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Modulation of intracellular signal pathway for preventing liver damage after extended hepatectomy

Research Project

Project/Area Number 18591497
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionAkita University

Principal Investigator

UCHINAMI Hiroshi  Akita University, School of medicine, Assistant Professor (40400486)

Co-Investigator(Kenkyū-buntansha) IIDA Masatake  Akita University, School of medicine, Assistant Professor (90372325)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,070,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥570,000)
Fiscal Year 2007: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsLiver Sureer / Stress Response
Research Abstract

Ischemia-reperfusion (I/R) injury of the liver is one of major problems after extended hepatectomy or liver transplantation. To perform operation much safer, some strategies to prevent I/R injury has been required.
Nrf2 is a transcription factor that protects cell and tissues from oxidative stress by activating protective antioxidant and detoxifying enzymes. It is likely that preoperative activation of Nrf2 in liver-consisting cells results in prevention of I/R injury of the liver. In this protocol, we evaluated whether Nrf2 activation confer the tolerance for I/R injury of the liver.
Oltipraz, 15-deoxy-Δ 12, 14-prostagrandine J2 (PGJ2), and diallyl sulfide (DAS) were used to confirm whether these drugs activate Nrf2 in liver-consisting cells. Liver epithelial cells and liver stellate cells were isolated from rat and mouse liver and cultured. Immunofluorescent assay revealed that Nrf-2 translocated into the nucleus immediately after stimulating by these drugs in both types of cells. The expression of HO-1 was also induced by PGJ2 in a dose dependent manner.
It has been reported that activation of stellate cells has detrimental effect during hepatic I/R. To evaluate the effect of PGJ2 on stellate cell activation, the mRNA expression of alpha smooth muscle actin and type I collagen was examined by real time PCR. PGJ2 significantly inhibited the expression of both genes, suggesting that PGJ2 effectively suppressed the activation of stellate cells.
Finally, the effect of PGJ2 on I/R injury was examined. C57/B16 mouse was used. We applied 70% ischemia model (60 min). PGJ2 was administrated intravenously via tail vein 3 hours before ischemia.
The increasing of AST/ALT level 3 and 6 hours after reperfusion was significantly suppressed by PGJ2. In addition, TUNEL assay revealed that apoptosis after I/R was also suppressed.
These data suggested that Nrf2 activation by PGJ2 may bring the beneficial effect in the field of liver surgery.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (11 results)

All 2007 2006

All Journal Article (9 results) (of which Peer Reviewed: 5 results) Presentation (2 results)

  • [Journal Article] Gene expression profiles during hepatic stellate cell activation in culture and in vivo2007

    • Author(s)
      De, minicis S.
    • Journal Title

      Gastroenterology 132(5)

      Pages: 1937-1946

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells2007

    • Author(s)
      Adachi, M.
    • Journal Title

      Gastroenterology 132(4)

      Pages: 1434-1446

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Gene expression profiles during hepatic stellate cell activation in culture and in vivo2007

    • Author(s)
      De minicis S
    • Journal Title

      Gastroenterology 132(5)

      Pages: 1937-1946

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells2007

    • Author(s)
      Adachi M
    • Journal Title

      Gastroenterology 132(4)

      Pages: 1434-1446

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Gene expression profiles during hepatic stellate cell activation in culture and in vivo2007

    • Author(s)
      De minicis S, Seki E, Uchinami H, 他
    • Journal Title

      Gastroenterology 132(5)

      Pages: 1937-1946

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells2007

    • Author(s)
      Adachi M, Osawa Y, Uchinami H, 他
    • Journal Title

      Gastroenterology 132(4)

      Pages: 1434-1446

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of MMP13 attenuates murine hepatic injury and fibrosis during cholestasis2006

    • Author(s)
      Uchinami, H.
    • Journal Title

      Hepatology 44(2)

      Pages: 420-429

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Loss of MMP13 attenuates murine hepatic injury and fibrosis during cholestasis2006

    • Author(s)
      Uchinami H
    • Journal Title

      Hepatology 44(2)

      Pages: 420-429

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Loss of MMP13 attenuates murine hepatic injury and fibrosis during cholestasis2006

    • Author(s)
      打波 宇
    • Journal Title

      Hepatology 44/2

      Pages: 420-429

    • Related Report
      2006 Annual Research Report
  • [Presentation] 肝幹細胞誘導による肝虚血耐性獲得の試み2007

    • Author(s)
      阿部ゆき
    • Organizer
      第107回日本外科学会定期学術総会
    • Place of Presentation
      大阪
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Acquisition of ischemic tolerance in the liver by induction of liver epithelial cells2007

    • Author(s)
      Abe Y
    • Organizer
      The 107th Annual Congress of Japan Surgical Society
    • Place of Presentation
      Osaka
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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