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The study of mechanism of liver cell injury induce by edotoxin shock and ischemia, and its clinical application

Research Project

Project/Area Number 10671116
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionHIROSHIMA UNIVERSITY

Principal Investigator

MARUBAYASHI Seiji  Hiroshima University, Medical Hospital, Associate Professor, 医学部・附属病院, 助教授 (80144814)

Co-Investigator(Kenkyū-buntansha) SUGINO Keizo  Hiroshima University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (80162882)
岡田 和郎  広島大学, 医学部, 大学院生
福馬 寿幸  広島大学, 医学部, 研究生
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordsendotoxin shock / liver injury / Nuclear factor -kB / TNF-α / lazaroid / Kupffer cells / cell injury / cytokine / エンドトキシン
Research Abstract

Lazaroid (21-aminosteroid) is a nonglucocorticoid steroid that was synthesized to inhibit lipid peroxidation without the glucocorticoid activity. The present study was undertaken to determine whether lazaroid could suppress pro-inflammatory gene up-regulation through inhibition of nuclear factor-kB (NF-kB) activation in Kupffer cells.
Lazaroid treatment significantly increased survival rates 48 hours after LPS injection and protected against LPS-induced liver injury in vivo, as indicated by the decreased hepatic lipid peroxidation, TNF-α, hepatic enzyme release, and neutrophil infiltration in the liver. Lararoid also showed inhibitory effects on NF-kB activation in the liver. In the experiment of Kupffer cells, lazaroid treatment suppressed the release of TNF-α in a dose dependent manner. Lazaroid also inhibited the increase of TNF mRNA expression and NF-kB activation in Kupffer cells 1 h and 30 min, respectively, after LPS addition. Furthermore, lazaroid treatment suppressed the degradation of IkB proteins in LPS-stimulated Kupffer cells.
These results suggest that lazaroid can suppress proinflammatory gene up-regulation through inhibition of NF-kB activation in Kupffer cells and that this is a promising new drug for the treatment of endotoxin shock.

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Marubayashi S. et al.: "Protective effect of monoclonal antibodies to adhesion molecules on rat liver ischemia-reperfusion injury."Transplant Proc.. 31. 1054 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 福馬寿幸 他: "エンドトキシン血症における細胞障害機構の研究、ラザロイドU-74389Gの保護効果"G.I.Research. 6. 322 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 丸林誠二 他: "特集、臓器移植の最前線、臓器移植の今後、臓器保存"最新医学. 53. 2232-2241 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukuma K. et al.: "Effect of lazaroid U74389G and methylprednisolone on endotoxin-induced shock in mice."Surgery. 125. 421-430 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 岡田和郎 他: "ラザロイドU74389Gのエンドトキシン誘発肝障害抑制作用について"G.I.Research. 7. 326 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 丸林誠二 他: "特集、活性酸素と臓器保存、肝保存におけるラジカル発生と脂質過酸化障害"低温医学. 25. 85-91 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okada K. et al.: "Effect of the 21-aminosteroid on nuclear factor-kB activation of Kupffer cells in endotoxin shock."Surgery. 127. 79-86 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Marubayashi S. et al.: "Ischemia-reperfusion injury of liver and therapeutic intervention."Hepatology Res.. 16. 233-253 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 丸林誠二: "保存臓器とviability判定法"Organ Biology. 7. 43-52 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Marubayashi S.: "Protective effect of monoclonal antibodies to adhesion molecules on rat liver ischemia-reperfusion injury."Trasnplant Proc. 31. 1054 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukuma K.: "Study of liver cell injury in endotoxemia. Protective effect of lazaroid U-74389G administration."G.I.Research. 6. 322 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Marubayashi S.: "Review Organ preservation"Saishinn Igaku. 53. 2232-2241 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukuma K.: "Effect of lazaroid U-74389G and methyl prednisolone on endotoxin-induced shock in mice."Surgery. 125. 421-430 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okada K.: "Inhibitory effect of Lazaroid U-74389G endotoxin-induced liver cell injury."G.I.Research. 7. 326 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Marubayashi S.: "Review, Active oxygen species and organ preservation. Free radical generation and lipid peroxide formation in liver preservation."Low Temp Med. 25. 85-91 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okada K.: "Effect of the 21-aminosteroid on nuclear factor-kB activation of Kupffer cells in endotoxin shock."Surgery. 127. 79-86 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Marubayashi S.: "Ischemia-reperfusion injury of liver and therapeutic intervention."Hepatology Res. 16. 233-253 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Marubayashi S.: "Viability assessment of preserved organ"Organ Biology. 7. 43-52 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okada K. et al.: "Effect of the 21-aminosteroid on nuclear factor-kB activation of Kupffer cells in endotoxin shock."Surgery. 127. 79-86 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Marubayashi S.: "Ischemia-reperfusion injury of liver and therapeutic intervention."Hepatology Res.. 16. 233-253 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 丸林誠二: "保存臓器とviability判定法"Organ Biology. 7. 43-52 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fukuma K: "Effect of lazaroid U74389G amd methyl prednisolone on endotoxininduced shock in mice"Surgery. 125. 421-430 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Marubayashi S: "Protective effect monoclonal antibodies to adhesion molecules on rat liver ischemia-reperfusion injuey"Transplant Proc. 31. 1054 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Okada K: "Effect of the 21-aminosteroid on nuclear factor-κB activation of Kupffer cells in endotoxin shock"Surgery. 127. 79-86 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 丸林誠二: "肝保存と肝虚血再灌流障害"今日の移植. 12. 582-587 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 丸林誠二: "特集、臓器移植の最前線、臓器保存" 最新医学. 53(10). 2232-2241 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 福馬寿幸: "エンドトキシン血症における細胞障害機構の研究、ラザロイドU-74389Gの保護効果" G.I.Research. 6. 322 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fukuma K: "Effect of lazaroid U74389G and methyl prednisolone on endotoxin-induced shock in mice" Surgery. in press.

    • Related Report
      1998 Annual Research Report
  • [Publications] Okada K: "Effect of lazaroid on TNF-α release and NF-κB activation of Kupffer cell in endotoxin-induced liver cell injury" Shock. 9(Suppl). 33 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Marubayashi S: "Effect of lazaroid U-74389G on expression of tumor necrosis factor-α and inducible nitric oxide synthase in endotoxin-induced shock in mice" Shock. 9(Suppl). 30 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okada K: "21-aminosteroid (lazaroid) inhibits TNF-α release from Kupffer cells in vitro" European Surgical Research. 30(Suppl). 115 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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