Elucidation of epigenetic mechanism for new therapeutic strategies against COPD

• Project/Area Number: 16J07163
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Respiratory organ internal medicine
• Research Institution: Keio University
• Principal Investigator: 朝倉 崇徳 慶應義塾大学, 医学研究科, 特別研究員(DC2)
• Project Period (FY): 2016-04-22 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 2017: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2016: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: 慢性閉塞性肺疾患 / エピジェネティクス

Outline of Annual Research Achievements

既にDZNepおよびEzh2コンディショナルノックアウト(cKO)マウスを用いて、エラスターゼ誘導肺気腫モデルで気腫が増悪する結果を得ている。Ezh2 cKOマウスを用いたエラスターゼ誘導肺気腫モデルにおいて、投与7日後の全肺細胞をFACSで解析したところ、NK細胞お よびCD11b陽性マクロファージがEzh2 cKOマウス群でEzh2 cKO群で有意に上昇していた。同様に、DZNepを用いたエラスターゼ誘導肺気 腫モデルにおいてもNK細胞およびCD11b陽性マクロファージがDZNep投与群で有意に上昇していることを確認した。また、CD11b陽性細胞もしくはNK細胞に対するアンタゴニストを用いた実験ではDZNep投与による気腫増悪が相殺された。また、Ezh2 cKOマウスを用いて長期喫煙曝露モデルで検討した。喫煙開始12週間後の肺組織において、Ezh2 cKOマウス群で有意に気腫が増悪した。また、FACSではNK細胞およびCD11b陽性マクロファージが上昇していることを確認した。さらにEzh2 cKOマウスにおいて、タモキシフェン誘導性にEzh2をノックアウトし6ヶ月の長期観察を行ったところ、一部のマウスに腫瘍発生がみられることを確認した。また、肺組織を固定したところ、気腫形成がコントロール群に比較して増悪した可能性が示唆された。今後さらに、Ezh2 cKOマウス群での気腫増悪の機序およびヒト肺組織における検討を行う予定である。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Development of Necrotizing Myopathy Following Interstitial Lung Disease with Anti-signal Recognition Particle Antibody (2018)
  • Author(s): Kusumoto T, Okamori S, Masuzawa K, Asakura T, Nishina N, Chubachi S, Naoki K, Fukunaga K, Betsuyaku T.
  • Journal Title: Internal Medicine Volume: 57 Issue: 14 Pages: 2045-2049
  • DOI: 10.2169/internalmedicine.0303-17
  • NAID: 130007404881
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-07-15
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Health-related QOL of elderly patients with pulmonary M. avium complex disease in a university hospital (2018)
  • Author(s): Asakura T, Ishii M, Ishii K, Suzuki S, Namkoong H, Okamori S, Kamata H, Yagi K, Funatsu Y, Betsuyaku T, Hasegawa N
  • Journal Title: Int J Tuberc Lung Dis Volume: in press
  • Peer Reviewed
• [Journal Article] Aspergillus precipitating antibody in patients with Mycobacterium avium complex lung disease: a cross-sectional study. Aspergillus precipitating antibody in patients with Mycobacterium avium complex lung disease: a cross-sectional study. (2018)
  • Author(s): Suzuki S, Asakura T, Namkoong H, Okamori S, Yagi K, Kamata H, Uwamino Y, Funatsu Y, Yasushi Nakano, Tomoyasu Nishimura, Ishii M, Ebihara T, Betsuyaku T, Hasegawa N.
  • Journal Title: Respir Med Volume: in press
  • Peer Reviewed
• [Journal Article] Anti-aminoacyl tRNA Synthetase Antibody-Positive Clinically Amyopathic Dermatomyositis. (2018)
  • Author(s): Ebisudani T, Asakura T, Ueda S, Ishii M, Betsuyaku T.
  • Journal Title: QJM Volume: in press Issue: 6 Pages: 425-426
  • DOI: 10.1093/qjmed/hcy008
  • Peer Reviewed / Open Access
• [Journal Article] Clarithromycin Expands CD11b+Gr-1+ Cells via the STAT3/Bv8 Axis to Ameliorate Lethal Endotoxic Shock and Post-influenza Bacterial Pneumonia. (2018)
  • Author(s): Namkoong H, Ishii M, Fujii H, Yagi K, Asami T, Asakura T, Suzuki S, Hegab AE, Kamata H, Tasaka S, Atarashi K, Nakamoto N, Iwata S, Honda K, Kanai T, Naoki H, Koyasu S, Betsuyaku T.
  • Journal Title: PloS Pathog Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Anti-inflammatory roles of mesenchymal stromal cells during acute Streptococcus pneumoniae pulmonary infection in mice (2018)
  • Author(s): Asami Takahiro、Ishii Makoto、Namkoong Ho、Yagi Kazuma、Tasaka Sadatomo、Asakura Takanori、Suzuki Shoji、Kamo Tetsuro、Okamori Satoshi、Kamata Hirofumi、Zhang Haiyue、Hegab Ahmed E.、Hasegawa Naoki、Betsuyaku Tomoko
  • Journal Title: Cytotherapy Volume: 20 Issue: 3 Pages: 302-313
  • DOI: 10.1016/j.jcyt.2018.01.003
  • Peer Reviewed / Open Access
• [Journal Article] Mycobacterium triplex Pulmonary Disease with Acquired Macrolide Resistance inImmunocompetent Patients. (2018)
  • Author(s): Matsuda S, Suzuki S, Morimoto K, Aono A, Nishio K, Asakura T, Sasaki Y, Namkoong H, Nishimura T, Ogata H, Hasegawa N, Kurashima A, Ishii M, Tatsumi K, Mitarai S, Goto H.
  • Journal Title: Clin Microbiol Infect Volume: in press Issue: 6 Pages: 671-672
  • DOI: 10.1016/j.cmi.2017.12.018
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics of pulmonary Mycobacterium lentiflavum disease in adult patients. (2018)
  • Author(s): Yagi K, Morimoto K, Ishii M, Namkoong H, Okamori S, Asakura T, Suzuki S, Asami T, Uwamino Y, Funatsu Y, Fujiwara H, Kamata H, Nishimura T, Betsuyaku T, Kurashima A, Hasegawa N.
  • Journal Title: International Journal of Infectious Diseases Volume: 67 Pages: 65-69
  • DOI: 10.1016/j.ijid.2017.12.001
  • Peer Reviewed / Open Access
• [Journal Article] Long-term Outcome of Pulmonary Resection for Nontuberculous Mycobacterial Pulmonary Disease (2017)
  • Author(s): Asakura T, Hayakawa N, Hasegawa N, Namkoong H, Takeuchi K, Suzuki S, Ishii M, Bestuyaku T, Abe Y, Ouchi M
  • Journal Title: Clin Infect Dis Volume: in press Issue: 2 Pages: 244-251
  • DOI: 10.1093/cid/cix274
  • Peer Reviewed
• [Journal Article] Impact of Cavity and Infiltration on Pulmonary Function and Health-Related Quality of Life in Mycobacterium avium complex Pulmonary Disease: A 3-Dimensional Computed Tomographic Analysis (2017)
  • Author(s): Asakura T, Yamada Y, Namkoong H, Suzuki S, Niijima Y, Kamata H, Funatsu Y, Yagi K, Okamori S, Sugiura H, Ishii M, Jinzaki M, Betsuyaku T, Hasegawa N
  • Journal Title: Respir Med Volume: 126 Pages: 9-16
  • DOI: 10.1016/j.rmed.2017.03.010
  • Peer Reviewed / Open Access
• [Journal Article] Disseminated Mycobacterium genavense Infection in Patient with Adult-Onset Immunodeficiency. (2017)
  • Author(s): Asakura T, Namkoong H, Sakagami T, Hasegawa N, Ohkusu K, Nakamura A
  • Journal Title: Emerging Infectious Diseases journal Volume: 23(7) Issue: 7 Pages: 1208-1210
  • DOI: 10.3201/eid2307.161677
  • Peer Reviewed / Open Access
• [Journal Article] Impact of chronic Pseudomonas aeruginosa infection on health-related quality of life in Mycobacterium avium complex lung disease. (2017)
  • Author(s): Kamata H1, Asakura T1,2, Suzuki S1,2, Namkoong H1, Yagi K1, Funatsu Y1, Okamori S1, Uno S3, Uwamino Y4, Fujiwara H3, Nishimura T5, Ishii M1, Betsuyaku T1, Hasegawa N6.
  • Journal Title: BMC Pulmonary Medicine Volume: 17(1) Issue: 1 Pages: 198-198
  • DOI: 10.1186/s12890-017-0544-x
  • Peer Reviewed / Open Access
• [Journal Article] Bilateral upper lobe Pneumocystis pneumonia during aerosolized pentamidine prophylaxis. (2017)
  • Author(s): Ohara Y, Asakura T, Ueda S, Yamada Y, Ishii M, Betsuyaku T.
  • Journal Title: QJM Volume: in press Issue: 5 Pages: 337-338
  • DOI: 10.1093/qjmed/hcx233
  • Peer Reviewed / Open Access
• [Journal Article] Suspected accelerated disease progression after discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: Two case reports (2017)
  • Author(s): Okamori S, Asakura T, Masuzawa K, Yasuda H, Kamata H, Ishii M, Betsuyaku T.
  • Journal Title: Medicine(Baltimore) Volume: 96 Issue: 49 Pages: e9081-e9081
  • DOI: 10.1097/md.0000000000009081
  • Peer Reviewed / Open Access
• [Journal Article] Sternoclavicular joint osteomyelitis extending to lung abscess complicated by Staphylococcal infective endocarditis. (2017)
  • Author(s): Masuzawa K, Asakura T, Ishii M, Yasuda H, Sugiura H, Betsuyaku T.
  • Journal Title: IDCases Volume: 9 Pages: 36-37
  • DOI: 10.1016/j.idcr.2017.04.005
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy, safety, and feasibility of inhaled amikacin for the treatment of difficult-to-treat non-tuberculous mycobacterial lung diseases. (2017)
  • Author(s): Yagi K, Ishii M, Namkoong H, Asami T, Iketani O, Asakura T, Suzuki S, Sugiura H, Yamada Y, Nishimura T, Fujiwara H, Funatsu Y, Uwamino Y, Kamo T, Tasaka S, Betsuyaku T, Hasegawa N
  • Journal Title: BMC Infectious Diseases Volume: 17(1) Issue: 1 Pages: 558-558
  • DOI: 10.1186/s12879-017-2665-5
  • Peer Reviewed / Open Access
• [Journal Article] Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung (2017)
  • Author(s): Kuroda Aoi、Hegab Ahmed E.、Jingtao Gao、Yamashita Shuji、Hizawa Nobuyuki、Sakamoto Tohru、Yamada Hideyasu、Suzuki Satoshi、Ishii Makoto、Namkoong Ho、Asakura Takanori、Ozaki Mari、Yasuda Hiroyuki、Hamamoto Junko、Kagawa Shizuko、Soejima Kenzo、Betsuyaku Tomoko
  • Journal Title: Respir Res Volume: 18 Issue: 1 Pages: 69-69
  • DOI: 10.1186/s12931-017-0554-5
  • NAID: 120007129115
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary Cryptococcosis Developed from a Nodule After Treatment with Infliximab for Arthritis Associated with Ulcerative Colitis (2017)
  • Author(s): Asakura T, Arai D, Ishii M, Takei H, Sugiura H, Takeuchi T, Betsuyaku T
  • Journal Title: Ann Am Thorac Soc Volume: 14 Issue: 4 Pages: 603-605
  • DOI: 10.1513/annalsats.201612-952le
  • Peer Reviewed
• [Journal Article] Pneumothorax Associated with Nontuberculous Mycobacteria: A Retrospective Study of 69 Patients (2016)
  • Author(s): Ueyama M, Asakura T, Morimoto K, Namkoong H, Matsuda S, Osawa T, Ishii M, Hasegawa N, Kurashima A, Goto H
  • Journal Title: Medicine (Baltimore) Volume: 95 Issue: 29 Pages: e4246-e4246
  • DOI: 10.1097/md.0000000000004246
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Efficacy and Safety of Multidrug Therapy including Thrice Weekly Intravenous Amikacin Administration for Mycobacterium abscessus Pulmonary Disease in Outpatient Settings: A Case Series (2016)
  • Author(s): Namkoong H, Morimoto K, Nishimura T, Tanaka H, Sugiura H, Yamada Y, Kurosaki A, Asakura T, Suzuki S, Fujiwara H, Yagi K, Ishii M, Tasaka S, Betsuyaku T, Hoshino Y, Kurashima A, Hasegawa N
  • Journal Title: BMC Infect Dis Volume: 16 Issue: 1 Pages: 396-396
  • DOI: 10.1186/s12879-016-1689-6
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics of pulmonary Mycobacterium scrofulaceum disease in 2001-2011: a case series and literature review (2016)
  • Author(s): Suzuki S, Morino E, Ishii M, Namkoong H, Yagi K, Asakura T, Asami T, Fujiwara H, Uwamino Y, Nishimura T, Tasaka S, Betsuyaku T, Takasaki J, Iwata S, Hasegawa N
  • Journal Title: J Infect Chemother Volume: 22 Issue: 9 Pages: 611-616
  • DOI: 10.1016/j.jiac.2016.06.006
  • Peer Reviewed
• [Journal Article] Finger fractures as an early manifestation of primary hyperparathyroidism among young patients: a case report of a 30-year-old male with recurrent osteoporotic fractures (2016)
  • Author(s): Ozaki A, Tanimoto T, Yamagishi E, Sato S, Tsukada M, Sawano T, Leppold C, Tsuda K, Asakura T, Tsubokura M, Kato S, Kami M, Ohira H
  • Journal Title: Medicine (Baltimore) Volume: 95 Issue: 20 Pages: e3683-e3683
  • DOI: 10.1097/md.0000000000003683
  • Peer Reviewed / Open Access
• [Journal Article] Levels of soluble receptor for advanced glycation end products in bronchoalveolar lavage fluid in patients with various inflammatory lung diseases (2016)
  • Author(s): Kamo T, Tasaka S, Tokuda Y, Suzuki S, Asakura T, Yagi K, Namkoong H, Ishii M, Hasegawa N, Betsuyaku T
  • Journal Title: Clin Med Insights Circ Respir Pulm Med Volume: 9 Pages: 147-154
  • DOI: 10.4137/ccrpm.s23326
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment of a non-small-cell lung cancer patient with afatinib and a glucocorticoid after both gefitinib- and erlotinib- induced interstitial lung disease (2016)
  • Author(s): Tani T, Naoki K, Asakura T, Hirano T, Suzuki S, Masuzawa K, Hasegawa H, Kuroda A, Yasuda H, Ishii M, Soejima K, Betsuyaku T
  • Journal Title: Mol Clin Oncol Volume: 4 Issue: 4 Pages: 488-490
  • DOI: 10.3892/mco.2016.981
  • Peer Reviewed / Open Access
• [Presentation] 肺Mycobacterium aviumcomplex(MAC)症における抗重力筋評価の意義 (2018)
  • Author(s): 朝倉 崇徳、山田 祥岳、鈴木 翔二、南宮 湖、岡森 慧、楠本 竜也、新島 友輝、八木 一馬、鎌田 浩史、舩津 洋平、石井 誠、陣崎 雅弘、別役 智子、長谷川 直樹
  • Organizer: 第10回呼吸機能イメージング研究会
• [Presentation] 肺炎球菌による慢性閉塞性肺疾患の増悪マウスモデルにおいてS1P受容体修飾薬(ONO-4641)は気腫進行を抑制する (2018)
  • Author(s): 朝倉 崇徳、石井 誠、南宮 湖、鈴木 翔二、八木 一馬、岡森 慧、鎌田 浩史、岩田 敏、長谷川 直樹
  • Organizer: 第91回日本感染症学会総会・学術講演会
• [Presentation] S1P Receptor Modulation Expands CD11b+Gr-1+ Cells and Inhibits Lymphocyte Infiltration to Ameliorate Murine Pulmonary Emphysema. (2018)
  • Author(s): Asakura T, Ishii M, Namkoong H, Suzuki S, Kagawa S, Kamata H, Komiya T, Yagi K, Okamori S, Hasegawa N, Betsuyaku T.
  • Organizer: The 57th Japanese Respiratory Society Meeting
• [Presentation] S1P Receptor Modulation Expands CD11b+Gr-1+ Cells and Inhibits Lymphocyte in the Lungs Infiltration to Ameliorate Murine Pulmonary Emphysema. (2018)
  • Author(s): Asakura T, Ishii M, Namkoong H, Suzuki S, Kagawa S, Kamata H, Komiya T, Yagi K, Okamori S, Hasegawa N, Betsuyaku T.
  • Organizer: ATS International Conference
  • Int'l Joint Research
• [Presentation] Long-term Outcome of Pulmonary Resection for Nontuberculous Mycobacterial Pulmonary Disease. (2018)
  • Author(s): Asakura T, Hayakawa N, Hasegawa N, Namkoong H, Takeuchi K, Suzuki S, Ishii M, Bestuyaku T, Abe Y, Ouchi M.
  • Organizer: ERS International Congress
  • Int'l Joint Research
• [Presentation] 頸部・腹腔内リンパ節腫脹で発症した抗IFNγ中和自己抗体陽性の播種性Mycobacterium genavense症の1例 (2017)
  • Author(s): 朝倉 崇徳、南宮 湖、坂上 拓郎、長谷川 直樹、大楠 清文、中村 朗
  • Organizer: 第92回日本結核病学会総会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
  • Year and Date: 2017-03-23
• [Presentation] 肺Mycobacterium avium complex症で肺野浸潤影・粒状影の体積は肺機能と相関する (2017)
  • Author(s): 朝倉 崇徳、山田 祥岳、南宮 湖、鈴木 翔二、新島 友輝、鎌田 浩史、舩津 洋平、八木 一馬、岡森 慧、石井 誠、陣崎 雅弘、別役 智子、長谷川 直樹
  • Organizer: 第9回呼吸機能イメージング研究会
  • Place of Presentation: 京都大学百周年時計台記念館(京都府左京区)
  • Year and Date: 2017-01-27
• [Presentation] 節外性鼻型NK/T細胞リンパ腫と鑑別を要した播種性Mycobacterium marinum症の1例 (2016)
  • Author(s): 朝倉 崇徳、石井 誠、南宮 湖、八木 一馬、鈴木 翔二、鎌田 浩史、鹿住 祐子、中田 登、上蓑 義典、藤原 宏、西村 知泰、田坂 定智、星野 仁彦、長谷川 直樹
  • Organizer: 第91回日本結核病学会総会
  • Place of Presentation: 石川県立音楽堂(石川県金沢市)
  • Year and Date: 2016-05-26
• [Presentation] 肺Mycobacterium avium complex症で肺野浸潤影・粒状影の体積は最も肺機能と相関する：CT画像解析ソフトを用いた検討 (2016)
  • Author(s): 朝倉 崇徳、南宮 湖、八木 一馬、鈴木 翔二、浅見 貴弘、舩津 洋平、鎌田 浩史、上蓑 義典、藤原 宏、西村 知泰、石井 誠、田坂 定智、長谷川 直樹
  • Organizer: 第91回日本結核病学会総会
  • Place of Presentation: 石川県立音楽堂(石川県金沢市)
  • Year and Date: 2016-05-26
• [Presentation] 3-Deazaneplanocin A-An Inhibitor Of Histone Methyltransferase Ezh2-Exacerbates Elastase-Induced Emphysema In Mice (2016)
  • Author(s): Asakura T, Ishii M, Namkoong H, Yagi K, Tanosaki T, Suzuki S, Kamo T, Tasaka S, Hasegawa N, Betsuyaku T
  • Organizer: ATS International Conference 2016
  • Place of Presentation: サンフランシスコ（米国）
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] 肺MAC症患者の健康関連QOLは C反応性蛋白・年齢と負に相関する (2016)
  • Author(s): 朝倉 崇徳、石井 誠、舩津 洋平、南宮 湖、鈴木 翔二、八木 一馬、西村 知泰、田坂 定智、長谷川 直樹、別役 智子
  • Organizer: 第113回日本内科学会講演会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
  • Year and Date: 2016-04-15
• [Presentation] 3-Deazaneplanocin A, an inhibitor of histone methyltransferase EZH2, exacerbates elastase-induced emphysema in mice (2016)
  • Author(s): Asakura T, Ishii M, Namkoong H, Yagi K, Tanosaki T, Suzuki S, Kamo T, Tasaka S, Hasegawa N, Betsuyaku T
  • Organizer: he 56th Japanese Respiratory Society Meeting
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
  • Year and Date: 2016-04-08
• [Book] 呼吸器内科「肺非結核性抗酸菌症の診断と治療」 (2018)
  • Author(s): 朝倉 崇徳、長谷川 直樹
  • Publisher: 科学評論社
• [Book] THE LUNG PERSPECTIVES「非結核性抗酸菌症Up-to-date: 主に疫学, 病型と治療について」 (2018)
  • Author(s): 朝倉 崇徳、長谷川 直樹
  • Total Pages: 6
  • Publisher: メディカルレビュー社
• [Book] 呼吸器ジャーナル「症例で学ぶ非結核性抗酸菌症(第13回)肺NTM症における手術について」 (2018)
  • Author(s): 朝倉 崇徳、長谷川 直樹、早川 信崇、大内 基史
  • Total Pages: 7
  • Publisher: 医学書院
• [Book] 呼吸器ジャーナル「画像所見による肺結核と肺非結核性抗酸菌症との鑑別は可能か?」 (2017)
  • Author(s): 朝倉 崇徳、杉浦 弘明、長谷川 直樹
  • Total Pages: 11
  • Publisher: 医学書院
• [Book] レジデントノート「みんなで解決! 病棟のギモン : 研修医の素朴な質問にお答えします(第14回)喀痰抗酸菌塗抹検査が陽性になったら」 (2017)
  • Author(s): 朝倉 崇徳
  • Total Pages: 4
  • Publisher: 羊土社