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Investigation of Dysregulated Immunothrombosis in inflammatory diseases and development of a new therapeutic tool.

Research Project

Project/Area Number 15K09459
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionKeio University

Principal Investigator

Hirahashi Junichi  慶應義塾大学, 医学部(信濃町), 講師 (70296573)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsヒストン / 好中球 / 血小板 / Mac-1 / CD40L / PSGL-1 / 炎症 / 血栓 / 糖尿病 / Immunothrombosis
Outline of Final Research Achievements

Histones are released from damaged host cells and act as mediators of inflammation-related thrombosis. Platelet activation and aggregation is responsible for histone-induced thrombosis, but neutrophil-dependent mechanisms are still unclear. Immunodepletion of neutrophils and genetic ablation of Mac-1 protected mice from histone-induced pulmonary thromboembolism and prolonged survival. We utilized turbidimetric technic which estimates plasma clot production induced by interaction between human platelets and neutrophils in the presence of plasma in vitro. Histones augmented the plasma clot production in Mac-1-dependent manner and enhanced platelet-neutrophil complex formation which is inhibited by anti-Mac-1 antibody. Furthermore histones could directly activate Mac-1 besides through platelets . In conclusion, histones induces Mac-1-dependent thromboembolism through neutrophil-platelet interaction, which is a new therapeutic target for inflammation-induced thrombosis.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (9 results)

All 2018 2017 2016 2015 Other

All Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (4 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Book (2 results) Remarks (1 results)

  • [Journal Article] Macrophage extracellular chromatin release induced by Mac-1 mediated platelet-macrophage interactions triggers acute kidney injury in rhabdomyolysis.2018

    • Author(s)
      Okubo K, Kurosawa M, Kamiya M, Urano Y, Suzuki A, Yamamoto K, Hase K, Homma K, Sasaki J, Miyauchi H, Hoshino T, Hayashi M, Mayadas TN, Hirahashi J.
    • Journal Title

      Nat. Med.

      Volume: 24 Issue: 2 Pages: 232-238

    • DOI

      10.1038/nm.4462

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Lactoferrin Suppresses Neutrophil Extracellular Traps Release in Inflammation2016

    • Author(s)
      Okubo K, Kamiya M, Urano Y, Nishi H, Herter JM, Mayadas T, Hirohama D, Suzuki K, Kawakami H, Tanaka M, Kurosawa M, Kagaya S, Hishikawa K, Nangaku M, Fujita T, Hayashi M, Hirahashi J.
    • Journal Title

      EBioMedicine

      Volume: 10 Pages: 204

    • DOI

      10.1016/j.ebiom.2016.07.012

    • URL

      https://localhost/en/publications/8cb82691-23b7-40ca-8ff0-6762123351bd

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Histone requires Mac-1 (CD11b/CD18)-mediated neutrophil-platelet interaction to induce thromboembolism2017

    • Author(s)
      Miho Kurosawa ,Koshu Okubo ,Osamu Yamazaki ,Matsuhiko Hayashi , Junichi Hirahashi
    • Organizer
      第18回国際血管炎・ANCA学会
    • Place of Presentation
      伊藤国際学術研究センター(東京都文京区)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 糖尿病における易血栓性はhistone感受性の亢進を背景としたimmunothrombosis制御異常に起因する2016

    • Author(s)
      黒澤美穂、大久保光修、山崎 修、下澤達雄、南学正臣、林 松彦、平橋淳一
    • Organizer
      第59回日本腎臓学会総会
    • Place of Presentation
      パシフィコ横浜(神奈川県西区)
    • Year and Date
      2016-06-17
    • Related Report
      2016 Research-status Report
  • [Presentation] Lactoferrin modulates “Immunothrombosis” in inflammatory diseases2015

    • Author(s)
      Junichi Hirahashi
    • Organizer
      第12回国際ラクトフェリン学会
    • Place of Presentation
      ウエスティンナゴヤキャッスル(愛知県名古屋市西区)
    • Year and Date
      2015-11-03
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] ANCA血管炎・腎炎の免疫学と治療2015

    • Author(s)
      平橋淳一
    • Organizer
      第45回日本腎臓学会東部学術大会
    • Place of Presentation
      東京ミッドタウン(東京都港区)
    • Year and Date
      2015-10-03
    • Related Report
      2015 Research-status Report
    • Invited
  • [Book] 新膠原病・血管炎の腎障害2016

    • Author(s)
      大久保光修、平橋淳一
    • Publisher
      東京医学社
    • Related Report
      2016 Research-status Report
  • [Book] 医学のあゆみ2016

    • Author(s)
      山崎修、平橋淳一
    • Total Pages
      7
    • Publisher
      日本医学社
    • Related Report
      2015 Research-status Report
  • [Remarks] 慶應義塾大学医学部 総合診療科 HP

    • URL

      http://www.keio-generalmed.com/about

    • Related Report
      2015 Research-status Report

URL: 

Published: 2015-04-16   Modified: 2019-03-29  

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