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Mechanisms of sepsis-induced cholestatic liver injury

Research Project

Project/Area Number 11671162
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionOsaka University

Principal Investigator

NISHIDA Toshirou  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40263264)

Co-Investigator(Kenkyū-buntansha) UCHIYAMA Yasuo  Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (10049091)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥2,700,000 (Direct Cost: ¥2,700,000)
KeywordsEndotoxin / Apotosis / Hepatocyte / Kupffer cell / Bilirubin / Bile Acids / Caspase-3 / MAP Kinases / 肝障害 / 胆汁鬱滞
Research Abstract

We have examined the effect and mechanism of sepsis-induced cholestatic liver injury. We showed bilirubin and bile acid clearance from the blood and their output into the bile were reduced in the presence of infection. One of main causes of this phenomenon has been considered to be lipopolysaccharide (LPS) and peptidglycan from bacteria. Next, we examined cytological mechanisms using LPS-injection model of rats. Injection of LPS induced time- and dose-dependent hepatocyte apoptosis with concomitant activation of caspase-3 in hepatocytes. When Kupffer cells were inactivated, there was no apoptosis. Addition of anti-TNFα antibody decreased activation of caspase-3 as well as apoptosis of hepatocytes. Even in survived hepatocytes, expression of transport proteins for bile acids and bilirubin, such as NTCP, OATP and CMOAT, was time- and dosedependently decreased after injection of LPS.Decrease in these transport proteins was also suppressed by Kupffer cell inactivation. The decrease in NTCP, OATP and CMOAT expression was inhibited by addition of anti-IL-1α antibody, but not anti-TNFα antibody. By LPS addition, activation of MAP kinases (ERK, JNK and p38 MAP kinases) has been confirmed and we showed that inhibitors of these kinases inhibited decrease in expression of these transporters. These results suggested that LPS induced hepatocyte apoptosis (decrease in the number of hepatocytes) and decreased in expression of bile acid and bilirubin transporters via cytokines secreted from activated Kupffer cells. Consequently, it may be considered that bile secretion of the liver is decreased.

Report

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

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Nishida T,Nakahara M,Nakao K, et al.: "Biliary Bacterial Infection Decreased the Secretion of Bile Acids and Bilirubin into Bile"American Journal of Surgery. 177. 38-41 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hamada E,Nishida T, et al: "Activation of Kupffer Cells and Caspase-3 Involved in Rat Hepatocyte Apoptosis Induced by Endotoxin"J Hepatology. 30. 807-818 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakamura J,Nishida T, et al.: "Kupffer Cell-mediated Downregulation of Rat Hepatic CMOAT/MRP2 Gene Expression"Biochem.Biophys.Res.Commun.. 255. 143-149 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Taniguchi M,Nishida T, et al.: "Effect of c-kit Mutation on Prognosis of Gastrointestinal Stromal Tumors"Cancer Research. 59. 4297-4300 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishida T,Ueshima S, et al.: "The Vagus Nerve Involved in Lack of Blood Reflow into Sinusoids After Rat Hepatic Ischemia"American Journal of Physiology. 278. H1565-H1370 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishida T.,Hirota S: "Biological and Clinical Review of Stromal Tumors in the Gastrointestinal Tract."Histol Histopathol. 15(4). 1293-1301 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kitamura Y.,Hirota S.,Morii E.,Nishida T.: "Mast cells and Basophils."Gain-of-function mutations of c-kit in human diseases.. 21-29 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishida T., Nakahara M., Nakao K., Matsuda H.: "Biliary Bacterial Infection Decreased the Secretion of Bile Acids and Bilirubin into Bile."Am J Surg.. 177. 38-41 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hamada E., Nishida T., Uchiyama Y., et al.: "Activation of Kupffer Cells and Caspase-3 Involved in Rat Hepatocyte Apoptosis Induced by Endotoxin."J Hepatology. 30. 807-818 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakamura J., Nishida T., Hayashi K., et al.: "Kupffer Cell-mediated Downregulation of Rat Hepatic CMOAT/MRP2 Gene Expression."Biochem.Biophys Res Commun. 255. 143-149 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishida T., Ueshima S., Kazuo H., et al.: "The Vagus Nerve Involved in Lack of Blood Reflow into Sinusoids After Rat Hepatic Ischemia."Am J Physiol. 278. H1565-H1570 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Isahara, K., Ohsawa, Y., and, Uchiyama, Y.: "Regulation of a novel pathway for cell death by lysosomal aspartic and cysteine proteinases."Neuroscience. 91. 233-249 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sakahira, H., Enari, M., Uchiyama, Y., et al.: "Apoptotic nuclear morphological change without DNA fragmentation."Curr.Biol. 9. 543-546 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mcllroy, D., Tanaka, M., Uchiyama Y., et al.: "Apoptotic DNA fragmentation by phagocytosis."Gene Develop.. 14. 549-558 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chung, K.C., Park, J.H., Uchiyama, Y., et al.: "Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kB, and MAP kinases."J.Neurosci.Res.. 59. 117-125 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Gotow, T., Shibata, M., Uchiyama, Y.et al.: "Selective localization of Bcl-2 to the inner mitochondrial and smooth endoplasmic reticulum membranes in mammalian cells."Cell Death Diff.. 7. 666-674 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Koike, M., Nakanishi, H., Uchiyam, Y.et al.: "Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons."J.Neurosc. 20. 6898-6906 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujita, E., Urase, K., Uchiyama, Y., et al.: "Detection of caspase-9 activation in the cell death of Bcl-x-deficient mouse embryo nervous system by cleavage sites-directed antisera."Brain Res.Dev.Brain Res.. 122. 135-147 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsumura, H., Ohsawa, Y., Uchiyama, Y., et al: "Necrotic pathway in Fas receptor signaling."J.Cell Biol.. 151. 1247-1255 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishida T,Nakahara M,Nakao K, et al.: "Biliary Bacterial Infection Decreased the Secretion of Bile Acids and Bilirubin into Bile"American Journal of Surgery. 177. 38-41 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hamada E,Nishida T, et al: "Activation of Kupffer Cells and Caspase-3 Involved in Rat Hepatocyte Apoptosis Induced by Endotoxin"J Hepatology. 30. 807-818 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakamura J,Nishida T, et al.: "Kupffer Cell-mediated Downregulation of Rat Hepatic CMOAT/MRP2 Gene Expression"Biochem.Biophys.Res.Commun.. 255. 143-149 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Taniguchi M,Nishida T, et al.: "Effect of c-kit Mutation on Prognosis of Gastrointestinal Stromal Tumors"Cancer Research. 59. 4297-4300 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nishida T,Ueshima S, et al.: "The Vagus Nerve Involved in Lack of Blood Reflow into Sinusoids After Rat Hepatic Ischemia"American Journal of Physiology. 278. H1565-H1370 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nishida T.,Hirota S: "Biological and Clinical Review of Stromal Tumors in the Gastrointestinal Tract."Histol Histopathol. 15(4). 1293-1301 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kitamura Y.,Hirota S.,Morii E.,Nishida T.: "Mast cells and Basophils."Gain-of-function mutations of c-kit in human diseases.. 21-29 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nishida T.,Nakahara M.,Nakao K.et al.: "Biliary Bacterial Infection Decreased the Secretion of Bile Acids and Bilirubin into Bile"American Journal of Surgery. 177. 38-41 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hamada E.,Nishida T.et al.: "Activation of Kupffer Cells and Caspase-3 Involved in Rat Hepatocyte Apoptosis Induced by Endotoxin"J Hepatology. 30. 807-818 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakamura J.,Nishida T.et al.: "Kupffer Cell-mediated Downregulation of Rat Hepatic CMOAT/MRP2 Gene Expression"Biochem. Biophys. Res. Commun.. 255. 143-149 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Taniguchi M.,Nishida T.et al.: "Effect of c-kit Mutation on Prognosis of Gastrointestinal Stromal Tumors"Cancer Research. 59. 429-430 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nishida T.,Ueshima S.et al.: "The Vagus Nerve Involved in Lack of Blood Reflow into Sinusoids After Rat Hepatic Ischemia"American Journal of Physiology. (in press). (2000)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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