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Beneficial or deleterious role of nitric oxide in the liver

Research Project

Project/Area Number 11470491
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionKansai Medical University

Principal Investigator

OKUMURA Tadayoshi  Kansai University, Faculty of Engineering, Associate Professor, 医学部, 助教授 (80113140)

Co-Investigator(Kenkyū-buntansha) TAKETANI Shigeru  Kyoto institute of Technology, Biotechnology, Associate Professor, 繊維学部, 助教授 (20121949)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2001: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2000: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1999: ¥5,700,000 (Direct Cost: ¥5,700,000)
Keywordshepatocyte / inducible nitric oxide synthase / interleukin 1β / nuclear factor-kB / nitric oxide / liver injury / インターメイキン1β / 一酸化窒素合成酵素 / 低酸素 / 酸化フェニルアルシン / Hypoxia-response element / ミトコンドリア機能障害 / 免疫抑制剤FK506 / シクロスポリンA
Research Abstract

Under the pathological conditions, in flammatory cytokines including nterleukin 1β (IL-1β) and tumore necrosis factor a induce an excess amount of nitric oxide (NO) production via the induction of inducible nitric oxide synthase (iNOS) in parenchym al liver cells (hepatocytes). NO has beep shown to exert either beneficial or deleterious actions in liver failure. However, regulation mechanism of iNOS induction through nuclear factor NF-_kB remains to be established.
In this study, we found details of regulation mechanism by endogenous or exogenous factors, where iNOS induction is inhibited or enhanced in primary cultures of rat hepatocytes. Nuclear factor C/EBPβ has been found to be associated with NF-KB presumably on the KB site of iNOS promoter, resulting in an acceleration of the transactivation activity. We also found that a vicinalthiol residue in NF-KB molecule (p50/p65), has a crucial role on its DNA binding. Experiment with ischemia/reperfusion revealed that hpypoxia inhibited iNOS induction, but had no influence on NF-KB activation (translocation to the nucleus and DNA binding at _kB site), suggesting that there exists a novel pathway (factor), hich is necessary to activate the transactivation of iNOS promoter in addition to NF-KB involving pathway. It seems that IL-lb has such signaling pathway in parallel with NF-KB activation at the downstream of its type I IL-1 receptor. Further investigation is needed to identify an additional signal on iNOS induction in hepatocytes. Such studies may provide the foundation for novel pharmacological approaches to reduce liver injury.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] Tu, W.: "An enhancement of nitric oxide production regulates energy metabolism in rat hepatocytes after a partial hepatectomy"J. Hepatol. 30. 944-950 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaibori, M.: "Immunosuppressant FK506 inhibits inducible nitric oxide synthase gene expression at a step of NF-kB activation in rat hepatocytes"J. Hepatol. 30. 1138-1145 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Oda, M.: "Vicinal dithiol-binding agent, phenylarsine oxide, inhibits iNOS gene expression at a step of NF-kB DNA binding in hepatocytes"J. Biol. Chem.. 275. 4369-4373 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Inoue, T.: "Hypoxia and heat inhibit inducible nitric oxide synthase gene expression by different mechanisms in rat hepatocytes. Hepatology"Hepatology. 32. 1037-1044 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaibori, M.: "FK506, but not cyclosporin A, prevents mitochondrial dysfunction during hypoxia in rat hepatocytes"Life Sci.. 69. 17-26 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaibori, M.: "Exogenously administered HGF-activator augments liver regeneration through the production of biologically active HGF"Biochm. Biophys. Res. Commun.. 290. 475-481 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 奥村忠芳: "実験材料の調整:初心者のための研究室実験マニュアル(河本圭司 編集)"金芳堂、京都. 41-75 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tu, W.: "An enhancement of nitric oxide production regulates energy metabolism in rat hepatocytes after a partial hepatectomy"J Hepatol. 30. 944-950 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaibori, M.: "Immunosuppresant FK506 inhibits inducible nitric oxide synthase gene expression at a step of NF-kB activation in rat hepatocytes"J Hepatol. 30. 1138-1145 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Oda, M.: "vVicinal dithiol-binding agent, phenylarsine oxide, inhibits iNOS gene expression at a step of NF-kB DNA binding in hepatocytes"J Biol Chem.. 275. 4369-4373 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ioue, T.: "Hypoxia and heat inhibit inducible nitric oxide synthase gene expression by different mechanisms in rat hepatocytes"Hepatology. 32. 1037-1044 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaibori, M.: "FK506, but not cyclosporin A, prevents mitochondrial dysfunction during hypoxia in rat hepatocytes"Life Sci.. 69. 17-26 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaibori, M.: "Exogenously administered HGF-activator augments liver regeneration through the production of biologially active HGF"Biochem Biophys Res Commun. 290. 475-481 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kaibori, M.: "FK506, but not cyclosporin A, prevents mitochondrial dysfunction during hypoxia in rat hepatocytes"Life Sci.. 69. 17-26 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yasuda, K.: "Platelet-activating factor acetyihydrolase isoforms I and II in human uterus. Comparisons with pregnant uterus and myoma"Biol. Reprod.. 64. 339-344 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Inoue, M.: "High density 0-glycosylation of the MUC2 tandem repeat unit by N-acetylgalactosaminyltransferase-3 in colonic adenocarcinoma extracts"Cancer Res.. 61. 950-956 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Oyaizu, H.: "Proteasome inhibitor 1 enhances paclitaxel-induced apoptosis in human lung adenocarcinoma cell line"Oncol. Rep.. 8. 825-829 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato, Y.: "Effect of epidermal growth factor on intestinal adaptation after allogeneic small bowel transplantation in rats"Lif Sci.. 70. 809-819 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kaibori, M.: "Exogenously administered HGF-activator augments liver regeneration through the production of biologically active HGF"Biochem. Biophys. Res. Commun.. 290. 475-481 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 海堀昌樹: "今日の移植14"肝臓の低酸素障害に対するFK506の保護効果. 61-66 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Oda M.: "Vicinal dithiol-binding agent, phenylarsine oxide, inhibits iNOS gene expression at a step of NF-kB DNA binding in hepatocytes."J Biol Chem. 275. 4369-4373 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sakakura Y.: "Recombinant human hepatocyte growth factor protects the liver against hepatic ischemia and reperfusion injury in rats."J Surg Res. 92. 261-266 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kato Y.: "Epidermal growth factor enhances the intestinal adaptation of small bowel allografts in the postoperative period."Transplant Proc. 32. 1253-1254 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Inoue T.: "Hypoxia and heat inhibit inducible nitric oxide synthase gene expression by different mechanisms in rat hepatocytes."Hepatology. 32. 1037-1044 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kaibori M.: "Role of hepatocyte growth factor in hepatic ischemia and reperfusion injury."Transplant Proc. 32. 2285-2286 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kaibori M.: "FK506, but not cyclosporin A, prevents mitochondrial dysfunction during hypoxia in rat hepatocytes."Life Sci. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 奥村忠芳: "初心者のための研究室実験マニュアル(河本圭司 編集)"実験材料の調製. 41-75 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kaibori,M.: "Immunosuppressont FK506 inhibits iNOS gone expression at a step of NFkBactivation in rat hepatocytes"J.Hepatol.. 30. 1138-1145 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tu,W.: "An enhancement of NO production regulates energy metabolism in rat hepatocytes"J.Hepatol.. 30. 944-950 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kaibori,M.: "Inhibition of iNOS induction by FK506,but not cyclosporin A,in rat hapatocytes"Transplant.Proc. 31. 804-805 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 西澤 幹雄: "特集「NOと治療薬」7.NOと抗炎症薬"治療学. 33. 953-956 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 伊藤誠二: "一酸化窒素の光と影"日本救命医療研究会雑誌. 13. 1-9 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2021-11-22  

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