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Prophylactic and therapeutic strategy based on the molecular pathology of septic disseminated intravascular coagulation (DIC)

Research Project

Project/Area Number 17K08586
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionHealth Sciences University of Hokkaido (2019)
University of Toyama (2017-2018)

Principal Investigator

HATTORI Yuichi  北海道医療大学, その他, 客員教授 (50156361)

Co-Investigator(Kenkyū-buntansha) 大橋 若奈  富山大学, 学術研究部医学系, 助教 (50381596)
冨田 賢吾  富山大学, 大学院医学薬学研究部(医学), 助教 (20758213)
鈴木 登紀子  富山大学, 大学院医学薬学研究部(医学), 助教 (10415531)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords敗血症 / 播種性血管内凝固 / 転写因子 / 薬理学 / 転与因子
Outline of Final Research Achievements

We used the cecal ligation and puncture (CLP)-induced sepsis mouse model. In septic mice, the mRNA expression levels of tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) were greatly increased. In addition, the number of platelets in CLP-induced septic mice were markedly reduced and prothrombin time was significantly prolonged in CLP mice in comparison with controls. These results imply that CLP-induced sepsis is a relevant model of sepsis-associated disseminated intravascular coagulation (DIC). Transfection of NF-κB decoy oligodeoxynucleotides via intravenous injection, when given 1 h after CLP, resulted in a striking reduction in the DNA binding of NF-κB in lungs at 6 h and strongly inhibited elevations in blood levels of pro-inflammatory cytokines in CLP mice. However, NF-κB decoy transfection failed to affect the changes in measures as DIC in CLP mice, suggesting no involvement of the transcription factor NF-κB in the molecular mechanisms underlying septic DIC.

Academic Significance and Societal Importance of the Research Achievements

本研究により,盲腸結紮穿孔敗血症マウスは敗血症性DIC病態を研究するうえでよいモデルであることを明らかにした。本研究は,敗血症によるDICの分子病態機構の解明に新たな展開を与えるとともに,現時点で確立されたよい治療法の全くない本病態において,新たなDIC発症予防の開発を模索していくうえでも意義のある研究となったと考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (12 results)

All 2020 2019 2018 2017

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 1 results) Presentation (5 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

  • [Journal Article] Editorial: G protein-coupled receptor kinases (GRKs) and β-arrestins: New insights into disease regulators2020

    • Author(s)
      Yuichi Hattori, Martin C. Michel
    • Journal Title

      Forontiers in Pharmacology

      Volume: 10 Pages: 1654-1654

    • DOI

      10.3389/fphar.2019.01654

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 敗血症病態における血管内皮細胞の活性化と機能障害2019

    • Author(s)
      服部裕一、服部貢士、松田直之
    • Journal Title

      血管

      Volume: 42 Pages: 9-16

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Different involvement of the MAPK family in inflammatory regulation in human pulmonary microvascular endothelial cells stimulated with LPS and IFN-γ2018

    • Author(s)
      Suzuki T, Sakata K, Mizuno N, Palikhe S, Yamashita S, Hattori K, Matsuda N, Hattori Y
    • Journal Title

      Immunobiology

      Volume: 223 Issue: 12 Pages: 777-785

    • DOI

      10.1016/j.imbio.2018.08.003

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Anti-inflammatory properties of cilostazol: Its interruption of DNA binding activity of NF-κB from the Toll-like receptor signaling pathways2018

    • Author(s)
      Sakamoto T, Ohashi W, Tomita K, Hattori K, Matsuda N, Hattori Y
    • Journal Title

      Int Immunopharmacol

      Volume: 62 Pages: 121-131

    • DOI

      10.1016/j.intimp.2018.06.021

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Nucleic-acid based gene therapy approaches for sepsis2018

    • Author(s)
      Hattori Y, Hattori K, Suzuki T, Palikhe S, Matsuda N
    • Journal Title

      Eur J Pharmacol

      Volume: 833 Pages: 403-410

    • DOI

      10.1016/j.ejphar.2018.06.031

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cardioprotective and functional effects of levosimendan and milrinone in mice with cecal ligation and puncture-induced sepsis2018

    • Author(s)
      Yamashita S, Suzuki T, Iguchi K, Sakamoto T, Tomita K, Yokoo H, Sakai M, Misawa H, Hattori K, Nagata T, Watanabe Y, Matsuda N, Yoshimura N, Hattori Y
    • Journal Title

      Naunyn Schmiedebergs Arch Pharmacol

      Volume: 391 Issue: 9 Pages: 1021-1032

    • DOI

      10.1007/s00210-018-1527-z

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Recent advances in the pathophysiology and molecular basis of sepsis-associated organ dysfunction: Novel therapeutic implications and challenges2017

    • Author(s)
      Yuichi Hattori, Kohshi Hattori, Tokiko Suzuki, Naoyuki Matsuda
    • Journal Title

      Pharmacology & Therapeutics

      Volume: 177 Pages: 56-66

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 敗血症性急性肺傷害の病態メカニズムと新たな治療戦略2020

    • Author(s)
      服部裕一
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] STAT3 decoy oligodeoxynucleotides improve end-organ tissue injury and survival in septic mice2020

    • Author(s)
      Naoyuki Matsuda, Samar Imbaby, Kohshi Hattori, Yuichi Hattori
    • Organizer
      Experimental Biology 2020
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 敗血症モデルマウスにおける各種デコイ核酸を用いた遺伝子治療2019

    • Author(s)
      冨田賢吾,服部裕一
    • Organizer
      第92回日本薬理学会年会(シンポジウム:感染・炎症システムを対象とした定量生命科学研究の最前線と創薬への新展開)
    • Related Report
      2018 Research-status Report
  • [Presentation] 盲腸結紮穿刺誘発性敗血症マウスモデルにおける播種性血管内凝固症候群(DIC)2019

    • Author(s)
      坂本卓弥,Samar Imbaby,冨田賢吾、服部裕一
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Histamine as a potential mediator that actively promotes the development of organ injury in sepsis2017

    • Author(s)
      Yuichi Hattori
    • Organizer
      1st Joint Meeting of the European Histamine Research Society and the Japanese Histamine Research Society
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited

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Published: 2017-04-28   Modified: 2021-02-19  

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