Mechanism of emphysema formation by controlling the Keap1-Nrf2 system and its application to COPD treatment strategies

• Project/Area Number: 19K08660
• 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: Osaka City University
• Principal Investigator: ASAI KAZUHISA 大阪市立大学, 大学院医学研究科, 准教授 (10382053)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: COPD / Nrf2 / タバコ / バルドキソロン / 慢性閉塞性肺疾患 / アイリシン / マイオカイン / バルドキソロンメチル

Outline of Research at the Start

慢性閉塞性肺疾患（COPD）は末梢気道病変と気腫性病変が複合的に作用し、正常に復することのない気流閉塞を示すが、組織破壊・リモデリングの予防や再生治療は確立されていない。
研究代表者らは、タバコ煙曝露COPDモデルマウスにおいて抗酸化能を司る転写因子であるnuclear factor erythroid 2-related factor2 (Nrf2)の運動を介した発現増強による気腫化抑制効果を見出している。本研究では、Nrf2発現増強・活性化剤の気腫化抑制効果の評価ならびに機序を検討し、COPD新規治療戦略を提案する。

Outline of Final Research Achievements

Bardoxolone methyl is a drug that intervenes in the Keap1-Nrf2 system and has shown significant improvement and tolerability in GFR in a phase 2 clinical trial in patients with diabetic nephropathy. In this study, we planned to investigate the emphysema-suppressing effect and emphysema treatment-effect of Bardoxolone methyl in smoking-exposed COPD model mice. We confirmed the tolerability of Bardoxolone methyl. We found that there was no spontaneous improvement in emphysema and alveolar destruction until 4 weeks after the end of smoking exposure, and we formulated an experimental protocol suitable for evaluating the therapeutic effect on emphysema. The experiment was started, but the experiment was not completed due to the lockdown of the animal experiment facility due to the outbreak caused by COVID19.

Academic Significance and Societal Importance of the Research Achievements

本研究では喫煙曝露COPDモデルマウスにおけるバルドキソロンメチルの気腫化抑制効果、治療効果検討を計画した。本研究では、喫煙曝露終了後4週間までは自発的な気腫化、肺胞破壊の改善を認めないことを見出して、喫煙曝露COPDモデルマウスにおける気腫化治療効果の評価に適する実験プロトコールを策定した。今後、バルドキソロンメチルや他の治療候補物質での気腫化治療効果の検討を進める。

Research Products

• [Journal Article] Safety profile and risk factors for bleeding in transbronchial cryobiopsy using a two-scope technique for peripheral pulmonary lesions (2022)
  • Author(s): Nakai Toshiyuki、Watanabe Tetsuya、Kaimi Yuto、Ogawa Koichi、Matsumoto Yoshiya、Sawa Kenji、Okamoto Atsuko、Sato Kanako、Asai Kazuhisa、Matsumoto Yuji、Ohsawa Masahiko、Kawaguchi Tomoya
  • Journal Title: BMC Pulmonary Medicine Volume: 22 Issue: 1 Pages: 20-20
  • DOI: 10.1186/s12890-021-01817-8
  • Peer Reviewed / Open Access
• [Journal Article] The Fermented Soy Product ImmuBalanceTM Suppresses Airway Inflammation in a Murine Model of Asthma (2021)
  • Author(s): Kadotani Hideaki、Asai Kazuhisa、Miyamoto Atsushi、Iwasaki Kohei、Kawai Takahiro、Nishimura Misako、Tohda Mitsunori、Okamoto Atsuko、Sato Kanako、Yamada Kazuhiro、Ijiri Naoki、Watanabe Tetsuya、Kawaguchi Tomoya
  • Journal Title: Nutrients Volume: 13 Issue: 10 Pages: 3380-3380
  • DOI: 10.3390/nu13103380
  • NAID: 120007163638
  • Peer Reviewed / Open Access
• [Journal Article] Tumor microenvironment disparity in multiple primary lung cancers: Impact of non-intrinsic factors, histological subtypes, and genetic aberrations (2021)
  • Author(s): Izumi Motohiro、Sawa Kenji、Oyanagi Jun、Noura Ikue、Fukui Mitsuru、Ogawa Koichi、Matsumoto Yoshiya、Tani Yoko、Suzumura Tomohiro、Watanabe Tetsuya、Kaneda Hiroyasu、Mitsuoka Shigeki、Asai Kazuhisa、Nishiyama Noritoshi、Ohsawa Masahiko、Yamamoto Nobuyuki、Koh Yasuhiro、Kawaguchi Tomoya
  • Journal Title: Translational Oncology Volume: 14 Issue: 7 Pages: 101102-101102
  • DOI: 10.1016/j.tranon.2021.101102
  • Peer Reviewed / Open Access
• [Journal Article] Phase II Study of the Modified Weekly Nab-paclitaxel Regimen in Previously Treated Patients With Advanced Non?Small Cell Lung Cancer (2021)
  • Author(s): Yoshimura Naruo、Sawa Kenji、Nakai Toshiyuki、Matsumoto Yoshiya、Mitsuoka Shigeki、Kimura Tatsuo、Asai Kazuhisa、Yana Takashi、Kawaguchi Tomoya、Hirata Kazuto
  • Journal Title: American Journal of Clinical Oncology Volume: 44 Issue: 12 Pages: 613-618
  • DOI: 10.1097/coc.0000000000000876
  • Peer Reviewed
• [Journal Article] Ninjin’yoeito Ameliorates Skeletal Muscle Complications in COPD Model Mice by Upregulating Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Expression (2020)
  • Author(s): Miyamoto Atsushi、Asai Kazuhisa、Kadotani Hideaki、Maruyama Naomi、Kubo Hiroaki、Okamoto Atsuko、Sato Kanako、Yamada Kazuhiro、Ijiri Naoki、Watanabe Tetsuya、Kawaguchi Tomoya
  • Journal Title: International Journal of Chronic Obstructive Pulmonary Disease Volume: 15 Pages: 3063-3077
  • DOI: 10.2147/copd.s280401
  • NAID: 120006939380
  • Peer Reviewed / Open Access
• [Journal Article] 【COPD患者における栄養管理のポイント】COPDにおけるサルコペニア・フレイル (2020)
  • Author(s): 浅井一久
  • Journal Title: 臨床栄養 Volume: 136 Pages: 990-996
• [Journal Article] A Polymorphism rs6726395 in Nrf2 Contributes to the Development of Emphysema-Associated Age in Smokers Without COPD. (2019)
  • Author(s): Sugitani A, Asai K, Watanabe T, Suzumura T, Kojima K, Kubo H, Sato K, Ijiri N, Yamada K, Kimura T, Fukumoto S, Hirata K, Kawaguchi T.
  • Journal Title: Lung Volume: 197 Issue: 5 Pages: 559-564
  • DOI: 10.1007/s00408-019-00251-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Isoflavone Aglycones Attenuate Cigarette Smoke-Induced Emphysema via Suppression of Neutrophilic Inflammation in a COPD Murine Model. (2019)
  • Author(s): Kojima K, Asai K, Kubo H, Sugitani A, Kyomoto Y, Okamoto A, Yamada K, Ijiri N, Watanabe T, Hirata K, Kawaguchi T.
  • Journal Title: Nutrients Volume: 11 Issue: 9 Pages: 2023-2023
  • DOI: 10.3390/nu11092023
  • NAID: 120006716419
  • Peer Reviewed / Open Access
• [Journal Article] Astaxanthin Suppresses Cigarette Smoke-Induced Emphysema through Nrf2 Activation in Mice. (2019)
  • Author(s): Kubo H, Asai K, Kojima K, Sugitani A, Kyomoto Y, Okamoto A, Yamada K, Ijiri N, Watanabe T, Hirata K, Kawaguchi T.
  • Journal Title: Marine Drugs Volume: 17 Issue: 12 Pages: 673-673
  • DOI: 10.3390/md17120673
  • Peer Reviewed / Open Access
• [Journal Article] Exercise Ameliorates Emphysema Of Cigarette Smoke-Induced COPD In Mice Through The Exercise-Irisin-Nrf2 Axis. (2019)
  • Author(s): Kubo H, Asai K, Kojima K, Sugitani A, Kyomoto Y, Okamoto A, Yamada K, Ijiri N, Watanabe T, Hirata K, Kawaguchi T.
  • Journal Title: International Journal of COPD Volume: 14 Pages: 2507-2516
  • DOI: 10.2147/copd.s226623
  • Peer Reviewed / Open Access
• [Presentation] 喘息モデルマウスにおけるImmuBalanceの好酸球性炎症抑制効果の検討 (2022)
  • Author(s): 門谷 英昭、浅井 一久、小林 正典、山根 健志、宮本 篤志、岩﨑 剛平、川井 隆広、西村 美沙子、豊蔵 恵里佳、東田 充功、岡本 敦子、佐藤 佳奈子、井尻 尚樹、渡辺 徹也、金澤 博、川口 知哉、平田 一人
  • Organizer: 第62回日本呼吸器学会学術講演会
• [Presentation] 骨格筋バイオロジーからみた身体活動性の重要性 (2022)
  • Author(s): 浅井 一久
  • Organizer: 第62回日本呼吸器学会学術講演会
  • Invited
• [Presentation] COPDモデルマウスにおいて人参養栄湯は骨格筋合併症を改善する (2021)
  • Author(s): 宮本 篤志、浅井 一久、門谷 英昭、丸山 直美、久保 寛明、岡本 敦子、佐藤 佳奈子、井尻 尚樹、渡辺 徹也、川口 知哉
  • Organizer: 第61回日本呼吸器学会学術講演会
• [Presentation] 骨格筋のバイオロジーからみた身体活動性の重要性 (2021)
  • Author(s): 浅井 一久
  • Organizer: 第30回日本呼吸ケア・リハビリテーション学会学術集会
  • Invited
• [Presentation] 喫煙曝露COPDマウスにおけるアスタキサンチンのCOPD抑制効果の検討 (2020)
  • Author(s): 久保 寛明, 浅井 一久, 小島 和也, 杉谷 新, 門谷 英昭, 宮本 篤志, 丸山 直美, 岡本 敦子, 渡辺 徹也, 金澤 博, 川口 知哉, 平田 一人
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] CSE刺激時にLong non coding RNA:NEAT1は炎症性サイトカインの放出を促す (2020)
  • Author(s): 井尻 尚樹, 浅井 一久, 佐藤 佳奈子, 山田 一宏, 山本 典雄, 渡辺 徹也, 金澤 博, 平田 一人, 川口 知哉
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] Astaxanthin Suppresses Cigarette Smoke-Induced Emphysema Through Nrf2 Activation in Mice. (2020)
  • Author(s): H. Kubo , K. Asai , K. Iwasaki , T. Kawai , M. Nishimura , N. Maruyama , H. Kadotani , A. Miyamoto , A. Okamoto , K. Sato , K. Yamada , N. Ijiri , T. Watanabe , K. Hirata , T. Kawaguchi
  • Organizer: ATS 2020 International Conference
  • Int'l Joint Research
• [Presentation] Ninjin-yoeito ameliorates cigarette smoke-induced skeletal muscle complications in mice. (2020)
  • Author(s): A. Miyamoto, H. Kadotani, K. Asai, N. Maruyama, H. Kubo, A. Okamoto, N. Ijiri, K. Sato, T. Watanabe, K. Hirata, T. Kawaguchi
  • Organizer: ERS International Congress 2020
  • Int'l Joint Research
• [Presentation] Irisin secreted from muscle by exercise ameliorates emphysema of cigarette smoke-induced COPD in mice (2019)
  • Author(s): Hiroaki Kubo, Kazuhisa Asai, Atsushi Miyamoto, Hideaki Kadotani, Naomi Maruyama, Kazuya Kojima, Arata Sugitani, Yohkoh Kyomoto, Atsuko Okamoto, Kazuhiro Yamada, Tetsuya Watanabe, Tomoya Kawaguchi, Kazuto Hirata
  • Organizer: European Respiratory Society international Congress 2019
  • Int'l Joint Research
• [Presentation] ISOFLAVONE AGLYCONES ATTENUATE CIGARETTE SMOKE-INDUCED EMPHYSEMA VIA SUPPRESSION OF NEUTROPHILIC INFLAMMATION IN A COPD MURINE MODEL (2019)
  • Author(s): Kazuya Kojima, Kazuhisa Asai, Hiroaki Kubo, Arata Sugitani, Yohkoh Kyomoto, Atsuko Okamoto, Kazuhiro Yamada, Naoki Ijiri, Tetsuya Watanabe, Kazuto Hirata, Tomoya Kawaguchi
  • Organizer: The 24 th Congress of the Asian Pacific Society of Respirology
  • Int'l Joint Research