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The Role of Osteopontin in Macrophage Infiltration into Injured Liver.

Research Project

Project/Area Number 11670529
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionSaitama Medical School

Principal Investigator

MOCHIDA Satoshi  Saitama Medical School, Faculty of Medicine, Associate Professor, 医学部, 助教授 (20219968)

Co-Investigator(Kenkyū-buntansha) INAO Mie  Saitama Medical School, Faculty of Medicine, Assistant, 医学部, 助手 (70286037)
MATSUI Atsushi  Saitama Medical School, Faculty of Medicine, Assistant, 医学部, 助手 (40260484)
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: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1999: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsOsteopontin / Macrophages / Stellate cells / Hepatocytes / Chemokine / Liver fibrosis / Transgenic mice / Massive liver necrosis / 劇症肝炎 / Propionibacterium acnes / MCP-1 / MIP-1α
Research Abstract

Macrophage infiltration into the liver is assumed to be a critical event in the development of fulminant hepatic failure, since massive liver necrosis can develop as a result of microcirculatory disturbance due to sinusoidal fibrin deposition caused by activated macrophages. However, the precise mechanisms of such macrophage infiltration are to be elucidated. Osteopontin, an extracellular matrix with RGD sequence, has been shown to act as a chemokine that can induce macrophage migration. The possibility that osteopontin can play a role in infiltration of macrophages into the liver was investigated in rats and mice. Northern blot analysis revealed that osteopontin mRNA expression was minimal in Kupffer cells and hepatocytes immediately after isolation from normal rats, but slight in stellate cells cultured for 3 days on plastic dishes. When rats received carbon tetrachloride or heat-killed Propionibacterium acnes (P.acnes), osteopontin mRNA expression assessed by competitive RT-PCR was … More increased in the liver preceding the occurrence of macrophage infiltration. Kupffer cells and hepatic macrophages and stellate cells isolated from such liver showed marked expression of osteopontin mRNA on Northern blotting. Immunohistochemical examination disclosed that osteopontin was stained in the Golgi apparatus of macrophages including Kupffer cells and hepatic stellate cells in these rats. In P.acnes-treated rats, both mRNA expressions of MIC-1 and MIP-1α were increased in the liver. Although mice with allele B osteopontin gene, in which osteopontin expression was absent, showed similar increase of both chemokine expressions, hepatic macrophage infiltration was minimal in such mice following P.acnes administration. Osteopontin may play a central role in hepatic macrophage infiltration among various chemokines. Kupffer cells and hepatic macrophages and stellate cells may contribute to hepatic macrophage infiltration by expressing osteopontin.
Regulation mechanisms of osteopontin expression in the liver were examined using rat stellate cells and hepatocytes in primary culture. In both cells, mRNA and protein expressions of osteopontin were upregulated following stimulation by TGF-β in a dose-dependant manner. Immunohistochemical examination revealed that osteopontin was expressed in hepatocytes and stellate cells in the liver of patients with liver cirrhosis. Also, the expression was found in well-differentiated hepatocellular carcinoma cells in these patients. Thus, osteopontin might be involved in the process of liver fibrosis and carcinogenesis as well as massive liver necrosis. To clarify the role of osteopontin in the development of liver diseases, we established transgenic mice expressing osteopontin abundantly in the liver. Less

Report

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

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Osada N,Mochida S,Inao M,Mashimo Y,Fujiwara K.: "Apoptisis in dissociation between DNA synthesis and cellular functions of activated hepatic stellate cells : A study with carbon tetrachloride-induced rat liver injury."Biochemical Biophysical Research Communication. (In press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] YouSuFu Y,Mochida S,Matsui A,Okamoto H,Fujiwara K.: "TT virus infection in cases of fulminant hepatic failure : Evaluation by clonality based on amino acid sequence of hypervariable regions."Hepatology Research. (In press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Niimi Y,Mochida S,Matsui A,Inao M,Fujiwara K.: "PKC-and MAPK-independent upregulation of VEGF receptor expression in human umbilical venous endothelial cells following VEGF stimulation."Hepatology Research. (In press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujiwara K,Mochida S,Matsui A,Nagoshi S.: "Indication and criteria for liver transplantation for fulminant hepatic failure."J Gastroenterology and Hepatology. (In press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Funyu J,Mochida S,Inao M,Matsui A,Fujiwara K.: "VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells."Biochemical Biophysical Research Communication. 280. 481-485 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mochida S,Fujiwara K.: "Recent advances in acute and fulminant hepatitis in Japan."Internal Medicine. 40. 175-177 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mochida S,Fujiwara K.: "Angiogenesis in the liver : A communication system among liver cells through VEGF."Connective Tissue. 32. 389-393 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ikeda H,Yatomi Y,Yanase M,Satoh H,Maekawa H,Ogata I,Ozaki Y,Takawa Y,Mochida S,Fujiwara K.: "Biological activities of novel lipid mediator sphingosine 1-phosphate in rat hepatic stellate cells."American Journal of Physiology. 279. G304-G310 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wang YH,Mochida S,Kawashima R,Inao M,Matsui A,YouLuTuz Y,Nagoshi S,Uede T,Fujiwara K.: "Increased expression of osteopontin in activated Kupffer cells and hepatic macrophages during macrophage migration in Propionibacterium acnes-treated rat liver."Journal of Gastroenterology. 35. 691-701 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mochida S,Fujiwara.: "Hepatic microcirculation in massive liver necrosis and liver regeneration. In : Gastroenterology and Hepatology : Millennium 2000"Asakura H (eds), Elsevier Science, Amsterdam(In press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujiwara K,Mochida S: "Etiology and pathophysiology of fulminant hepatic failure. In : Molecular Biology and Immunology for the Treatment of Intractable Liver Diseases"Tsuji T, et al. (eds), Elsevier Science, Amsterdam(In press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Osada N, Mochida S, Inao M, Mashimo Y, Fujiwara K.: "Apoptosis in dissociation between DNA synthesis and cellular functions of activated hepatic stellate cells : A study with carbon tetrachloride-induced rat liver injury."Biochem Biophys Res Commun. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] YouSuFu Y, Mochida S, Matsui A, Okamoto H, Fujiwara K.: "TT virus infection in cases of fulminant hepatic failure : Evaluation by clonality based on amino acid sequence of hypervariable regions."Hepatology Res. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Niimi Y, Mochida S, Matsui A, Inao M, Fujiwara K.: "PKC- and MAPK-independent upregulation of VEGF receptor expressions in human umbilical venous endothelial cells following VEGF stimulation."Hepatology Res. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujiwara K, Mochida S, Matsui A, Nagoshi S.: "Indication and criteria for liver transplantation for fulminant hepatic failure."J Gastroenterol Hepatol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mochida S, Fujiwara K.: "Hepatic microcirculation in massive liver necrosis and liver regeneration."Gastroenterology and Hepatology : Millennium 2000.. Asakura H, et al (eds)(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujiwara K, Mochida S.: "Etiology and pathophysiology of fulminant hepatic failure."Molecular Biology and Immunology for the Treatment of Intractable Liver Diseases. Tsuji T, et al. (eds), Elsevier Science, Amsterdam, (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Funyu J, Mochida S, Inao M, Matsui A, Fujiwara K.: "VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells."Biochem Biophys Res Commun. 280. 481-485 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mochida S, Fujiwara K.: "Recent advances in acute and fulminant hepatitis in Japan."Inter Med. 40. 175-177 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mochida S, Fujiwara K.: "Angiogenesis in the liver : A communication system among liver cells through VEGF."Connective Tissue. 32. 389-393 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ikeda H, Yatomi Y, Yanase M, Satoh H, Maekawa H, Ogata I, Ozaki Y, Takawa Y, Mochida S, Fujiwara K.: "Biological activities of novel lipid mediator sphingosine 1-phosphate in rat hepatic stellate cells."Am J Physiol Gastroenterol Liver Physiol. 279. G304-G310 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wang YH, Mochida S, Kawashima R, Inao M, Matsui A, YouLuTuz Y, Nagoshi S, Uede T, Fujiwara K.: "Increased expression of osteopontin in activated Kupffer cells and hepatic macrophages during macrophage migration in Propionibacterium acnes-treated rat liver."J Gasreoenterol. 35. 696-701 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Osada N,Mochida S,Inao M,Mashimo Y,Fujiwara K.: "Apoptisis in dissociation between DNA synthesis and cellular functions of activated hepatic stellate cells : A study with carbon tetrachloride-induced rat liver injury."Biochemical Biophysical Research Communication. (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] YouSuFu Y,Mochida S,Matsui A,Okamoto H,Fujiwara K.: "TT virus infection in cases of fulminant hepatic failure : Evaluation by clonality based on amino acid sequence of hypervariable regions."Hepatology Research. (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Niimi Y,Mochida S,Matsui A,Inao M,Fujiwara K.: "PKC- and MAPK-independent upregulation of VEGF receptor expressions in human umbilical venous endothelial cells following VEGF stimulation."Hepatology Research. (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fujiwara K,Mochida S,Matsui A,Nagoshi S.: "Indication and criteria for liver transplantation for fulminant hepatic failure."J Gastroenterology and Hepatology. (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Funyu J,Mochida S,Inao M,Matsui A,Fujiwara K.: "VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells."Biochemical Biophysical Research Communication. 280. 481-485 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mochida S,Fujiwara K.: "Recent advances in acute and fulminant hepatitis in Japan."Internal Medicine. 40. 175-177 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mochida S,Fujiwara K.: "Angiogenesis in the liver : A communication system among liver cells through VEGF."Connective Tissue. 32. 389-393 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ikeda H,Yatomi Y,Yanase M,Satoh H,Maekawa H,Ogata I,Ozaki Y,Takawa Y,Mochida S,Fujiwara K.: "Biological activities of novel lipid mediator sphingosine 1-phosphate in rat hepatic stellate cells."American Journal of Physiology. 279. G304-G310 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Wang YH,Mochida S,Kawashima R,Inao M,Matsui A,YouLuTuz Y,Nagoshi S,Uede T,Fujiwara K.: "Increased expression of osteopontin in activated Kupffer cells and hepatic macrophages during macrophage migration in Propionibacterium acnes-treated rat liver."Journal of Gastroenterology. 35. 691-701 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mochida S,Fujiwara.: "Hepatic microcirculation in massive liver necrosis and liver regeneration.In : Gastroenterology and Hepatology : Millennium 2000"Asakura H (eds), Elsevier Science, Amsterdam (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fujiwara K,Mochida S: "Etiology and pathophysiology of fulminant hepatic failure. In : Molecular Biology and Immunology for the Treatment of Intractable Liver Diseases"Tsuji T, et al.(eds), Elsevier Science, Amsterdam (In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kawashima R, Mochida S, Matsui A, et al.: "Expression of osteopontin in Kupffer cells and hepatic macrophages and stellate cells in rat liver after CCl_4-intoxication: A possible factor for macrophage migration into hepatic necrotic areas"Biochem Biophys Res Commun. 256. 527-531 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mochida S, Arai M, Ohno A, et al.: "Deranged Blood Coagulation equilibrium as a factor of massive liver necrosis following endotoxin administration in partially hepatictomized rats"Hepatology. 29. 1532-1540 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Arai S, Mochida S, Ohno A, et al.: "Decreased expression of receptors for Vascular endothelial growth factor and sinusoidal endothelial cell damage in cold preserved rat liver"Transplant Proc. 31. 2668-2672 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mashiba S, Mochida S, Ishikawa K, et al.: "Inhibition of hepatic stellate cell contraction during activation in vitro by vasculer endothelial growth factor in association with upregulation of FLT tyrosi kirase recej family, flt"Biochem Biophys Res Commun. 258. 674-678 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mashimo Y, Mochida S, Inao M, et al.: "Decreased expression of Smooth muscle α actin in activated rat hepatic stellate cells at the S-phase of the cell cycle in vitro"Hepatology Res. 15. 22-31 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ishikawa K, Mochida S, Mashiba S, et al.: "Expression of Vascular endothelial growth factor in non-parenchymal as well as parenchymal cells in rat liver after necrosis"Biochem Biophys Res Commun. 254. 587-593 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mochida S, Ishikawa K, Mashiba S, et al.: "The cells of the Hepatic Sinusoid."Wiss E, et al. (eds) Kupffer cell Foundation, Netherland,(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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