashi Akira、Tokairin Yoshikane、Yamauchi Keiko、Kimura Tomomi、Nishiwaki Michiko、Nemoto Takako、Otaki Yoichiro、Sato Masamichi、Sato Kento、Machida Hiroyoshi、Yang Sujeong、Murano Hiroaki、Watanabe Masafumi、Shibata Yoko
  • Journal Title: Research Square (Preprint) Volume: -
  • DOI: 10.21203/rs.3.rs-249722/v1
  • Open Access
• [Journal Article] Effect of Iron Deficiency on a Murine Model of Smoke-induced Emphysema (2020)
  • Author(s): Sato Kento、Inoue Sumito、Igarashi Akira、Tokairin Yoshikane、Yamauchi Keiko、Kimura Tomomi、Nishiwaki Michiko、Nemoto Takako、Nakano Hiroshi、Sato Masamichi、Machida Hiroyoshi、Yang Sujeong、Minegishi Yukihiro、Furuyama Kodai、Watanabe Masafumi、Shibata Yoko
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 62 Issue: 5 Pages: 588-597
  • DOI: 10.1165/rcmb.2018-0239oc
  • Peer Reviewed
• [Presentation] 高ホモシステイン血症における喫煙曝露は小胞体ストレスを介して肺胞上皮細胞のアポトーシスを増加し，肺の気腫性変化を増強する (2020)
  • Author(s): 中野寛之1），邨野浩義，町田浩祥，佐藤建人，佐藤正道，東海林佳兼，五十嵐朗，井上純人，渡辺昌文，柴田陽光
  • Organizer: 第６０回日本呼吸器学会学術講演会