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Molecularbiological study for the role of sinusoidal cells in pathogenesis of liver disease.

Research Project

Project/Area Number 08407016
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionKeio University

Principal Investigator

ISHII Hiromasa  Keio University, School of Medicine, Professor, 医学部, 教授 (20051500)

Co-Investigator(Kenkyū-buntansha) HORIE Yoshinori  Keio University, School of medicine, Instructor, 医学部, 助手 (70229227)
KUROSE Iwao  Keio University, School of medicine, Instructor, 医学部, 助手 (50234604)
YOKOYAMA Hirokazu  Keio University, School of medicine, Assistant Prof., 保健管理センター, 講師 (70200920)
KATO Shinzo  Keio University, School of medicine, Assistant Prof., 医学部, 講師 (30177448)
MIURA Soichiro  Keio University, School of medicine, Ex-Associate Professor, 医学部(平成8,9年分担), 前助教授 (50138012)
中村 雄二  慶応義塾大学, 医学部, 助手 (80276253)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥27,200,000 (Direct Cost: ¥27,200,000)
Fiscal Year 1998: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1997: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1996: ¥20,400,000 (Direct Cost: ¥20,400,000)
KeywordsKupffer cells / Sinusoidal cells / Mitochondrion / NO / TNF-alpha / NF-kB / Endotoxin / Alcohol / TNFα / NF-kB / 肝疾患 / 接着因子 / カルシウム / NF-κB / アポトーシス
Research Abstract

Aim of this study is to investigate the role of sinusoidal cells, especially Kupffer cells, on various experimental liver injuries. Oxidative stress and release of nitric oxide by Kupffer cells analyzed in relation to hepatocyte injury and apoptosis.
The metabolic changes in hepatoma cells co-cultured with isolated rat Kupffer cells were investigated. NO from Kupffer cells induced mitochondrial dysfunction in tumor cells followed by membrane barrier dysfunction in the liver sinusoid. Increased expression of iNOS and iNOS mRNA in the Kupffer cells co-cultured with hepatoma cells was shown. It is also suggested that CD 18/ICAM-1 dependent cell-to-cell interaction with hepatoma cells causes calcium mobilization and oxidative activation of NF-kB , which may lead to the increase production of NO in Kupffer cells. Kupffer cells stimulated by lipopolysaccharides was also shown to release NO and TNF-a, which resulted in mitochondrial injury in hepatocyte.
Experimental model of alcoholic liver damage in perfused liver showed that superoxide anion was released from Kupffer cells into sinusoid by ethanol administration, and lead to damage in sinusoidal endothelial cells. Kupffer cells were shown to metabolize ethanol by cytochrome P450 2E1. After chronic ethanol feeding, LPS elicited microcirculatory disturbance with smaller dose. Expression of adhesion molecules on leukocytes, and adhesion of leukocytes in sinusoid was shown.

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 results)

  • [Publications] Ishii H, et al.: "Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stress." J.Gastroenterol. Hepatol.12(9-10). S272-282 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurose I, et al.: "CD18/ICAM-1-dependent oxidative NF-kB activation leading to nitric oxide production in rat Kupffer cells cocultured with syngeneic hepatoma cells." J Clin Invest. 99(3). 867-878 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohki E, Kato S, et al.: "Chronic ethanol consumption enhances endotoxin induced hepatic sinusoidal leukocyte adhesion." Alcoholism : Clin Exp Res. 20. 350A-355A (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Horie Y, Kato S, et al: "Effect of lipopolysaccharides on erythrocyte flow velocity in rat liver." J.Gastroenterol. 32. 783-790 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokoyama H, et al: "Splenectomy attenuates superoxide anion release into the hepatic sinusoids after lipopolysaccharide challenge." J.Hepatology. (in press). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurose I, et al: "Oxidative stress on mitochondria and cell membrane of cultured rat hepatocytes and perfused liver exposed to ethanol." Gastroenterology. 112(4). 1331-1343 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohki E,Kato S,Horie Y,Mizukami T,et al.: "Chronic ethanol consumption enhances endotoxin induced hepatic sinusoidal leukocyte adhesion. Alcoholism" Clin Exp Res. 20. 350A-355A (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurose I,Miura S,Higuchi H,et al: "Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes : Roles for tumor necrosis factor-alpha" Hepatology. 24 (5). 1185-1192 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Higuchi H,Kurose I,Kato S,Miura S,Ishii H: "Ethanol-induced oxidative stress and apoptosis. Alcoholism" Clin Exp Res. 20 (9). 340A-346A (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fukumura D,Yonei Y,Kurose I,et al: "Role of nitric oxide in Kupffer cell-mediated hepatoma cell cytotoxicity in vitro and ex vivo" Hepatology. 24 (1). 141-149 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurose I,Higuchi H,Yonei Y,et al: "Rat Kupffer cell-derived nitric oxide suppresses proliferation and induce apoptosis of syngeneic hepatoma cells" Gastroenterology. 111 (4). 1058-1070 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurose I,Saito H,Miura S,et al: "CD18/ICAM-1-dependent oxidative NF-kB activation leading to nitric oxide production in rat Kupffer cells co-cultured with syngeneic hepatoma cells." J Clin Invest. 99 (3). 867-878 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurose I,Higuchi H,Miura S,et al: "Oxidative stress-mediated apoptosis of hepatocytes exposed to acute ethanol intoxication" Hepatology. 25(2). 368-378 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurose I,Higuchi H,Watanabe N,et al: "CD18/ICAM-1-dependent nitric oxidc production of Kupffer cells as a cause of mitochondrial dysfunction in hepatoma cells : Influence of chronic alcohol feeding." Free Radical Biology Medicine. 22 (1). 229-239 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Horie Y,Kato S,Ohki E,et al: "Effect of lipopolysaccharides on erythrocyte flow velocity in rat liver." J.Gastroenterol. 32. 783-790 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kurose I,Higuchi H,Kato S,et al: "Oxidative stress on mitochondria and cell membrane of cultured rat hepatocytes and perfused liver exposed to ethanol." Gastroenterology. 112 (4). 1331-1343 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ishii H,Kurose I,Kato S: "Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stress." J.Gastroenterol.Hepatol. 12 (9-10). S272-S282 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohki E,Kato S,Horie Y,et al: "Effect of chronic ethanol feeding on endotoxin-induced hepatic injury" Alcoholism : Clin Exp Res. 22. 129A-132A (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokoyama H,Fukuda M,Okamura S,et al: "Formation of superoxide anion in the hepatic sinusoid after lipopolysaccharide challenge" Alcoholism : Clin Exp Res. 22. 133A-136A (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mizukami T,Yokoyama H,Okamura Y,et al.: "Splenectomy attenuates superoxide anion release into the hepatic sinusoids after lipopolysaccharide challenge" J.Hepatology. (In press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nakamura Y,Yokoyama H,Okamura Y,et al: "Evidence for ethanol oxidation by Kupffer cell" Alcoholism : Clin Exp Res. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shinzo Kato et al: "Effect of Chronic Ethanol Feeding on Endotoxin-Induced Hepatic Injury" Alcoholism,Clin Exp Res. Vol.22・3. 129S-132S (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hirokazu Yokoyama et al: "Formation of Superoxide Anion in the Hepatic Sinusoid after Lipopolysaccharide Challenge" Alcoholism,Clin Exp Res. Vol.22・3. 133S-136S (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hirokazu Yokoyama et al: "Splenectomy attenuates superoxide anion release into the hepatic sinusoids after lipopolysaccharide challenge" J Hepatology.

    • Related Report
      1998 Annual Research Report
  • [Publications] Hirokazu Yokoyama et al: "Superoxide anion release into the hepatic sinusoid after an acuate ethanol challenge and its attenuation by Kupffer cell depletion." Alcoholism,Clin Exp Res.

    • Related Report
      1998 Annual Research Report
  • [Publications] Yuji Nakamura et al: "Evidence for ethanol oxidation by Kupffer Cells" Alcoholism,Clin Exp Res.

    • Related Report
      1998 Annual Research Report
  • [Publications] Hiromasa I: "Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stress" J Gastroenterology Hepatology. 12. S272-S282 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Iwao Kurose: "CD18/ICAM-1-dependent intric oxide production of Kupffer cells As a casuse of mitochondrial dysfunction in hepatoma cells" Free Radical Biology & Medicine. 22. 229-239 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Iwao Kurose: "Increased nitric oxide synthase activity as a cause of mitochondrial Dysfunction in rat hepatocytes : Roles for TNF α" Hepatology. 24. 1185-1192 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Iwao Kurose: "CD18/ICAM-1-dependent oxidative NF-kB activation leading to nitric oxide Production in rat Kupffer cells cultured with synergeneic hepatoma cells" J Clin Invest. 99. 867-878 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Iwao Kurose: "Oxidative stress-mediated apoptosis of hepatocytes exposed to acute ethanol intoxication" Hepatology. 25. 368-378 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Iwao Kurose: "Oxidative stress on mitochondria and cell membrane of Cultured rat hepatocytes and perfused liver exposed to ethanol" Gastroenterology. 112. 1331-1343 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fukumura D: "Role of nitric oxide in Kupffer cell-mediated hepatoma cell cytotoxicity in vitro and ex vivo." Hepatology. 24. 141-149 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kurose I: "Rat Kupffer cell derived nitric oxide suppress proliferation and induces apotosis of syn c hepatoma cells" Gastroenterology. 111. 1058-1070 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Saito H: "Kupffer cell-mediated mitochondrial dysfunction in hepatoma cells by production of nitric oxide and the involvement of ICAM-I/LFA-1 molecules" International Immunology. 8. 1165-1172 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kurose I: "Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes : Rule of tumor necrosis factor-α" Hepatology. 24. 1185-1192 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kurose I: "CD18/ICAM-1 dependent nitric oxide production of Kupffer cells as a cause of mitochondrial dysfunction in hepatoma cells" Free Radical Biology & Medicine. 22. 229-239 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kato S: "chronic ethanol feeding reduces anti-tumor cell activity of Kupffer cells." Alcoholism : Clin Exp Res. 20. 69A-72A (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 石井裕正: "Bio Scienceアポトーシス" 羊土社東京, 190-191 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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