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Immunological Study on the Mechanism of Acute Intrahepatic Cholestasis.

Research Project

Project/Area Number 01570408
Research Category

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

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionOsaka University Medical School

Principal Investigator

MIZOGUCHI Yasuhiro  Osaka City University Medical School, Associate Professor., 医学部, 助教授 (00094491)

Co-Investigator(Kenkyū-buntansha) NAKAJIMA Shinya  Osaka City University Medical School, Research Associate., 医学部, 助手 (50180287)
OKA Hiroko  Osaka City University Medical School, Research Associate., 医学部, 助手 (40169090)
SHIOMI Susumu  Osaka City University Medical School, Lecturer., 医学部, 講師 (30170848)
SEKI Shuichi  Osaka City University Medical School, Lecturer., 医学部, 講師 (50145778)
KUROKI Tetsuo  Osaka City University Medical School, Lecturer., 医学部, 講師 (30047328)
Project Period (FY) 1989 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1990: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1989: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordsintrahepatic cholestasis / cytokine / cholestatic factor / ursodeoxycholic acid / クロ-ン細胞 / 急性肝内胆汁うつ滞 / 催胆汁うつ滞因子 / ウルソデオキシコ-ル酸 / ジェニピン / パトリノシド / Caイオン / リンホカイン / クロ-ン化
Research Abstract

Intrahepatic cholestasis is frequently observed in drug-induced allergic hepatitis, even when liver cells are not remarkably injured. But little is known of the exact mechanisms causing the intrahepatic cholestasis in the disease. To study the immunopathogenesis of intrahepatic cholestasis, peripheral blood lymphocytes obtained from the patients were stimulated in vitro with a specific antigen. When the culture supernatants were injected into the mesenteric vein of normal rats, marked decrease in bile flow and the excretion of bile acid was demonstrated in many cases. Thus the sensitized lymphocytes produced a kind of lymphokin, a bile flow-decreasing factor, which we designated "cholestatic factor." For further investigation of this newly detected lymphokine, we conducted experimental studies on its functional mechanism both in vivo and in vitro. The main results obtained were following :
1. Tuberculin-sensitized guinea pigs were intravenously injected with heat-killed Propionibacteriu … More m acnes followed by an intravenous injection of purified protein derivatives 7 day later, resulting in the induction of intrahepatic cholestasis. Using this experimental model, the following results were obtained. 1) Both uptake and release of bile acid were inhibited in the hepatocytes prepared from the guinea pigs with cholestasis. 2) The results of the erythritol clearance method indicated that the decrease in bile flow observed in the cholestatic guinea pigs was mostly attributable to the reduced bile excretion from canaliculi. 3) The decrease in the bile acid-independent bile flow was caused by the decrease in bile flow observed in the guinea pigs with cholestasis. 4) There was no change in the permeability of the intrahepatocellular tight junction of the hepatocytes of the cholestatic guinea pigs.
2. T-cell clone producing the cholestatic factor was established in order to study the characteristics of the cells which produce the cholestatic factor. 1) Five T-cell clones which produce the cholestatic factor were established from PPD-stimulated human peripheral blood mononuclear cells. 2) All of the established T cell clones were shown to be CD2^+, CD3^+, CD4^+, CD8^- and CD25^+ by flow cytometrical analysis. 3) These cloned T cells produced the cholestatic factor, IL-2 and IFNgamma, but not IL-4 or IL-4 or IL-6 when stimulated with PPD. 4) The reduction in bile flow was not induced, which a considerably large amount of IL-1, IL-2, IL-4, IL-6, TNF, or IFNgamma were injected into the mesenteric vein of rats. These results suggested that the cholestatic factor may be a novel lymphokine different from the known cytokines.
3. When ursodeoxycholic acid was injected into the mesenteric vein of rats with the cholestatic factor, the decrease in the excretion of bile flow and bile acid was significantly suppressed. Remarkable increase in bile flow was also noted, when ursodeoxycholic acid was administered to normal rats. These results suggested that ursodeoxycholic acid may be effective in the treatment of intrahepatic cholestasis. Less

Report

(3 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Mizoguchi Y,: "Choleretic effect of ursodoxycholic acid on experimentallyーinduced intrahepatic cholestasis" Osaka City Med J. 35. 83-91 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Mizoguchi Y,: "Effect of ursodeoxycholic acid on intrahepatic cholestasis" Osaka City Med J. 35. 71-82 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 木岡 清英: "催胆汁うっ滞因子の作用機構ー肝細胞内cAMP量に及ぼす催胆汁うっ滞因子の影響について" 日本消化器病学会雑誌. 86. 45-49 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yamada S: "Immunocyto chemical studies on cholestatic factor in human liver with or without cholestasis" Liver. 10. 129-136 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Shin T: "Study on the mechanism of an experimental immunological intrahepatic cholestasis model" Osaka City Med J.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kioka K: "The characters of cholestatic factor producing Tーcell clones" Osaka City Med J.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 溝口 靖紘: "“黄疸"病態生理の新しい視点" へるす出版, 12 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Mizoguchi Y, Mitajima K, Kioka K, Seki S Kobayashi K, Morisawa S: "Choleretic effects of ursodeoxycholic acid on experimentally-induced intrahepatic cholestasis" Osaka City Med J. 35. 83-91 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Mizoguchi Y, Kioka K, Seki S, Kobayashi K, Morisawa S: "Effects of ursodeoxycholic acid on intrahepatic cholestasis." Osaka City Med J. 35. 71-82 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yamada S, Takehara K, Arai T, Takezawa J, kobayashi S, Mizoguchi Y, Morisawa S, Yamamoto S, Nagura H: "Immunocytochemical studies on cholestatic factor in human liver with or without cholestasis." Liver. 10. 129-136 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kioka K, Mizoguchi Y, Ichikawa Y, Shin T, Sakagami Y, Kobayashi K, Morisawa S, Yamamoto S: "Effect of cholestatic factor and prostaglandin E_1 derivative on the level of cAMP in isolated hepatocytes of rats." Jpn J Gastroenterology. 86. 45-49 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yamada S: "Immunocyto chemical studies on cholestatic factor in human liver with or without cholestasis" Liver. 10. 129-136 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 阪上 干博: "Panax ginsengより抽出した粗サポニン分画および非サポニン分画の催胆汁うつ滞因子活性に及ぼす影響" 和漢医薬学会誌.

    • Related Report
      1990 Annual Research Report
  • [Publications] Shin T: "Study on the mechanism of an experimental immunological intrahepatic cholestasis model." Osaka City Med J.

    • Related Report
      1990 Annual Research Report
  • [Publications] Kioka K: "The characters of cholestatic factorーProducing Tーcell clones" Osaka City Med J.

    • Related Report
      1990 Annual Research Report
  • [Publications] 溝口 靖紘: "催胆汁うつ滞因子" 臨床科学. 26. 835-840 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 溝口 靖紘: "催胆汁うつ滞因子" 臨床医. 16. 462-464 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 溝口靖紘他7名: "催胆汁うっ滞因子の作用機構-肝細胞内CAMP量に及ぼす催胆汁うっ滞因子の影響について" 日本消化器病学会誌. 86. 45-49 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 溝口靖紘: "薬物による急性肝内胆汁うっ滞" 臨牀消化器内科. 4. 1763-1772 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 溝口靖紘他6名: "催胆汁うっ滞因子を産生するT-cell cloneの確立とその性状について" 肝臓. 31. 104-105 (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Yasuhiro Mizoguchi et al: "The characters of the cloned T-cell producting the cholestatic factor" J Gastroenterology Hepatology.

    • Related Report
      1989 Annual Research Report
  • [Publications] 溝口靖紘(分担): "黄疸:病態生理の新しい視点" へるす出版, 85-96 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 溝口靖紘(分担): "肝臓フォ-ラム" 医事出版社, 53-75 (1989)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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