Challenges in Overcoming Severe Asthma ~Research of anti-inflammatory lipid mediators toward drug discovery~

• Project/Area Number: 18K08382
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Gunma University
• Principal Investigator: Hisada Takeshi 群馬大学, 大学院保健学研究科, 教授 (10344938)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 気管支喘息 / 重症喘息 / resolvin / ω３脂肪酸 / 脂質メディエーター / 炎症収束 / 糖尿病 / インスリン抵抗性 / 重症気管支喘息 / エイコサペンタエン酸 / ω3脂肪酸

Outline of Final Research Achievements

The basis of bronchial asthma pathogenesis is chronic inflammation of the airways. In recent years, advances in treatment, mainly inhaled corticosteroids, have resulted in good control of the disease in many cases. However, about 5-10% of patients with severe asthma do not receive adequate benefit. In this study, the effects of a series of Resolvin (Rv) compounds, a novel lipid mediator derived from ω3 fatty acids with resolution of inflammation and anti-inflammatory properties, were confirmed by basic experiments, and further experiments were conducted for drug discovery. The results showed that RvE3 was effective in an experimental mouse asthma model and is promising for future drug discovery research. The anti-inflammatory effect of RvE3 may also improve insulin resistance in diabetes mellitus.

Academic Significance and Societal Importance of the Research Achievements

ω３脂肪酸から生成され、炎症収束作用を持つ抗炎症性脂質メディエーター群は、生体が本来持っているホメオスタシス調整機能の一端を担う物質である。その産生低下や機能不全が炎症収束破綻をもたらして喘息発症、増悪などにもつながる可能性がある。この病態の解明と治療への応用を発展させることは、炎症の側面をもつ喘息などのアレルギー疾患全般のみならず糖尿病、動脈硬化、がんなどの疾患に対する治療アプローチとしても応用できる可能性があり有望である。炎症の収束をターゲットとする本研究アプローチは新たな治療法になりうる。また、内在性の炎症収束性物質は安全性も高く、新しいタイプの創薬研究につながることが期待される。

Research Products

• [Journal Article] Editorial: Pathophysiological and clinical advances in asthmatic inflammation from the nasopharynx to the peripheral airway in the respiratory tract systems (2023)
  • Author(s): Koga Yasuhiko、Kamide Yosuke、Hisada Takeshi、Ishizuka Tamotsu
  • Journal Title: Frontiers in Pharmacology Volume: 14 Pages: 1037610-1037610
  • DOI: 10.3389/fphar.2023.1037610
  • Peer Reviewed / Open Access
• [Journal Article] Design and Synthesis of Cyclopropane Congeners of Resolvin E3, an Endogenous Pro-Resolving Lipid Mediator, as Its Stable Equivalents. (2022)
  • Author(s): (2)Arai S, Fujiwara K, Kojima M, Aoki-Saito H, Yatomi M, Saito T, Koga Y, Fukuda H, Watanabe M, Matsunaga S, Hisada T, Shuto S
  • Journal Title: The Journal of Organic Chemistry Volume: 87(15) Issue: 15 Pages: 10501-10508
  • DOI: 10.1021/acs.joc.2c01110
  • Peer Reviewed / Open Access
• [Journal Article] Perspectives on the Efficacy of Benralizumab for Treatment of Eosinophilic Granulomatosis With Polyangiitis (2022)
  • Author(s): Koga Y, Aoki-Saito H, Kamide Y, Sato M, Tsurumaki H, Yatomi M, Ishizuka T, Hisada T.
  • Journal Title: Front Pharmacol Volume: なし Pages: 865318-865318
  • DOI: 10.3389/fphar.2022.865318
  • Peer Reviewed / Open Access
• [Journal Article] Resolvin E3 ameliorates high‐fat diet‐induced insulin resistance via the phosphatidylinositol‐3‐kinase/Akt signaling pathway in adipocytes (2022)
  • Author(s): Shimizu Tomohiko、Saito Tsugumichi、Aoki‐Saito Haruka、Okada Shuichi、Ikeda Hiroyuki、Nakakura Takashi、Fukuda Hayato、Arai Syota、Fujiwara Kouichi、Nakajima Yasuyo、Horiguchi Kazuhiro、Yamada Sayaka、Ishida Emi、Hisada Takeshi、Shuto Satoshi、Yamada Masanobu
  • Journal Title: The FASEB Journal Volume: 36 Issue: 3
  • DOI: 10.1096/fj.202100053r
  • Peer Reviewed / Open Access
• [Journal Article] Metal-Stimulated Interleukin-6 Production Through a Proton-Sensing Receptor, Ovarian Cancer G Protein-Coupled Receptor 1, in Human Bronchial Smooth Muscle Cells: A Response Inhibited by Dexamethasone (2021)
  • Author(s): Kadowaki Maiko、Sato Koichi、Kamio Hisashi、Kumagai Makoto、Sato Rikishi、Nyui Takafumi、Umeda Yukihiro、Waseda Yuko、Anzai Masaki、Aoki-Saito Haruka、Koga Yasuhiko、Hisada Takeshi、Tomura Hideaki、Okajima Fumikazu、Ishizuka Tamotsu
  • Journal Title: Journal of Inflammation Research Volume: Volume 14 Pages: 7021-7034
  • DOI: 10.2147/jir.s326964
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis of Resolvin E3, a Proresolving Lipid Mediator, and Its Deoxy Derivatives: Identification of 18-Deoxy-resolvin E3 as a Potent Anti-Inflammatory Agent (2020)
  • Author(s): Fukuda Hayato、Ikeda Hiroyuki、Muromoto Ryuta、Hirashima Koki、Ishimura Kohei、Fujiwara Koichi、Aoki-Saito Haruka、Hisada Takeshi、Watanabe Mizuki、Ishihara Jun、Matsuda Tadashi、Shuto Satoshi
  • Journal Title: The Journal of Organic Chemistry Volume: 85 Issue: 21 Pages: 14190-14200
  • DOI: 10.1021/acs.joc.0c01701
  • NAID: 120007168587
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic nutritional index as a predictor of mortality in nontuberculous mycobacterial lung disease (2020)
  • Author(s): Hachisu Yoshimasa、Murata Keisuke、Takei Kousuke、Tsuchiya Takuma、Tsurumaki Hiroaki、Koga Yasuhiko、Horie Takeo、Takise Atsushi、Hisada Takeshi
  • Journal Title: Journal of Thoracic Disease Volume: 12 Issue: 6 Pages: 3101-3109
  • DOI: 10.21037/jtd-20-803
  • Peer Reviewed / Open Access
• [Journal Article] Bacteriologically Determined <i>De Novo</i> Tuberculosis during Tumor Necrosis Factor-α Inhibitor Therapy (2019)
  • Author(s): Takahashi Gen、Kobayashi Hiroyuki、Saito Yasuyuki、Ohsawa Sho、Suzuki Kuniaki、Ishihara Shinichi、Hisada Takeshi
  • Journal Title: Internal Medicine Volume: 58 Issue: 24 Pages: 3593-3596
  • DOI: 10.2169/internalmedicine.3054-19
  • NAID: 130007761434
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-12-15
  • Peer Reviewed / Open Access
• [Journal Article] Resolvin E3 Attenuates Allergic Airway Inflammation via the interleukin-23-interleukin-17A Pathway (2019)
  • Author(s): Sato M, Aoki-Saito H, Fukuda H, Ikeda H, Koga Y, Yatomi M, Tsurumaki H, Maeno T, Saito T, Nakakura T, Mori T, Yanagawa M, Abe M, Sako Y, Dobashi K, Ishizuka T, Yamada M, Shuto S, Hisada T.
  • Journal Title: FASEB J. Volume: Nov;33(11) Issue: 11 Pages: 12750-12759
  • DOI: 10.1096/fj.201900283r
  • Peer Reviewed / Open Access
• [Journal Article] Treatment with Tumor Necrosis Factor-α Inhibitors, History of Allergy, and Hypercalcemia Are Risk Factors of Immune Reconstitution Inflammatory Syndrome in HIV-Negative Pulmonary Tuberculosis Patients (2019)
  • Author(s): Hachisu Yoshimasa、Koga Yasuhiko、Kasama Shu、Kaira Kyoichi、Yatomi Masakiyo、Aoki-Saito Haruka、Tsurumaki Hiroaki、Kamide Yosuke、Sunaga Noriaki、Maeno Toshitaka、Ishizuka Tamotsu、Hisada Takeshi
  • Journal Title: Journal of Clinical Medicine Volume: 9 Issue: 1 Pages: 96-96
  • DOI: 10.3390/jcm9010096
  • Peer Reviewed / Open Access
• [Journal Article] Rapid Effect of Benralizumab for Hypereosinophilia in a Case of Severe Asthma with Eosinophilic Chronic Rhinosinusitis (2019)
  • Author(s): Tsurumaki、Matsuyama、Ezawa、Koga、Yatomi、Aoki-Saito、Chikamatsu、Hisada
  • Journal Title: Medicina Volume: 55 Issue: 7 Pages: 336-336
  • DOI: 10.3390/medicina55070336
  • Peer Reviewed / Open Access
• [Journal Article] Pirfenidone Improves Familial Idiopathic Pulmonary Fibrosis without Affecting Serum Periostin Levels (2019)
  • Author(s): Koga Yasuhiko、Hachisu Yoshimasa、Tsurumaki Hiroaki、Yatomi Masakiyo、Kaira Kyoichi、Ohta Shoichiro、Ono Junya、Izuhara Kenji、Dobashi Kunio、Hisada Takeshi
  • Journal Title: Medicina Volume: 55 Issue: 5 Pages: 161-161
  • DOI: 10.3390/medicina55050161
  • Peer Reviewed / Open Access
• [Journal Article] Possible Serological Markers to Predict Mortality in Acute Exacerbation of Idiopathic Pulmonary Fibrosis (2019)
  • Author(s): Hachisu Yoshimasa、Murata Keisuke、Takei Kousuke、Tsuchiya Takuma、Tsurumaki Hiroaki、Koga Yasuhiko、Horie Takeo、Takise Atsushi、Hisada Takeshi
  • Journal Title: Medicina Volume: 55 Issue: 5 Pages: 132-132
  • DOI: 10.3390/medicina55050132
  • Peer Reviewed / Open Access
• [Journal Article] Roles of Cyclic AMP Response Element Binding Activation in the ERK1/2 and p38 MAPK Signalling Pathway in Central Nervous System, Cardiovascular System, Osteoclast Differentiation and Mucin and Cytokine Production (2019)
  • Author(s): Koga Yasuhiko、Tsurumaki Hiroaki、Aoki-Saito Haruka、Sato Makiko、Yatomi Masakiyo、Takehara Kazutaka、Hisada Takeshi
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 6 Pages: 1346-1346
  • DOI: 10.3390/ijms20061346
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular acidification-induced CXCL8 production through a proton-sensing receptor OGR1 in human airway smooth muscle cells: a response inhibited by dexamethasone. (2019)
  • Author(s): M. Kadowaki, H. Yamada, K. Sato, H. Shigemi, Y. Umeda, M. Morikawa, Y. Waseda, M. Anzai, Y. Kamide, H. Aoki-Saito, T. Hisada, F. Okajima, T. Ishizuka
  • Journal Title: J. Inflamm. (Lond.) Volume: 16 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12950-019-0207-1
  • Peer Reviewed / Open Access
• [Presentation] アレルギー疾患における免疫細胞による病態形成とその解明 Resolvin E3のマクロファージ内シグナル伝達経路に及ぼす影響の解析 (2022)
  • Author(s): 矢冨 正清 , 古賀 康彦, 齋藤 悠, 佐藤 真季子, 山口 公一, 山口 彩, 三浦 陽介, 鶴巻 寛朗, 原 健一郎, 砂長 則明, 前野 敏孝, 周東 智, 久田 剛志
  • Organizer: 日本アレルギー学会
• [Presentation] ResolvinE1、E2、E3のアレルギー性気道炎症に対する効果の検討 (2022)
  • Author(s): ResolvinE1、E2、E3のアレルギー性気道炎症に対する効果の検討 佐藤 真季子, 青木 悠, 鶴巻 寛朗, 矢冨 正清, 古賀 康彦, 砂長 則明, 石塚 全, 土橋 邦生, 周東 智, 前野 敏孝, 久田 剛志
  • Organizer: 日本呼吸器学会
• [Presentation] Resolvin E3の細胞内シグナル伝達経路に及ぼす影響の解析 (2022)
  • Author(s): Resolvin E3の細胞内シグナル伝達経路に及ぼす影響の解析 矢冨 正清, 古賀 康彦, 齋藤 悠, 佐藤 真季子, 山口 公一, 山口 彩, 伊藤 優志, 三浦 陽介, 鶴巻 寛朗, 原 健一郎, 砂長 則明, 前野 敏孝, 周東 智, 久田 剛志
  • Organizer: 日本呼吸器学会
• [Presentation] 喘息発症・重症化のメカニズムはどこまで分かったか 喘息発症・重症化と環境因子 (2022)
  • Author(s): 久田剛志
  • Organizer: 日本呼吸器学会
• [Presentation] Resolvin E3(RvE3)誘導体の生物学的安定性の解析について (2021)
  • Author(s): 齋藤 悠, 佐藤 真季子, 古賀 康彦, 矢冨 正清, 鶴巻 寛朗, 齋藤 従道, 山口 彩, 山口 公一, 澤田 友里, 原 健一郎, 砂長 則明, 前野 敏孝, 石塚 全, 福田 隼, 周東 智, 久田 剛志
  • Organizer: 日本アレルギー学会
• [Presentation] アレルギー性炎症の新規誘導/収束メカニズム Resolvinの線維化増殖因子に及ぼす影響の解析 (2021)
  • Author(s): 矢冨 正清, 古賀 康彦, 齋藤 悠, 佐藤 真季子, 山口 公一, 山口 彩, 鶴巻 寛朗, 原 健一郎, 砂長 則明, 前野 敏孝, 周東 智, 久田 剛志
  • Organizer: 日本アレルギー学会
• [Presentation] 脂質メディエーターResolvinの抗線維化効果の解析 (2021)
  • Author(s): 矢冨 正清, 古賀 康彦, 齋藤 悠, 佐藤 真季子, 鶴巻 寛朗, 原 健一郎, 砂長 則明, 前野 敏孝, 周東 智, 久田 剛志
  • Organizer: 日本呼吸器学会
• [Presentation] ResolvinE3誘導体の樹状細胞に対する抗炎症性作用の解析 (2021)
  • Author(s): 齋藤 悠, 佐藤 真季子, 矢冨 正清, 古賀 康彦, 鶴巻 寛朗, 齋藤 従道, 宇野 翔吾, 若松 郁生, 花里 千春, 増田 友美, 澤田 友里, 原 健一郎, 砂長 則明, 前野 敏孝, 周東 智, 久田 剛志
  • Organizer: 日本呼吸器学会
• [Presentation] ResolvinE1,E3のアレルギー性気道炎症に対する効果の検討 (2021)
  • Author(s): 佐藤 真季子, 齋藤 悠, 鶴巻 寛朗, 矢冨 正清, 古賀 康彦, 砂長 則明, 石塚 全, 土橋 邦生, 周東 智, 前野 敏孝, 久田 剛志
  • Organizer: 日本呼吸器学会
• [Presentation] Rerationship between interstitial pneumonia related systemic sclerosis and esophageal motility abnormalities (2020)
  • Author(s): Kenichiro Hara, Kouichi Yamaguchi, Masakiyo Yatomi, Hiroaki Tsurumaki, Takeshi Hisada, Toshitaka Maeno
  • Organizer: European Respiratory Society 2020
  • Int'l Joint Research
• [Presentation] Resolvin E1 and E3 dampens asthmatic inflammation in a murine model (2020)
  • Author(s): Makiko Sato, Haruka Aoki-Saito, Masakiyo Yatomi, Hiroaki Tsurumaki, Yasuhiko Koga, Noriaki Sunaga, Toshitaka Maeno, Kunio Dobashi, Satoshi Shuto, Masataka Yamada, Takeshi Hisada
  • Organizer: European Respiratory Society 2020
  • Int'l Joint Research
• [Presentation] Resolvin E3 reduces profibrotic factor production from macrophages leading to tissue homeostasis (2020)
  • Author(s): Masakiyo Yatomi, Yasuhiko Koga, Haruka Saito, Makiko Sato, Hiroaki Tsurumaki, Kenichiro Hara, Noriaki Sunaga, Toshitaka Maeno, Hiroyuki Ikeda, Hayato Fukuda, Shouta Arai, Koichi Fujiwara, Satoshi Shuto, Takeshi Hisada
  • Organizer: European Respiratory Society 2020
  • Int'l Joint Research
• [Presentation] Resolvin E3 dampens asthmatic inflammation in a murine model through IL-23 pathway (2019)
  • Author(s): Makiko Sato, Haruka Aoki-Saito, Hayato Fukuda, Hiroyuki Ikeda, Yasuhiko Koga, Masakiyo Yatomi, Hiroaki Tsurumaki, Kazutaka Takehara, Takashi Nakakura, Tetsuya Mori, Tsugumichi Saito, Kunio Dobashi, Masanobu Yamada, Satoshi Shuto, Takeshi Hisada
  • Organizer: European Respiratory Society 2019, Madrid, Spain
  • Int'l Joint Research
• [Presentation] T cell death associated gene 8 mediates MUC5AC expression in acidic conditions (2019)
  • Author(s): Hiroaki Tsurumaki, Haruka Saito-Aoki, Chihiro Mogi, Koichi Sato, Takashi Nakakura, Yasuhiko Koga, Masakiyo Yatomi, Makiko Sato, Toshitaka Maeno, Kunio Dobashi, Fumikazu Okajima, Takeshi Hisada
  • Organizer: European Respiratory Society 2019, Madrid, Spain
  • Int'l Joint Research
• [Presentation] Resolvin E3 attenuates House Dust Mite (HDM) -induced asthmatic inflammation in a murine model (2018)
  • Author(s): Makiko Sato, Haruka Aoki-Saito, Hayato Fukuda, Hiroyuki Ikeda, Yasuhiko Koga, Masakiyo Yatomi, Hiroaki Tsurumaki , Yoshimasa Hachisu, Takashi Nakakura, Tetsuya Mori, Kunio Dobashi, Masanobu Yamada, Satoshi Shuto, Takeshi Hisada
  • Organizer: European Respiratory Society 2018, Paris, France
  • Int'l Joint Research
• [Presentation] 17(R)-resolvinD1 mediates a pathway involving the transcription factor c-Fos to reduce bleomycin-induced pulmonary fibrosis in mice. (2018)
  • Author(s): Masakiyo Yatomi, Takeshi Hisada, Yoshimasa Hachisu, Yusuke Tsukagoshi, Norimitsu Kasahara, Makiko Sato, Hiroaki Tsurumaki, Haruka Saito, Kenichiro Hara, Yasuhiko Koga, Noriaki Sunaga, Toshitaka Maeno, Kunio Dobashi
  • Organizer: European Respiratory Society 2018, Paris, France
  • Int'l Joint Research
• [Presentation] Resolvin E3 attenuates asthmatic inflammation in a murine model of House Dust Mite (HDM) -induced airway inflammation (2018)
  • Author(s): Makiko Sato*, Haruka Aoki-Saito, Hayato Fukuda, Yasuhiko Koga, Masakiyo Yatomi, Hiroaki Tsurumaki, Takashi Nakakura, Masanobu Yamada, Satoshi Shuto, Takeshi Hisada
  • Organizer: Asia Pacific Society of Respirology 2018, Taipei, Taiwan
  • Int'l Joint Research