炎症性閉塞性呼吸器疾患における難治化メカニズムに関する研究

2016 Fiscal Year Research-status Report

• Project/Area Number: 15K09233
• Research Institution: Jikei University School of Medicine
• Principal Investigator: 中山 勝敏 東京慈恵会医科大学, 医学部, 准教授 (40321989)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 喘息 / COPD / ACOS / 難治化 / 疲労 / HHV-6 / HHV-7 / SITH-1

Outline of Annual Research Achievements

炎症性閉塞性呼吸器疾患,COPD,喘息(BA),その合併(ACOS)の病態難治化を解析するため,疲労の新規指標であるヒトヘルペスウイルス(HHV)-6,HHV-7の再活性化因子を検討する.これには,唾液中のHHV-6/7(DNA)量およびHHV-6再活性化時に嗅球で発現するSITH-1に対する抗体価がある.HHV-6(DNA)は1週間程度,HHV-7(DNA)は1ヶ月程度の疲労を反映する.また抗SITH-1抗体はメンタル異常と関連し,鬱や双極性障害では陽性率50％を超える(正常1.7%).我々は,前回(n=26名)から症例数を63名に増加させ,疲労指標と各疾患,重症度,症状強度等との関連を検討した.
対象は63名(60.6±11.4歳,男/女=47/16名,COPD/BA/ACOS=15/33/15名,全て安定期).HHV-6再活性化率(%)は,BAで最も高く(COPD/BA/ACOS=33.3/48.5/33.3),しかし喘息とCOPD両方で重症度や症状スコアとは一定の傾向は認められなかった.一方,HHV-7再活性化率(%)も,BAで最も高く(COPD/BA/ACOS=46.7/48.5/33.3),また喘息とCOPD両方で重症度には関係しなかったが,症状スコアでは症状が強い程,HHV-7再活性化率(%)も高い傾向がみられた(ACT最良/良/不良=26.7/41.7/66.7,CAT良/不良=40/50).また,抗SITH-1抗体陽性率(%)は(COPD/BA/ACOS= 20/35.5/23),鬱スコアBDI＞9p,19pの率(%)は(6.7/21.2/20,0/9.1/0)であった.
以上から,炎症性閉塞性呼吸器疾患では,BAが最も疲労が高く,HHV-7(DNA)が半減期が長いためか喘息とCOPD両方で症状スコアとの関連性がみられた.BAはメンタル異常の存在が示唆された.これらの成果は、2016年の呼吸器学会および同年の欧州胸部疾患学会にて発表された。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

疲労関連因子に関して、症例数をある程度に増やして検討することができた。
疲労マーカーと疾患の関連について、特に喘息について鬱スコアが有意に高く、抗SITH-1抗体価が高いなど、興味深い知見を得ることができた。鬱や気分障害は喘息でしばしば認められ、かつ難治化の要因となると考えられている。
一方、共同研究の基礎のデータにおいてSITH-1が中枢神経に働き、ホルモン異常や鬱を発症するメカニズムが明らかにされつつある。
今後は対象疾患患者数をさらに増やして、特に喘息に関して抗SITH-1抗体価と予後などに関して検討する。

Strategy for Future Research Activity

以下を企画推進する。
１）炎症性閉塞性呼吸器疾患(COPD/ BA/ ACOS)の対象患者数を増大させ、疲労関連因子(HHV-6/7とSITH-1)と各疾患病態、疾患重症度、症状スコアとの関連をより詳細に検討する。
２）対象患者を前向きに評価し、疲労関連因子(HHV-6/7とSITH-1)と病態予後(疾患増悪、肺機能減衰、生命予後等)との関連を検討する。
３）炎症性閉塞性呼吸器疾患の中で、特に喘息に関して抗SITH-1抗体価と予後(鬱スコア、発作頻度、症状スコア、重症度)について検討する。喘息の難治化のメカニズムにSITH-1 Ab高値のメンタル異常がどの様に関与するのかを明らかにする。
４）喘息において、抗SITH-1抗体高値となる要因を検討する。SITH-1は嗅球に発現し、中枢神経系やホルモン系に影響することが考えられるので、副鼻腔炎の有無や視床下部ホルモンの発現を検討する。

Research Products

• [Journal Article] Mild Lung Tuberculosis in a Patient Suffering from Status Epilepticus Caused by the Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH). (2017)
  • Author(s): Hashimoto M, Kuriiwa S, Kojima A, Shinhuku K, Sato A, Sasaki R, Hasegawa T, Ito A, Utsumi H, Yanagisawa H, Wakui H, Minagawa S, Kojima J, Numata T, Hara H, Araya J, Kaneko Y, Nakayama K, Kuwano K.
  • Journal Title: Intern Med. Volume: 56 Pages: 429-433
  • DOI: 10.2169/internalmedicine.56.7224.
  • Peer Reviewed / Open Access
• [Journal Article] Increased levels of prostaglandin E-major urinary metabolite (PGE-MUM) in chronic fibrosing interstitial pneumonia. (2017)
  • Author(s): Horikiri T, Hara H, Saito N, Araya J, Takasaka N, Utsumi H, Yanagisawa H, Hashimoto M, Yoshii Y, Wakui H, Minagawa S, Ishikawa T, Shimizu K, Numata T, Arihiro S, Kaneko Y, Nakayama K, Matsuura T, Matsuura M, Fujiwara M, Okayasu I, Ito S, Kuwano K.
  • Journal Title: Respir Med. Volume: 122 Pages: 43-50
  • DOI: 10.1016/j.rmed.2016.11.017.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Macroscopic inflammatory tracheal and endobronchial nodules in Sjögren's syndrome. (2016)
  • Author(s): Hara H, Kuwano K, Minagawa S, Numata T, Araya J, Nakayama K.
  • Journal Title: Thorax. Volume: - Pages: -
  • DOI: 10.1136/thoraxjnl-2016-209390
  • Peer Reviewed
• [Journal Article] Cellular senescence and autophagy in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). (2016)
  • Author(s): Kuwano K, Araya J, Hara H, Minagawa S, Takasaka N, Ito S, Kobayashi K, Nakayama K.
  • Journal Title: Respir Investig. Volume: 54 Pages: 397-406
  • DOI: 10.1016/j.resinv.2016.03.010.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Metformin attenuates lung fibrosis development via NOX4 suppression. (2016)
  • Author(s): Sato N, Takasaka N, Yoshida M, Tsubouchi K, Minagawa S, Araya J, Saito N, Fujita Y, Kurita Y, Kobayashi K, Ito S, Hara H, Kadota T, Yanagisawa H, Hashimoto M, Utsumi H, Wakui H, Kojima J, Numata T, Kaneko Y, Odaka M, Morikawa T, Nakayama K, Kohrogi H, Kuwano K.
  • Journal Title: Respir Res. Volume: 17 Pages: -
  • DOI: 10.1186/s12931-016-0420-x.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of pathogens by comprehensive real-time PCR versus conventional methods in community-acquired pneumonia in Japanese adults. (2016)
  • Author(s): Yoshii Y, Shimizu K, Morozumi M, Chiba N, Ubukata K, Uruga H, Hanada S, Wakui H, Ito S, Takasaka N, Minagawa S, Kojima J, Numata T, Hara H, Kawaishi M, Saito K, Araya J, Kaneko Y, Nakayama K, Kishi K, Kuwano K.
  • Journal Title: Infect Dis (Lond). Volume: 48 Pages: 782-788
  • DOI: 10.1080/23744235.2016.1193788.
  • Peer Reviewed
• [Journal Article] Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis. (2016)
  • Author(s): Kobayashi K, Araya J, Minagawa S, Hara H, Saito N, Kadota T, Sato N, Yoshida M, Tsubouchi K, Kurita Y, Ito S, Fujita Y, Takasaka N, Utsumi H, Yanagisawa H, Hashimoto M, Wakui H, Kojima J, Shimizu K, Numata T, Kawaishi M, Kaneko Y, Asano H, Yamashita M, Odaka M, Morikawa T, Nakayama K, Kuwano K.
  • Journal Title: J Immunol. Volume: 197 Pages: 504-516
  • DOI: 10.4049/jimmunol.1600265.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Evaluation of fatigue state with virus-related novel biomarkers in obstructive lung diseases (2016)
  • Author(s): Y. Kaneko, K. Nakayama, N. Saito, K. Tsubouchi, N. Sato, M. Yoshida, Y. Kurita, K. Kobayashi, H. Utsumi, H. Yanagisawa, Mi. Hashimoto, H. Wakui, S. Minagawa, A. Kojima, H. Hara, T. Numata, J. Araya, K. Kuwano, N. Kobayashi, K. Kondo
  • Organizer: European Respiratory Society International Congress 2016 (国際学会)
  • Place of Presentation: London, UK
  • Year and Date: 2016-09-03 – 2016-09-07
  • Int'l Joint Research
• [Presentation] Risk factors of postoperative pulmonary complications in bronchial asthma and COPD patients (2016)
  • Author(s): Takanori Numata, Katsutoshi Nakayama, Nayuta Saito, Kazuya Tsubouchi, Nahoko Sato, Masahiro Yoshida, Yusuke Kurita, Kenji Kobayashi, Hirofumi Utsumi, Haruhiko Yanagisawa, Mitsuo Hashimoto, Hiroshi Wakui, Shunsuke Minagawa, Jun Kojima, Hiromichi Hara, Jun Araya, Yumi Kaneko, Kazuyoshi Kuwano
  • Organizer: European Respiratory Society International Congress 2016 (国際学会)
  • Place of Presentation: London, UK
  • Year and Date: 2016-09-03 – 2016-09-07
  • Int'l Joint Research
• [Presentation] Involvement of ferroptosis in COPD pathogenesis (2016)
  • Author(s): Masahiro Yoshida (Tokyo, Japan), Masahiro Yoshida, Shunsuke Minagawa, Jun Araya, Hiromichi Hara, Nayuta Saito, Nahoko Sato, Kazuya Tsubouchi, Yusuke Kurita, Kenji Kobayashi, Saburo Ito, Takanori Numata, Yumi Kaneko, Katsutoshi Nakayama, Kazuyoshi Kuwano
  • Organizer: European Respiratory Society International Congress 2016 (国際学会)
  • Place of Presentation: London, UK
  • Year and Date: 2016-09-03 – 2016-09-07
  • Int'l Joint Research
• [Presentation] Pirfenidone attenuates myofibroblast differentiation during insufficient mitophagy (2016)
  • Author(s): Yusuke Kurita, Jun Araya, Hiromiti Hara, Shunsuke Minagawa, Nayuta Saito, Nahoko Sato, Kazuya Tubouchi, Masahiro Yoshida, Kenji Kobayashi, Takanori Numata, Yumi Kaneko, Katutoshi Nakayama, Kazuyoshi Kuwano
  • Organizer: European Respiratory society international congress 2016 (国際学会)
  • Place of Presentation: London, UK
  • Year and Date: 2016-09-03 – 2016-09-07
  • Int'l Joint Research
• [Presentation] Azithromycin Suppresses TGF-β-Induced Myofibroblast Differentiation By Promoting Proteasomal Degradation Of NOX4 (2016)
  • Author(s): K. Tsubouchi, J. Araya, H. Hara, S. Minagawa, N. Saito, N. Sato, M. Yoshida, Y. Kurita, K. Kobayashi, J. Kojima, T. Numata, Y. Kaneko, K. Nakayama, T. Morikawa, K. Kuwano,
  • Organizer: American Thoracic Society 2016 International Conference
  • Place of Presentation: San francisco, USA
  • Year and Date: 2016-05-13 – 2016-05-18
• [Presentation] Involvement Of PARK2-Mediated Mitophagy In Idiopathic Pulmonary Fibrosis Pathogenesis (2016)
  • Author(s): Kobayashi K, Araya J, Hara H, Minagawa S, Yoshida M, Tsubouchi K, Kadota T, Saito N, Sato N, Kurita Y, Ito S, Kojima J, Numata T, Kaneko Y, Asano H, Yamashita M, Odaka M, Morikawa T, Nakayama K, Kuwano K,
  • Organizer: American Thoracic Society 2016 International Conference
  • Place of Presentation: San francisco, USA
  • Year and Date: 2016-05-13 – 2016-05-18
  • Int'l Joint Research
• [Presentation] Involvement Of Lamin B1 In COPD Pathogenesis (2016)
  • Author(s): Saito N, Araya J, Ito S, Kadota T, Yoshida M, Sato N, Tsubouchi K, Kurita Y, Kobayashi K, Minagawa S, Hara H, Utsumi H, Yanagisawa H, Hashimoto M, Wakui H, Kojima J, Numata T, Kaneko Y, Morikawa T, Nakayama K, Kuwano K,
  • Organizer: American Thoracic Society 2016 International Conference
  • Place of Presentation: San francisco, USA
  • Year and Date: 2016-05-13 – 2016-05-18
• [Presentation] Metformin Suppresses Myofibroblast Differentiation By Inhibition Of Nox4-Mediated Smad Signaling (2016)
  • Author(s): N. Sato, N. Takasaka, M. Yoshida, S. Minagawa, J. Araya, N. Saito, K. Tsubouchi, Y. Kurita, K. Kobayashi, H. Hara, J. Kojima, T. Numata, Y. Kaneko, K. Nakayama, T. Morikawa, K. Kuwano.
  • Organizer: American Thoracic Society 2016 International Conference
  • Place of Presentation: San francisco, USA
  • Year and Date: 2016-05-13 – 2016-05-18
  • Int'l Joint Research
• [Book] Annual Review呼吸器2016. III. 診断の進歩 1. IGRAの臨床的重要性. (2016)
  • Author(s): 金子 有吾, 中山 勝敏, 桑野 和善.
  • Total Pages: 238
  • Publisher: 中外医学社