Elucidation of epigenetic mechanism for new therapeutic strategies against COPD

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16J07163
• 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
• 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] 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 Pages: in press
  • DOI: 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 Pages: in press
  • DOI: 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 Pages: in press
  • 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 Pages: in press
  • DOI: in press
  • Peer Reviewed / Open Access
• [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: Intern Med Volume: in press Pages: in press
  • DOI: 10.2169/internalmedicine.0303-17.
  • 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 T, Ishii M, Namkoong H, Yagi K, Tasaka S, Asakura T, Suzuki S, Kamo T, Okamori S, Kamata H, Zhang H, Hegab AE, Hasegawa N, Betsuyaku T.
  • Journal Title: Cytotherapy Volume: 20 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 Pages: in press
  • DOI: 10.1016/j.cmi.2017.12.018.
  • Peer Reviewed
• [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: Int J Infect Dis 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: 65 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
• [Journal Article] Disseminated Mycobacterium genavense Infection in a Patient with Adult-onset Immunodeficiency. (2017)
  • Author(s): Asakura T, Namkoong H, Sakagami T, Hasegawa N, Ohkusu K, Nakamura A.
  • Journal Title: Emerg Infect Dis Volume: 23 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 H*, Asakura T*, Suzuki S, Namkoong H, Yagi K, Funatsu Y, Okamori S, Uno S, Uwamino Y, Fujiwara H, Nishimura T, Ishii M, Betsuyaku T, Hasegawa N.
  • Journal Title: BMC Pulm Med Volume: 17 Pages: 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 Pages: in press
  • 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 Pages: 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 Infect Dis Volume: 17 Pages: 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 A, Hegab AE, Jingtao G, Yamashita S, Hizawa N, Sakamoto T, Yamada H, Suzuki S, Ishii M, Namkoong H, Asakura T, Ozaki M, Yasuda H, Hamamoto J, Kagawa S, Soejima K, Betsuyaku T.
  • Journal Title: Respir Res Volume: 18 Pages: 69
  • DOI: 10.1186/s12931-017-0554-5.
  • 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
• [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
  • Total Pages: in press
  • 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