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ROLE OF OXIDATIVE STRESS IN THE MECHANISM OF HEPATIC DAMAGE

Research Project

Project/Area Number 02454237
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionKEIO UNIVERSITY

Principal Investigator

ISHII Hiromasa  KEIO UNIVERSITY SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 助教授 (20051500)

Co-Investigator(Kenkyū-buntansha) HAMAMATSU Hisayoshi  KEIO UNIVERSITY SCHOOL OF MEDICINE, INSTRUCTOR, 医学部, 助手 (00208597)
SUEMATSU Makoto  KEIO UNIVERSITY SCHOOL OF MEDICINE, INSTRUCTOR, 医学部, 助手 (00206385)
KATO Shinzo  KEIO UNIVERSITY SCHOOL OF MEDICINE, INSTRUCTOR, 医学部, 助手 (30177448)
柳沢 徹  慶應義塾大学, 医学部・消化器内科, 助手 (80191154)
Project Period (FY) 1990 – 1991
Project Status Completed (Fiscal Year 1991)
Budget Amount *help
¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1991: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1990: ¥6,000,000 (Direct Cost: ¥6,000,000)
KeywordsOxidative stress / Hepatic microcirculation / Carbon tetrachloride / Ischemic damage / Endotoxin / Nitric oxide / Xanthine oxidase / Digital image process / NADH自家蛍光 / redox state
Research Abstract

Oxidative stress in the perfused rat liver was attempted to be analyzed by digital microfluorography using a fluorescent probe for hydroperoxide, dichlorofluorescin (DCFH). DCFH is known to be oxidized by hydorperoxide to dichlorofluorescein (DCF). Hepatic damage was also assessed by propidium iodide (PI), which is known to label the nuclei of non viable cells. Fluorescence of these probes was observed by fluorescence microscope equipped with silicon intensified target camera, and digitally processed by a image processor (ARGUS-200, Hamamatsu photonicus, Japan). Carbon tetrachloride induced oxidative stress was demonstrated in zone 3 by DCF fluorescence, followed by cell damage assessed by PI. These changes were prevented by SKF525A, an inhibitor of cytochrome P450, or promethazine, a radical scavanger. Low flow hypoxia increase DCF fluorescence in zone 2 first, and spread to zone 3. PI fluorescence was observed in zone 3 after increase in DCF fluorescence, suggesting midzonal oxidative stress preceed cell death. These changes were prevented by addition of allopurinol, a xanthine oxidase inhibitor, or PGE1.
Rhodamine 123(Rh123), an indicator of mitochondrial energization, was used to assess lipololysaccharide induced liver damage. Addition of LPS to perfusate decreased Rh123 fluorescence, and the change was blocked by LNMA, and in hibitor of nitric oxide synthetase. Mitochondrial dysfunction in hepatocytes induced by LPS was observed only in the presence of Kupffer cell, suggesting that nitric oxide released from activated Kupffer cell mediates hepatic mitochondiral dysfunction in LPS induced liver damage.

Report

(3 results)
  • 1991 Annual Research Report   Final Research Report Summary
  • 1990 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Suematsu M et al: "Intralobular heterogeneity of carbon tetrachloride-induced oxidative stress in perfused rat liver visualized by digital imaging fluorescence microsco" Lab Invest. 64. 167-173 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Kato S et al: "Histochemical and immunohistochemical evidence for hepatic zone3 distribution of alcohol dehydrogenase" Hepatology. 12. 66-69 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Suematsu M et al: "Midzonal oxidative stress preceeding cell death in hyroperfused rat liver" Gastroenterology. (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Kurose I et al: "Nitric oxide mediates lipopoly saccharide(LPS)-induced mitochondrial dysfunction in isolated perfused liver"

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Suzuki H et al: "Fluorescent probe analysis of oxidative stress,mitochondrial function and cell death in hyroperfused rat liver by digital microfluorography"

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] 石井 裕正ら: "アルコール性肝障害における脂質過酸化の関与" 医学のあゆみ. 153. 420-422 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Suematsu M. et al: "Intralobular heterogeneity of carbon tetrachloride-induced oxidative stress in perfused rat liver visualized by digital imaging fluorescence microscopy." Lab Invest. 64. 167-173 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Kato S. et al: "Histochemical and immunohistochemical evidence for hepatic zone 3 distribution of alcohol dehydrogenase." Hepatology. 12. 66-69 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Suematsu M. et al: "Midzonal oxidative stress preceeding cell death in hypoperfused rat liver." Gastroenterlogy. (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Kurose I. et al: "Nitric oxide mediates lipopolysaccharide(LPS)-induced mitochondrial dysfunction in isolated perfused liver."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Kato S. et al: "Intralobular heterogeneity of NADH levels and its increase by ethanol."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Suzuki H. et al: "Fluorescent probe analysis of oxidative stress, mitochondiral function and cell death in hypoperfused rat liver by digital microfluorography."

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Suematsu M.et al: "Intralobular heterogeneity of carbon tetrachlorideーinduced oxidative stress in perefused rat liver visualized by digital imaging fluorescence microscopy" Laboratory Investigation. 64. 167-173 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Suematsu M.et al: "Midzonal oxidative stress preceeding cell death in hypo perfused rat liver" Gastroenterology. (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] KuroseI.et al: "Nitric Oxide mediates Iipopolysaccharide (LPS)ーinduced mitochondrial dysfunction in isolated peerfused liver"

    • Related Report
      1991 Annual Research Report
  • [Publications] Kato S.et al: "Intralobular heterogeneity of NADH levels and its increase by ethanol"

    • Related Report
      1991 Annual Research Report
  • [Publications] Suzuki H.et al: "Fluorescent probe analysis of oxidative stress,mitochondiral function and cell death in hypo perfused rat liver by digital microfluorography"

    • Related Report
      1991 Annual Research Report
  • [Publications] Suematsu,M.,et al.: "Intralobular heterogeneity of carbon tetrachlorideーinduced oxidative stress in perfused ratliver visualized by digital imaging fluorescence microscopy." Lab.Invest. 64. (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] Suematsu,M.,et al.: "Microtopographic analysis of oxidative stress in organ microcirculatory units." Adv.Exp.Med.Biol.(1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 末松 誠: "血管内皮細胞障害とフリ-ラジカル" 病理と臨床. 9. 65-70 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] Suematsu,M.,et al.: "Midzonal oxidative stress preceding cell death in hypoperfused rat liver." J.Clin.Invest.

    • Related Report
      1990 Annual Research Report
  • [Publications] 石井 裕正ら: "アルコ-ル性肝障害における脂質過酸化の関与ーエタノ-ル摂取に伴う酸素ストレスの機序ー" 医学のあゆみ. 153. 420-422 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Kato,S.,et al.: "Histochemical and immunohistochemical evidence for hepatic zone 3 distribution of alcohol dehydrogenase in rats." Hepatology. 12. 66-69 (1990)

    • Related Report
      1990 Annual Research Report

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Published: 1990-04-01   Modified: 2016-04-21  

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