マクロライド系抗菌薬の抗炎症作用解明と炎症性肺疾患への臨床応用

• Project/Area Number: 13J07208
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: 呼吸器内科学
• Research Institution: Keio University
• Principal Investigator: 南宮 湖 慶應義塾大学, 医学研究科, 特別研究員(DC2)
• Project Period (FY): 2013-04-26 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥1,800,000 (Direct Cost: ¥1,800,000); Fiscal Year 2014: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2013: ¥900,000 (Direct Cost: ¥900,000)
• Keywords: 抗炎症作用 / CD11b(+)Gr-1(+)細胞 / マクロライド系抗菌薬 / LPS 腹腔内投与ショックモデル / 肺炎球菌性肺炎モデル / CD11b(+)Gr-1(+)cells / LPS 腹腔内投与ショックモデルマウス

Outline of Annual Research Achievements

マクロライド系抗菌薬は抗菌作用以外に抗炎症作用を有することが知られており、病態が各々異なる炎症性肺疾患に対して幅広く有用性が報告され、新たな治療法として期待されているマクロライド系抗菌薬が抗炎症作用を発揮するメカニズムに関する先行研究としては、肺胞マクロファージからの炎症性サイトカイン産生抑制、気道上皮細胞からのIL-8等の好中球遊走因子抑制やムチン産生抑制など、いずれも液性因子に関する研究が主であり、マクロライド系抗菌薬自身が、宿主側の免疫抑制性の細胞集団を誘導するかということに注目した先行研究はなく、細胞レベルで研究を進めた。
クラリスロマイシン（CAM）を3日間腹腔内投与し、肺と脾臓の免疫担当細胞をFACSにて解析を行ったCAM投与により肺・脾臓にそれぞれ、CD11b(+)Gr-1(+)細胞が有意に増加している事を新たに見出した。この細胞集団の増加は経口投与でも同様の傾向が確認された。
クラリスロマイシンによって誘導されるCD11b(+)Gr-1(+)細胞をでマイクロアレイ解析を行ったところ、CAMによって誘導されたCD11b(+)Gr-1(+)細胞において、Arginase-1が最も強く発現し、in vitroにおいて、CAMによって誘導されるCD11b(+)Gr-1(+)細胞は免疫抑制性に作用することが示された。
さらに、CAMはCD11b(+)Gr-1(+)細胞を介して、LPS 腹腔内投与ショックモデル及び肺炎球菌性肺炎モデルの予後を改善させることを明らかにした。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Comparison of the immunogenicity and safety of polysaccharide and protein-conjugated pneumococcal vaccines among the elderly aged 80 years or older in Japan: an open-labeled randomized study. (2015)
  • Author(s): Namkoong H, Funatsu Y, Oishi K, Akeda Y, Hiraoka R, Takeshita K, Asami T, Yagi K, Kimizuka Y, Ishii M, Tasaka S, Suzuki Y, Iwata S, Betsuyaku T, Hasegawa N.
  • Journal Title: Vaccine Volume: 33 Issue: 2 Pages: 327-332
  • DOI: 10.1016/j.vaccine.2014.11.023
  • Peer Reviewed / Open Access
• [Journal Article] The diagnostic usefulness of 18F-fluorodoxyglucose-positron emission tomography/CT in SAPHO syndrome (2015)
  • Author(s): Namkoong H, Ishii M, Tasaka S, Betsuyaku T
  • Journal Title: BMJ Case Rep Volume: undecided Pages: bcr2015209394-bcr2015209394
  • DOI: 10.1136/bcr-2015-209394
  • Peer Reviewed / Open Access
• [Journal Article] Recurrence of Disseminated Mycobacterium avium Complex Disease in a Patient with Anti-Gamma Interferon Autoantibodies by Reinfection. (2015)
  • Author(s): Nishimura T, Fujita-Suzuki Y, Yonemaru M, Ohkusu K, Sakagami T, Carpenter SM, Otsuka Y, Namkoong H, Yano I, Hasegawa N
  • Journal Title: J Clin Microbiol Volume: 53 Issue: 4 Pages: 1436-1438
  • DOI: 10.1128/jcm.03339-14
  • Peer Reviewed / Open Access
• [Journal Article] Fatal Fulminant Pneumonia Caused by Methicillin-Sensitive Staphylococcus aureus Negative for Major High-Virulence Factors Following Influenza B Virus Infection (2015)
  • Author(s): 5.Masaki K, Ishii M, Anraku M, Namkoong H, Miyakawa R, Nakajima T, Fukunaga K, Naoki K, Tasaka S, Soejima K, Sayama K, Sugita K, Iwata S, Cui L, Hanaki H, Hasegawa N, Tomoko Betsuyaku T
  • Journal Title: Am J Case Rep Volume: 16 Pages: 454-458
  • DOI: 10.12659/ajcr.894022
  • Peer Reviewed
• [Journal Article] The efficacy, safety, and pharmacokinetics of biapenem administered thrice daily for the treatment of pneumonia in the elderly. (2014)
  • Author(s): Namkoong H, Kameyama Y, Yasuda H, Nakayama S, Kaneko H, Kawashima C, Terajima T, Maezawa K, Hayashi T, Sandoh M, Ishii M, Tasaka S, Kanayama A, Kobayashi I, Betsuyaku T, Kizu J, Iwata S, Sato Y, Hasegawa N
  • Journal Title: J Infect Chemother Volume: 20 Issue: 6 Pages: 356-360
  • DOI: 10.1016/j.jiac.2013.12.010
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary nocardiosis caused by Nocardia cyriacigeorgica in patients with Mycobacterium avium complex lung disease: two case reports. (2014)
  • Author(s): Yagi K, Ishii M, Namkoong H, Asami T, Fujiwara H, Nishimura T, Saito F, Kimizuka Y, Asakura T, Suzuki S, Kamo T, Tasaka S, Gonoi T, Kamei K, Betsuyaku T, Hasegawa N.
  • Journal Title: BMC Infect Dis Volume: 14 Pages: 684-684
  • Peer Reviewed
• [Journal Article] Serum (1 → 3) β-D-glucan assay for discrimination between Pneumocystis jirovecii pneumonia and colonization. (2014)
  • Author(s): Tasaka S, Kobayashi S, Yagi K, Asami T, Namkoong H, Yamasawa W, Ishii M, Hasegawa N, Betsuyaku T.
  • Journal Title: J Infect Chemother Volume: 20 Issue: 11 Pages: 678-681
  • DOI: 10.1016/j.jiac.2014.07.001
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacokinetics of arbekacin in bronchial epithelial lining fluid of healthy volunteers. (2014)
  • Author(s): Funatsu Y, Hasegawa N, Fujiwara H, Namkoong H, Asami T, Tasaka S, Kimizuka Y, Kamata H, Ishii M, Iketani O, Ogata H, Iwata S, Betsuyaku T
  • Journal Title: J Infect Chemother Volume: 20 Issue: 10 Pages: 607-611
  • DOI: 10.1016/j.jiac.2014.05.007
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of murine macrophage TLR7/8-mediated cytokine expression by mesenchymal stem cell-conditioned medium (2013)
  • Author(s): 15.Asami T, Ishii M, Fujii H, Namkoong H, Tasaka S, Matsushita K, Ishii K, Yagi K, Fujiwara H, Funatsu Y, Hasegawa N, Betsuyaku T
  • Journal Title: Mediators Inflamm Volume: undecided Pages: 1-13
  • DOI: 10.1155/2013/264260
  • Peer Reviewed
• [Presentation] 9.Namkoong H, Ishii M, Fujii H, Yagi K, Asakura T, Suzuki S, Kamo T, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T. Clarithromycin Expands CD11b+Gr-1+Cells to Ameliorate Post-Influenza Pneumococcal Pneumonia. (2015)
  • Author(s): 9.Namkoong H, Ishii M, Fujii H, Yagi K, Asakura T, Suzuki S, Kamo T, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T
  • Organizer: Keystone Symposia(Granulomas in Infectious and Non-Infectious Diseases),
  • Place of Presentation: New Mexico, USA
  • Year and Date: 2015-01-22 – 2015-01-27
• [Presentation] Obesity Worsens The Outcome Of Influenza Virus Infection Via Impaired IFN -Beta Induction In Mice (2014)
  • Author(s): 9.Namkoong H, Ishii M, Fujii H, Yagi K, Asakura T, Suzuki S, Kamo T, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T
  • Organizer: ATS 2014 International Conference
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] Clarithromycin expands CD11b+Gr-1+ cells to protect against LPS-induced lethal shock and polymicrobial sepsis. 28th International Congress of Chemotherapy and Infection (2013)
  • Author(s): 4.Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Fujiwara H, Saitoh F, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T.
  • Organizer: 28th International Congress of Chemotherapy and Infection
  • Place of Presentation: Yokohama
  • Year and Date: 2013-06-07 – 2013-06-08
• [Presentation] Clarithromycin expands CD11b+Gr-1+ cells to protect against LPS-induced lethal shock and polymicrobial sepsis. (2013)
  • Author(s): 16.Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Fujiwara H, Saitoh F, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T
  • Organizer: 109th International Conference of American Thoracic Society
  • Place of Presentation: Philadelphia
  • Year and Date: 2013-05-17 – 2013-05-22
• [Book] 「EBMを活かす呼吸器診療」 (2015)
  • Author(s): 南宮湖,長谷川直樹
  • Total Pages: 592
  • Publisher: メジカルビュー社
• [Book] 「呼吸器内科」 (2015)
  • Author(s): 南宮湖,長谷川直樹
  • Total Pages: 75
  • Publisher: 科学評論社
• [Book] 肺MAC症診療Up to Date －非結核性抗酸菌症のすべて－ (2013)
  • Author(s): 南宮湖，長谷川直樹
  • Total Pages: 259
  • Publisher: 南江堂
• [Book] 【呼吸器疾患-state of arts Ver.6】 医学のあゆみ 別冊呼吸器疾患-state of arts Ver.6 (2013)
  • Author(s): 南宮湖，長谷川直樹
  • Total Pages: 520
  • Publisher: 医歯薬出版