Effect of a retinoid X receptor partial agonist on airway inflammation, airway hyperresponsiveness, and emphysema.

• Project/Area Number: 26461189
• 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: Okayama University
• Principal Investigator: KANEHIRO ARIHIKO 岡山大学, 医学部, 客員研究員 (20243503)
• Co-Investigator(Kenkyū-buntansha): 宮原 信明 岡山大学, 保健学研究科, 教授 (70335610)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 気管支喘息 / 肺気腫 / COPD / 好酸球性気道炎症 / 好中球性気道炎症 / レチノイドX受容体 / レチノイドX受容体パーシャルアゴニスト / 核内受容体 / 気道炎症 / アレルギー性気道炎症 / パーシャルアゴニスト / RXR選択的アゴニスト

Outline of Final Research Achievements

Oral administration of a novel Retinoid X receptor (RXR) partial agonist (NEt-4IB) significantly suppressed airway hyperresponsiveness, inflammatory cell accumulation in the airways, and attenuated the levels of TNF-α in the lung, and IL-5, IL-13 and NO levels in bronchoalveolar lavage fluid, and goblet cells hyperplasia and NF-κB expression in lung tissue in a murine model of asthma. Furthermore, in a porcine pancreas elastase (PPE)- and cigarette smoke extract (CSE)-induced emphysema model, treatment with NEt-4IB significantly suppressed the emphysematous changes and neutrophilic airway inflammation, proteinase/anti-proteinase imbalance, and increased anti-oxidant activity. These data suggest that RXRs may play crucial roles in the mechanism of airway inflammation, airway hyperresponsiveness, and emphysematous change, and the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of asthma and COPD.

Research Products

• [Journal Article] Severe asthma concomitant with allergic bronchopulmonary aspergillosis successfully treated with mepolizumab (2018)
  • Author(s): Oda N, Miyahara N, Senoo S, Itano J, Taniguchi A, Morichika D, Fujii U, Maeda Y, Kiura K, Kanehiro A.
  • Journal Title: Allergology International Volume: 67 Issue: 4 Pages: 521-523
  • DOI: 10.1016/j.alit.2018.03.004
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma. (2017)
  • Author(s): Fujii U, Miyahara N, Taniguchi A, Oda N, Morichika D, Murakami E, Nakayama H, Waseda K, Kataoka M, Kakuta H, Tanimoto M, Kanehiro A.
  • Journal Title: Respir Res Volume: 18:23 Issue: 1 Pages: 1-10
  • DOI: 10.1186/s12931-017-0507-z
  • Peer Reviewed / Open Access
• [Journal Article] Long-term effects of beta-blocker use on lung function in Japanese patients with chronic obstructive pulmonary disease. (2017)
  • Author(s): Oda N, Miyahara N, Ichikawa H, Tanimoto Y, Kajimoto K, Sakugawa M, Kawai H, Taniguchi A, Morichika D, Tanimoto M, Kanehiro A, Kiura K.
  • Journal Title: Int J COPD Volume: 12 Pages: 1119-1124
  • DOI: 10.2147/copd.s133071
  • Peer Reviewed / Open Access
• [Journal Article] Pneumocystis Pneumonia Concomitant with Ectopic ACTH Syndrome Caused by a Large Cell Neuroendocrine Carcinoma of the Thymus (2017)
  • Author(s): Oda N, Miyahara N, Tabata M, Minami D, Ninomiya K, Kanehiro A, Komatsubara M, Inagaki K, Tanimoto M, Kiura K.
  • Journal Title: Internal Medicine Volume: 56 Issue: 5 Pages: 551-555
  • DOI: 10.2169/internalmedicine.56.7655
  • NAID: 130005399422
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Protective Effects of Bisoprolol against Acute Exacerbation in Moderate-to-Severe Chronic Obstructive Pulmonary Disease (2017)
  • Author(s): Taniguchi A, Miyahara N, Oda N, Morichika D, Ichihara E, Oze I, Tanimoto Y, Ichikawa H, Fujii U, Tanimoto M, Kanehiro A, Kiura K.
  • Journal Title: Acta Medica Okayama Volume: 71 Issue: 5 Pages: 453-457
  • DOI: 10.18926/AMO/55446
  • NAID: 120006352368
  • URL: https://ousar.lib.okayama-u.ac.jp/55446
  • Peer Reviewed
• [Journal Article] Yellow nail症候群 (2017)
  • Author(s): 金廣有彦
  • Journal Title: Respiratory Medicine 呼吸器内科 Volume: 31 Pages: 68-71
  • NAID: 40021077595
• [Journal Article] 呼吸器疾患と慢性炎症. 喘息とCOPDの研究モデル. (2017)
  • Author(s): 谷口暁彦、金廣有彦
  • Journal Title: 別冊BIO Clinica Volume: 6 Pages: 27-32
• [Journal Article] IL-23 is essential for the development of elastase-induced pulmonary inflammation and emphysema. (2016)
  • Author(s): Fujii U, Miyahara N,Taniguchi A, Waseda K, Morichika D, Kurimoto E, Koga H, Kataoka M, Gelfand EW, Cua DJ, Yoshimura A, Tanimoto M, Kanehiro A
  • Journal Title: Am J Respir Cell Mol Biol Volume: 55 Issue: 5 Pages: 697-707
  • DOI: 10.1165/rcmb.2016-0015oc
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Heerfordt's Syndrome Associated with a High Fever and Elevation of TNF-α. (2016)
  • Author(s): Makimoto G, Miyahara N, Yoshikawa M, Taniguchi A, Kanehiro A, Tanimoto M, Kiura K.
  • Journal Title: Acta Med Okayama Volume: 70 Pages: 273-277
  • NAID: 120005828915
  • Peer Reviewed
• [Journal Article] 実地医家はどのように最新治療を実践すべきか.喘息における課題への対応.喘息とCOPDのオーバーラップ. (2016)
  • Author(s): 金廣有彦
  • Journal Title: Medical Practice Volume: 33 Pages: 1986-1992
• [Journal Article] Emphysema requires the receptor for advanced glycation end products triggering on structural cells. (2015)
  • Author(s): Waseda K, Miyahara N, Taniguchi A, Kurimoto E, Ikeda G, Koga H, Fujii U, Yamamoto Y, Gelfand EW, Yamamoto H, Tanimoto M, Kanehiro A.
  • Journal Title: Am J Respir Cell Mol Biol Volume: 52(4) Issue: 4 Pages: 482-491
  • DOI: 10.1165/rcmb.2014-0027oc
  • Peer Reviewed
• [Journal Article] Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness. (2015)
  • Author(s): Taniguchi A, Miyahara N, Waseda K, Kurimoto E, Fujii U, Tanimoto Y, Kataoka M, Yamamoto Y, Gelfand EW, Yamamoto H, Tanimoto M, Kanehiro A.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 309 Issue: 8 Pages: L789-L800
  • DOI: 10.1152/ajplung.00087.2015
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] BRONCHIAL ASTHMA AND LIFE ENVIRONMENT (2015)
  • Author(s): Kanehiro A
  • Journal Title: Arerugi Volume: 64 Pages: 1117-1126
  • NAID: 130005104815
  • Peer Reviewed
• [Journal Article] Effect of a Cysteinyl Leukotriene Receptor Antagonist on Experimental Emphysema and Asthma Combined with Emphysema (2014)
  • Author(s): Ikeda G, Kanehiro A, et al
  • Journal Title: Am J Respir Cell Mol Biol Volume: 50 Issue: 1 Pages: 18-29
  • DOI: 10.1165/rcmb.2012-0418oc
  • Peer Reviewed / Open Access
• [Journal Article] Lavender essential oil inhalation suppresses allergic airway inflammation and mucous cell hyperplasia in a murine model of asthma (2014)
  • Author(s): Ueno-Iio T, Shibakura M, Yokota K, Aoe M, Hyoda T, Shinohata R, Kanehiro A, Tanimoto M, Kataoka M
  • Journal Title: Life Sc Volume: 108 Issue: 2 Pages: 109-115
  • DOI: 10.1016/j.lfs.2014.05.018
  • Peer Reviewed
• [Presentation] 難治性喘息の新展開．難治性喘息の病態；フェノタイプ・エンドタイプ. (2018)
  • Author(s): 金廣有彦
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] 気管支喘息の病態と治療戦略． (2017)
  • Author(s): 金廣有彦
  • Organizer: 第14回日本病院総合診療医学会学術総会
  • Place of Presentation: 岡山
  • Year and Date: 2017-03-03
  • Invited
• [Presentation] Effect of a Retinoid X Receptor partial agonist on the development of emphysema and airway inflammation in a murine model of emphysema. (2017)
  • Author(s): Morichika D, Kanehiro A, Kakuta H, Taniguchi A, Fujii U, Oda N, Miyahara N, Kiura K, Tanimoto M.
  • Organizer: Annual International Conference of the American Thoracic Society 2017 International Conference
  • Int'l Joint Research
• [Presentation] IL-23 is essential to the development of elastase-induced pulmonary inflammation and emphysema. (2016)
  • Author(s): Fujii U, Miyahara N, Taniguchi A, Morichika D, Oda N, Murakami E, Nakayama M, Kataoka M, Yoshimura A, Gelfand EW, Tanimoto M, Kanehiro A.
  • Organizer: European Respiratory Society Annual Congress. 2016.
  • Place of Presentation: ロンドン
  • Year and Date: 2016-09-03
  • Int'l Joint Research
• [Presentation] 難治性喘息の病態と治療戦略． (2016)
  • Author(s): 金廣有彦
  • Organizer: 第56回臨床呼吸機能講習会
  • Place of Presentation: 岡山
  • Year and Date: 2016-08-24
  • Invited
• [Presentation] The Role of Retinoid X Receptor in allergen-induced Airway Inflammation in Mice. (2016)
  • Author(s): Fujii U, Kanehiro A, Kakuta H, Taniguchi A, Oda N, Morichika M, Ikeda G, Koga H, Waseda K, Kurimoto E, Miyahara N, Kataoka M, Tanimoto M.
  • Organizer: 65th Annual meeting of Japanese Society of Allergology, 2016. (English oral session)
  • Place of Presentation: 東京
  • Year and Date: 2016-06-17
• [Presentation] Treatment with Retinoid X Receptor partial agonist attenuates eosinophilic inflammation and airway hyperresponsiveness. (2016)
  • Author(s): Fujii U, A. Kanehiro A, Taniguchi A, Oda N, Morichika D, Waseda K, Murakami E, Nakayama M, Kataoka M, Kakuta H, Miyahara N, Kiura K, Tanimoto M.
  • Organizer: Annual International Conference of the American Thoracic Society International Conference. 2016.
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2016-05-14
  • Int'l Joint Research
• [Presentation] Endobronchial ultrasound-guided transbronchial needle aspiration of hilar and mediastinal lymph nodes detected on 18F-fluoradeoxyglucose positoron emission tomography/computed tomography. (2016)
  • Author(s): Minami D, Takigawa Y, Kato T, Ninomiya T, Kubo K, Ohashi K, Hotta T, Shibayama N, Miyahara N, Tabata A, Kanehiro A, Tanimoto M, Kiura K.
  • Organizer: Annual International Conference of the American Thoracic Society International Conference. 2016.
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2016-05-14
  • Int'l Joint Research
• [Presentation] IL-23 is Essential to the Development of Elastase-induced Pulmonary Inflammation and Emphysema. (2016)
  • Author(s): Fujii U, Miyahara N, Taniguchi A, Waseda K, Morichika D, Kurimoto E, Koga H, Kataoka M, Gelfand EW, Cua DJ, Yoshimura A, Tanimoto M, Kanehiro A.
  • Organizer: 56th Annual meeting of Japanese Respiratory Society, 2016. (English oral session)
  • Place of Presentation: 京都
  • Year and Date: 2016-04-08
• [Presentation] 難治性喘息の個別化治療: 新規抗喘息薬の有用性と展望. 非好酸球性気道炎症. (2016)
  • Author(s): 金廣有彦
  • Organizer: 第57回日本呼吸器学会学術講演会
  • Place of Presentation: 京都
  • Year and Date: 2016-04-08
  • Invited
• [Presentation] Effect of Retinoid X Receptor partial agonist on airway inflammation and hyperresponsiveness. (2015)
  • Author(s): Fujii U, A. Kanehiro A, Taniguchi A, Morichika D, Waseda K, Murakami E, Nakayama M, Kataoka M, Kakuta H, Miyahara N, Tanimoto M
  • Organizer: European Respiratory Society Annual Congress 2015.
  • Place of Presentation: Amsterdam NETHERLANDS
  • Year and Date: 2015-09-26
  • Int'l Joint Research
• [Presentation] Current condition and future perspective of a monoclonal anti-IgE antibody treatment -Adult-. (2015)
  • Author(s): Kanehiro A.
  • Organizer: 25th Congress of interasma Japan/North Asia 2015
  • Place of Presentation: Yokohama Japan
  • Year and Date: 2015-09-03
  • Int'l Joint Research / Invited
• [Presentation] Importance of IL-23 to the development of elastase-induced pulmonary inflammation and emphysema. (2015)
  • Author(s): Fujii U, Miyahara N, Taniguchi A, Kawano K, Waseda K, Morichika D, Koga H, Kataoka M, Tanimoto M, Yoshimura A, Kanehiro A.
  • Organizer: Annual International Conference of the American Thoracic Society International Conference 2015.
  • Place of Presentation: Denver CO USA
  • Year and Date: 2015-05-14
  • Int'l Joint Research
• [Presentation] Allergen-induced airway inflammation requires the receptor for advanced glycation end-products triggering on airway structural cells (2014)
  • Author(s): Taniguchi Y, Miyahara N, Kanehiro A, Waseda K, Kurimoro E, Fujii U, Tanimoto Y, Kataoka M, Yamamoto Y, Gelfand EW, Tanimoto M
  • Organizer: International Conference of the American Thoracic Society
  • Place of Presentation: サンフランシスコ、米国
  • Year and Date: 2014-05-17 – 2014-05-24
• [Patent(Industrial Property Rights)] 炎症性呼吸器疾患の予防又は治療用医薬組成物 (2016)
  • Inventor(s): 金廣有彦、加来田博貴、宮原信明、藤井詩子、森近大介、小田尚廣
  • Industrial Property Rights Holder: 金廣有彦、加来田博貴、宮原信明、藤井詩子、森近大介、小田尚廣
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016
  • Acquisition Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] 炎症性呼吸器疾患の予防又は治療用医薬組成物 (2016)
  • Inventor(s): Kanehiro A, Kakuta H et al.
  • Industrial Property Rights Holder: Kanehiro A, Kakuta H et al.
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-09-10
  • Overseas
• [Patent(Industrial Property Rights)] 炎症性呼吸器疾患の予防および治療のための組成物 (2015)
  • Inventor(s): Kanehiro A, Kakuta H et al.
  • Industrial Property Rights Holder: Kanehiro A, Kakuta H et al.
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-178885
  • Filing Date: 2015-09-10