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Role of lipid mediators in hepatic sinusoidal obstruction syndrome

Research Project

Project/Area Number 18K16330
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 55020:Digestive surgery-related
Research InstitutionKitasato University

Principal Investigator

Ohkubo Hirotoki  北里大学, 医学部, 助教 (50406930)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords肝類洞閉塞症候群 / トロンボキサン / 類洞内皮 / 肝類洞閉塞 / 肝臓 / 類洞 / 内皮細胞 / 内皮 / 脂質メディエーター
Outline of Final Research Achievements

Sinusoidal obstruction syndrome (SOS) is a major complication of chemotherapy and hematopoietic stem cell transplantation. In this study, we explored the role of TP signaling in a monocrotaline (MCT)-induced mouse model of SOS. Relative to wild-type (WT) mice, TP-deficient (TP-/-) mice exhibited more severe MCT-liver injury, as indicated by elevated levels of alanine aminotransferase (ALT) and coagulative necrosis. TP expression co-localized with CD31-positive LSECs. MCT treatment caused LSEC destruction, concomitant with elevated expression of matrix metalloproteinases (MMPs) and adhesion molecules in WT mice, and LSEC damage was further exacerbated in TP-/- mice. Viability of isolated LSECs was lower in cells from TP-/- mice, whereas mRNA levels of MMPs and adhesion molecules were higher; U46619, a TxA2 agonist, reduced these levels in WT mice. These data suggest that TP signaling prevents injury by suppressing LSEC damage.

Academic Significance and Societal Importance of the Research Achievements

SOSの病態解明の基盤研究は大腸がん治療を安全に行うために必要である。これまでマウスではSOSモデルが確立されていなかったことから、申請者らのモデルは研究発展のために極めて有用なツールとなる。SOS発症には肝類洞内皮細胞のTP受容体シグナル発現が重要であることが示唆された。肝修復・肝再生の有効な治療方法の開発につながる可能性のほか、化学療法施行期間,肝切除までの休薬期間,肝予備能に応じた肝切除術式の選択などの判断基準を再考慮する契機となりうる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (9 results)

All 2020 2019 2018

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (5 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Risk Factors for Progression of Distal Deep Vein Thrombosis2020

    • Author(s)
      Fujioka Shunichiro、Ohkubo Hirotoki、Kitamura Tadashi、Mishima Toshiaki、Onishi Yoshihiko、Tadokoro Yuki、Araki Haruna、Matsushiro Takuya、Yakuwa Kazuki、Miyamoto Takashi、Torii Shinzo、Miyaji Kagami
    • Journal Title

      Circulation Journal

      Volume: 84 Issue: 10 Pages: 1862-1865

    • DOI

      10.1253/circj.CJ-20-0270

    • NAID

      130007907589

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2020-09-25
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regional thigh tissue oxygen saturation during cardiopulmonary bypass predicts acute kidney injury after cardiac surgery2020

    • Author(s)
      Sakaki Kenjiro、Kitamura Tadashi、Kohira Satoshi、Torii Shinzo、Mishima Toshiaki、Hanayama Naoji、Kobayashi Kensuke、Ohkubo Hirotoki、Miyaji Kagami
    • Journal Title

      Journal of Artificial Organs

      Volume: 23 Issue: 4 Pages: 315-320

    • DOI

      10.1007/s10047-020-01175-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thromboxane A(2) receptor signaling in endothelial cells attenuates monocrotaline-induced liver injury.2019

    • Author(s)
      Otaka F, Ito Y, Inoue T, Ohkubo H, Nishizawa N, Kojo K, Betto T, Yamane S, Narumiya S, Koizumi W, Majima M
    • Journal Title

      Toxicol Appl Pharmacol

      Volume: 381 Pages: 114733-114733

    • DOI

      10.1016/j.taap.2019.114733

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of microsomal prostaglandin E synthase-1 facilitates liver repair after hepatic injury in mice.2018

    • Author(s)
      Nishizawa N, Ito Y, Eshima K, Ohkubo H, Kojo K, Inoue T, Raouf J, Jakobsson PJ, Uematsu S, Akira S, Narumiya S, Watanabe M, Majima M.
    • Journal Title

      J Hepatol.

      Volume: S0168-8278(18) Issue: 1 Pages: 30126-30130

    • DOI

      10.1016/j.jhep.2018.02.009

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 肝類洞閉塞症候群におけるトロンボキサンA2受容体の役割について2020

    • Author(s)
      大高史聖、伊藤義也、井上 智仁、大久保博世、津留 世里、細野 加奈子、小泉 和三郎、馬嶋 正隆
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] RAMP1 signaling in hepatic macrophages plays a critical role in immune-mediated hepatitis2019

    • Author(s)
      伊藤義也、井上智仁、大高史聖、美島利昭、大久保博世、馬嶋正隆
    • Organizer
      日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] トロンボキサンA2受容体シグナルの肝類洞閉塞症候群における役割2019

    • Author(s)
      伊藤義也、大高史聖、大久保博世、馬嶋正隆
    • Organizer
      肝類洞壁細胞研究会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Prostaglandin E receptor subtype EP3 promotes liver repair after acute liver injury2019

    • Author(s)
      S Nakamoto, Y Ito, N Nishizawa, H Ohkubo, M Watanabe, M Majima.
    • Organizer
      第44回日本微小循環学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Role of endogenous PGE2 in liver repair after hepatic ischemia/reperfusion2018

    • Author(s)
      Yoshiya Ito, Nobuyuki Nishizawa, Koji Eshima, Hirotoki Ohkubo, Tomoyoshi Inoue, Hideki Amano, Masataka Majima.
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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