重症感染症に伴うＡＲＤＳにおけるＰＧＤ２／ＣＲＴＨ２を介する病態メカニズムの解明

• Project/Area Number: 17J05376
• 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: 鈴木 翔二 慶應義塾大学, 医学研究科, 特別研究員(DC2)
• Project Period (FY): 2017-04-26 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 2018: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2017: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: CRTH2 / エンドトキシンショック / 急性肺損傷

Outline of Annual Research Achievements

エンドトキシンショックに続発する急性肺損傷におけるPGD2/CRTH2の役割の解明が目的だが、前段階として、CRTH2特異的阻害薬がLPS誘導性エンドトキシンショックにおける保護的役割のメカニズムを引き続き検討した。
まず、腹膜炎誘導敗血症マウスモデルと同様に、LPS誘導性エンドトキシンショックモデルにおいても腹腔内のProstaglandin D2濃度は経時的に上昇していくことを確認した。
CRTH2特異的阻害薬をLPS投与13時間前から12時間おきに投与したところ、LPS投与12時間後の時点でProstaglandin D2濃度が低下傾向だった。これは炎症が抑えられた結果を見ている可能性があると考えた。
次に腹腔内洗浄液中の細胞分画を評価したところ、CRTH2特異的阻害薬において腹腔内好中球遊走を抑制することが分かった。
好中球遊走に関わるケモカインとして、CXCL1, CXCL2が挙げられる。腹腔内好中球数増加の原因として、これらケモカインの腹腔内洗浄液中濃度が変化するか、ELISAで評価した。LPS投与後の腹腔内洗浄液中のCXCL1, CXCL2濃度はCRTH2特異的阻害薬投与群と対照群で差を認めなかった。ただしCRTH2特異的阻害薬投与群ではLPS投与後の末梢血中のCXCR2発現好中球の割合が対照群よりもより減少する傾向だった。このことはCRTH2特異的阻害薬投与群において腹腔内への好中球浸潤が抑制されたことの一因になりうると考えられる。
さらに、前年の検討でIFN-γがCRTH2阻害薬投与群での生存率改善に関連している可能性が示唆されたため、IFN-γ産生源を確認するために細胞内染色を行った。LPS投与6時間後の脾細胞を単離し細胞内染色を試みたが、T cellやNK cellのIFNγ発現量に群間差を認めなかった。リンパ球系以外の細胞集団が関与していることが考えられた。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Efficacy and safety of intermittent maintenance therapy after successful treatment of Mycobacterium avium complex lung disease (2019)
  • Author(s): T Asakura, T Nakagawa, S Suzuki et al.
  • Journal Title: Journal of infection and chemotherapy Volume: 25 Pages: 218-221
• [Journal Article] Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice. (2019)
  • Author(s): Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Suzuki S et al.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: in Press
• [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 H1,2, Ishii M1, Fujii H3, Yagi K1, Asami T1, Asakura T1, Suzuki S1, Hegab AE1, Kamata H1, Tasaka S1, Atarashi K4, Nakamoto N5, Iwata S6,7, Honda K4, Kanai T5, Hasegawa N6, Koyasu S4,8, Betsuyaku T1.
  • Journal Title: PLOS Pathogens Volume: 14(4) Issue: 4 Pages: e1006955-e1006955
  • DOI: 10.1371/journal.ppat.1006955
  • Peer Reviewed / Open Access
• [Journal Article] A Therapeutic Strategy for All Pneumonia Patients: A 3-Year Prospective Multicenter Cohort Study Using Risk Factors for Multidrug-resistant Pathogens to Select Initial Empiric Therapy. (2018)
  • Author(s): T Maruyama, T Fujisawa, T Ishida, A Ito, Y Oyamada, K Fujimoto, M Yoshida, H Maeda, N Miyashita, H Nagai, Y Imamura, N Shime, S Suzuki et al.
  • Journal Title: Clinical Infectious Diseases Volume: in Press
  • Peer Reviewed
• [Journal Article] Sphingosine 1-phosphate receptor modulator ONO-4641 stimulates CD11b+Gr-1+ cell expansion and inhibits lymphocyte infiltration in the lungs to ameliorate murine pulmonary emphysema. (2018)
  • Author(s): T Asakura, M Ishii, H Namkoong, S Suzuki et al.
  • Journal Title: Mucosal immunology Volume: 6 Pages: 1606-1620
• [Journal Article] Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease (2018)
  • Author(s): K Yagi, T Asakura, H Namkoong, S Suzuki et al.
  • Journal Title: BMC pulmonary medicine Volume: 18 Pages: 114-114
• [Journal Article] Quantitative assessment of erector spinae muscles in patients with Mycobacterium avium complex lung disease (2018)
  • Author(s): T Asakura, Y Yamada, S Suzuki et al.
  • Journal Title: Respiratory medicine Volume: 145 Pages: 66-72
• [Journal Article] 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, Nakano Y, Nishimura T, Ishii M, Ebihara T, Betsuyaku T, Hasegawa N
  • Journal Title: Respiratory Medicine Volume: in Press
  • Peer Reviewed / Int'l Joint Research
• [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: pii: S1465-3249(18)30009-4.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mycobacterium triplex Pulmonary Disease with Acquired Macrolide Resistance in Immunocompetent 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: pii: S1198-743X(17)30713-9
  • Peer Reviewed / Int'l Joint Research
• [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
  • Peer Reviewed / Int'l Joint Research
• [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: 198-198
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of cavity and infiltration on pulmonary function and health-related quality of life in pulmonary Mycobacterium avium complex 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
  • Peer Reviewed / Int'l Joint Research
• [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, Betsuyaku T, Abe Y, Ouchi M
  • Journal Title: Clin Infect Dis Volume: 65 Pages: 244-251
  • Peer Reviewed / Int'l Joint Research
• [Presentation] アスペルギルス沈降抗体陽性である肺Mycobacterium avium complex症患者の臨床的特徴 (2018)
  • Author(s): 鈴木 翔二 他
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] ADAM17 Protects Mice Against Elastase-Induced Emphysema Via Inactivation of CD62L. (2018)
  • Author(s): Shoji Suzuki et al
  • Organizer: The 58th Annual Meeting of the Japanese Respiratory Society
• [Presentation] ADAM17 protects mice against elastase-induced emphysema via inactivation of CD62L (2018)
  • Author(s): Shoji Suzuki et al
  • Organizer: European Respiratory Society International Congress 2018
• [Presentation] ADAM17が肺気腫発症に与える影響の検討 (2017)
  • Author(s): 鈴木 翔二、石井 誠、朝倉 崇徳、南宮 湖、八木 一馬、加茂 徹郎、岡森 慧、鎌田 浩史、堀内 圭輔、長谷川 直樹、別役 智子
  • Organizer: 第57回日本呼吸器学会学術講演会
• [Presentation] Protective Role of a Disintegrin and Metalloprotease 17 (ADAM17) in Elastase-Induced Emphysema in Mice (2017)
  • Author(s): Suzuki S, Ishii M, Asakura T, Namkoong H, Okamori S, Yagi K, Kamata H, Kagawa S, Horiuchi K, Horiuchi K, Hasegawa N, Betsuyaku T
  • Organizer: The Annual International Conference of American Thoracic Society
  • Int'l Joint Research