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Development of measurement for hepatic isc hemia-repetfusion in jiry accoidirg to are gulation of activin-follistin system

Research Project

Project/Area Number 18591516
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionThe University of Tokushima

Principal Investigator

MORINE Yuji  The University of Tokushima, University Medical and Dental Hospital, assistant professor (60398021)

Co-Investigator(Kenkyū-buntansha) IMURA Satoru  The University of Tokushima, University Medical and Dental Hospital, assistant professor (90380021)
SHIMADA Mitsuo  The University of Tokushima, Institute of Health Bioscience, Guraduate School, professor (10216070)
NAKAMURA Takanori  The University of Kagawa, Graduate School, professor (70183887)
MIYAKE Kotaro  The University of Tokushima, Institute of Health Bioscience, Guraduate School, researcher (20403727)
藤井 正彦  徳島大学, 医学部・歯学部附属病院, 助手 (20380040)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥270,000)
Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2006: ¥2,600,000 (Direct Cost: ¥2,600,000)
Keywordshepatic ischemia-renerfusioninjury / hepatic resection / liver transplantation / follistatin / activin / fluvacratin / inflamatory cylokine / real-time RT-PCR / fluvasatin / 肝虚血再灌流障害 / アクチビン / フォリスタチン / PCR / 免疫染色 / サイトカイン
Research Abstract

Background)
Ischemia-reperfusion injury to the liver are of clinical importance in humans after hemorrhagic and cardiogenic shock, liver surgery, or liver transplantation. It was reported that blockade of the action of activin with administration of follistatin accelerates recovery from ischemia renal injury by accelerating regeneration after ischemia. In this study we evaluated the role of activin-follistatin on hepatic ischemia reperfusion injury and develop the new measurement for hepatic ischemia reperfusion injury.
Method and Results)
1) Effects of preactivation by portal vein ligation on liver regeneration (assessment according to activin)
This study evaluated the effect of regenerating livers preactivated by PVL following massive hepatectomy. The mRNA expression levels of activin A and ActR II A were significantly higher in regenerating liver group than in normal liver group at late pahse. The regenerating liver preactivated by PVL is restricted late-phase liver regeneration after m … More assive hepatectomy.
2) Beneficial Effects of follistatin in hepatic ischemia reperfusion injury Total hepatic ischemia for 30 min was performed followed by reperfusion. Follistatin (1mg/ body) was administered at the time of reperfusion. Four of 5 animals died in control group within 3days after reperfusion, whereas 80% of animals survived in follistatin group (P<0.05). AST was significantly lower at 3 hr after reperfusion in follistatin group (P<0.05). LDH was also lower at 6 hr after reperfusion in follistatin group (P<0.05). Follistatin inhibited the mRNA expression of bA subunit of activin. Moreover the expression of IL-6, which is inflammatory cytokine, was suppressed at 6 hr after reperfusion (P<0.05).
3)Beneficial Effects of fluvastatin on Hepatic Ischemia-Reperfusion Injury
Rats were divided into 3 groups: fluvastatin group; oral administration of fluvastatin (20mg/kg/day)for 2 days before the operation, control group, sham group. Fluvastatin and control groups were given total hepatic warm ischemia for 30 min. After reperfusion, an expression of mRNA level of endotherial NO synthase (eNOS) and NOX4 was determined by reverse transcriptase (RT)-PCR, tumor necrosis factor- a (TNF-α)and interleukine-1 β(IL-1β) mRNA by real-time RT-PCR. In the fluvastatin group, the expression of eNOS mRNA was significantly higher, and NOX4 mRNA was significantly lower (p<0.05). Furthermore, the expression of inflammatory cytokines mRNA were suppressed in the fluvastatin group. In particular, TNF- α was significantly lower in the fluvastatin group (P<0.05).
4) Beneficial Effects of fluvastatin on Liver Microcirculation and Regeneration The liver regeneration rate in fluvastatin group was significantly higher at 72 hours after hepatectomy (p<0.05). Sinusoidal area in fluvastatin group was maintained histologicaly. Furthermore, the expression of-SMA protein in the liver was inhibited in fluvastatin group at 48 hours after hepatectomy.
Summary) We were not able to elucidate the regulation of liver regneration using activin, because we had difficulty with the purification of activin. In this study, we clarified the regulatory mechanism of hepatic ischemia-reperfusion injury and effect of several modulators including follistatin for hepatic ischemia-reperfusion injury using molecular biological method. Less

Report

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

    (29 results)

All 2008 2007 2006 Other

All Journal Article (12 results) (of which Peer Reviewed: 7 results) Presentation (17 results)

  • [Journal Article] Beneficial effects of herbal medicine Inchin-ko-to, on liver function and regeneration after hepatectomy in rats.2008

    • Author(s)
      Ogasawara T,
    • Journal Title

      Hepatol Res. (In press)

    • 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] Effects of preactivation by portal vein ligation on liver regeneration following massive hepatectomy in rats.2007

    • Author(s)
      Morine Y
    • Journal Title

      Hepatogastroenterology 54(76):

      Pages: 1216-1221

    • 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] Beneficial effects of hyperbaric oxygen pretreatment on massive hepatectomy model in rats.2007

    • Author(s)
      Mori H
    • Journal Title

      Transplantation. 84(12)

      Pages: 1656-1661

    • 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] Pharmacokinetics of Cyclosporine A After Massive Hepatectomy: A Hint for Small-for-Size, Graft in Living Donor Liver Transplation.2007

    • Author(s)
      Shinohara H
    • Journal Title

      Dig Dis Sci. 52(10)

      Pages: 2490-2496

    • 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] Effects of preactivation by portal vein ligation on liver regeneration following massive hepatectomy in rats2007

    • Author(s)
      Morine, Y
    • Journal Title

      Hepatogastroenterology 54(76)

      Pages: 1216-21

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Beneficial effects of hyperbaric oxygen pretreatment on massive hepatectomy model in rats2007

    • Author(s)
      Mori, H
    • Journal Title

      Transplantation 84(12)

      Pages: 1656-61

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Pharmacokinetics of Cyclosporine A After Massive Hepatectomy : A Hint for Small-for-Size Graft in Living Donor Liver Transplantation2007

    • Author(s)
      Shinohara, H
    • Journal Title

      Dig Dis Sci 52(10)

      Pages: 2490-6

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Effects of preactivation by portal vein ligation on liver regeneration following massive hepatectomy in rats.2007

    • Author(s)
      Morine Y
    • Journal Title

      Hepatogastroenterology 54(76)

      Pages: 1216-1221

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmacokinetics of Cyclosporine A After Massive Hepatectomy: A Hint for Small-for-Size Graft in Living Donor Liver Transplantation.2007

    • Author(s)
      Shinohara H
    • Journal Title

      Dig Dis Sci. 52(10)

      Pages: 2490-2496

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Beneficial effects of hyperbaric oxygen pretreatment on massive hepatectomy model in rats.2007

    • Author(s)
      Mori H
    • Journal Title

      Transplantation 84(12)

      Pages: 1656-1661

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 特集肝不全の各種病態と新しい治療の視点7.術後肝不全に対する治療法の選択2007

    • Author(s)
      居村 暁
    • Journal Title

      Surgery Frontier 14

      Pages: 160-168

    • Related Report
      2007 Annual Research Report
  • [Journal Article] Beneficial effects of herbal medicine Inchin-ko-to, on liver function and regeneration after hepatectomy in rats

    • Author(s)
      Ogasawara, T
    • Journal Title

      Hepatol Res (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 菌ちん蕎湯(ICKT)の肝再生に対する効果(第2報)2007

    • Author(s)
      森根 裕二
    • Organizer
      第37回日本創傷治癒学会
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-06
    • Related Report
      2007 Annual Research Report
  • [Presentation] 高圧酸素療法(HBO)によるpreconditioningの大量肝切除術後肝障害改善効果2007

    • Author(s)
      森 大樹
    • Organizer
      第62回日本消化器外科学会定期学術総会
    • Place of Presentation
      東京
    • Year and Date
      2007-07-18
    • Related Report
      2007 Annual Research Report
  • [Presentation] 高圧酸素療法は肝臓にheat shock proteinを誘導し、肝切除術後早期の肝障害を軽減する2007

    • Author(s)
      森 大樹
    • Organizer
      第43回日本肝臓学会総会
    • Place of Presentation
      東京
    • Year and Date
      2007-06-01
    • Related Report
      2007 Annual Research Report
  • [Presentation] 若手外科医の安全確実な肝葉切除を目指した術式標準化の工夫2007

    • Author(s)
      森根 裕二
    • Organizer
      第107回日本外科学会定期学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2007-04-12
    • Related Report
      2007 Annual Research Report
  • [Presentation] 大量肝切除術後におけるFluvastain投与の意義2007

    • Author(s)
      徳永 卓哉
    • Organizer
      第107回日本外科学会定期学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2007-04-11
    • Related Report
      2007 Annual Research Report
  • [Presentation] Usefullness of gemcitabine combined with 5-fluorouracil and cisplatin(GFP)in patients with advanced gallbladder carcinoma2007

    • Author(s)
      Morine Y,
    • Organizer
      First Biennial Congress of the Asian-Pacific Hepato-Panceato-Biliary Association.
    • Place of Presentation
      Fukuoka Japan
    • Year and Date
      2007-03-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Usefullness of gemcitabine combined with 5-fluorouracil and cisplatin (GFP) in patients with advanced gallbladder carcinoma2007

    • Author(s)
      Morine, Y
    • Organizer
      First Biennial Congress of the Asian-Pacific Hepato-Panceato-Biliary Association
    • Place of Presentation
      Japan
    • Year and Date
      2007-03-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] The role of thymidylate synthase(TS)and dihydropyrimidine dehydrogenas(DPD)expression in biliary tract carcinoma2007

    • Author(s)
      Morine Y,
    • Organizer
      American Hepato-Pancreato-Biliary Association(AHPBA)
    • Place of Presentation
      Las Vagas USA
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Beneficial Effects of Fluvastatin on massive hepatectomy in Rats.2007

    • Author(s)
      Takuya T
    • Organizer
      17th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists (IASGO)
    • Place of Presentation
      Romania
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Beneficial effects of hyperbaric oxygen preconditioning on liver injury after massive hepatectomyin rats.2007

    • Author(s)
      Mori H
    • Organizer
      13th Congress of the European Society for Organ Trans plantation (ESOT)
    • Place of Presentation
      Prague
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Beneficial Effects of Fluvastatin on massive hepatectomy in Rats2007

    • Author(s)
      Takuya, T
    • Organizer
      17th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists (IASGO)
    • Place of Presentation
      Romania
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Beneficial effects of hyperbaric oxygen preconditioning on liver injury after massive hepatectomyin rats2007

    • Author(s)
      Mori, H
    • Organizer
      13th Congress of the European Society for Organ Transplantation (ESOT)
    • Place of Presentation
      Prague
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Beneficial effects of the herbal medicine Inchin-ko-to on liver function and regeneration after massive hepatectomy in rats.2006

    • Author(s)
      Ogasawara T,
    • Organizer
      DDW2006 American Association for the Study of Liver Diseases
    • Place of Presentation
      Los Angeles USA
    • Year and Date
      2006-05-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Beneficial effects of the herbal medicine Inchin-ko-to on liver function and regeneration after massive hepatectomy in rats2006

    • Author(s)
      Ogasawara, T
    • Organizer
      DDW2006 American Association for the Study of Liver Diseases
    • Place of Presentation
      Los Angeles
    • Year and Date
      2006-05-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Surgical strategy for advanced gallbladder carcinoma according to invasive depth of the tumor2006

    • Author(s)
      Morine Y,
    • Organizer
      15th World Congress of The International Associasion of Surgeons and Gastroenterologists(IASG)
    • Place of Presentation
      Madrid Spain
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Surgical strategy for advanced gallbladder carcinoma according to invasive depth of the tumor2006

    • Author(s)
      Morine, Y
    • Organizer
      15th World Congress of The International Associasion of Surgeons and Gastroenterologists (IASG)
    • Place of Presentation
      Madrid Spain
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] The role of thymidylate synthase (TS) and dihydropyrimidine dehydrogenas(DPD) expression in biliary tract carcinoma

    • Author(s)
      Morine, Y
    • Organizer
      American Hepato-Pancreato-Biliary Association (AHPBA) Las Vagas
    • Place of Presentation
      USA
    • 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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