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1998 Fiscal Year Final Research Report Summary

The Mechanisms of Impaired Liver Regeneration in Fulminant Hepatic Failure : The Significance of Sinusoidal Endothelial Cell Proliferation.

Research Project

Project/Area Number 09670571
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) YAMANOBE Fumio  Saitama Medical School, Faculty of Medicine, Assistant, 医学部, 助手 (90286097)
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)
FUJIWARA Kenji  Saitama Medical School, Faculty of Medicine, Professor and Chairman, 医学部, 教授 (80101088)
Project Period (FY) 1997 – 1998
KeywordsLiver Regeneration / Fulminant Hepatic Failure / Sinusoidal Endothelial Cells / VEGF / ft-1 / KDR / flk-1
Research Abstract

The prognosis of fulminant hepatic failure is extremely poor in most cases of the patients, since impaired liver regeneration frequently develops. Sinusoidal endothelial cell injury is a major abnormal finding in the liver of such patients. Proliferation of sinusoidal endothelial cells seems to be essential for the progression of liver regeneration, since the cells play a role in the supply of blood flow to the injured liver. Vascular endothelial growth factor, VEGF, is shown to induce proliferation of cultured sinusoidal endothelial cells. Thus, VEGF expression was examined in rat liver following partial resection, injury and cold preservation to clarify the relation between sinusoidal endothelial cell proliferation and the development of impaired liver regeneration.
In partially resected and injured liver, VEGF mRNA and protein were expressed increasingly in regenerating hepatocytes. Marked VEGE expression was also found in activated Kupifer cells, macrophages and stellate cells in th … More e necrotic areas of injured liver, However, activated sinusoidal cells induced proliferation of vascular endothelial cells leading to capillarization of the hepatic sinusoids, since they produced PDGF and basic FGF as well VEGE In contrast, VEGF derived from regenerating hepatocytes seems to be essential for the reconstruction of the hepatic sinusoids through proliferation of sinusoidal endothelial cells. Plasma VEGF concentration was measured serially in fulminant hepatic failure patients in whom the presence of impaired liver regeneration was suspected based on ultrasonography and/or CT scan. In all patients, VEGF was undetectable in their plasma, suggesting that sinusoidal endothelial cell proliferation was retarded in the patients complicated with impaired liver regeneration.
VEGF expression was increased in hepatocytes in the liver following cold preservation in UW solution. In such liver, however, the expressions of VEGF receptors, fit-i and KDR/flk-1 , diminished preceding the occurrance of sinusoidal endothelial cell injury. The derangement in communication between VEGF and its receptors may be a factor respopsible for the development of such sinusoidal endothelial cell injury, as VEGF is a maintenance factor as well as a growth factor of the cells. When recombinant VEGF was added to the culture medium of endothelial cells, mRNA expressions of VEGF receptors increased in a dose-related manner, Thus, administration of recombinant VEGE may be effective for proliferation as well as protection of sinusoidal endotbelial cells in fulininant hepatic failure patients in whom hepatic microcirculatory disturbance develops Recently, we found that VEGF receptors were also expressed in hepatic stellate cells and VEGF can inhibit contraction of the ste1late cells during activation by culture, probably through attenuation of smooth muscle a actin expression via upregulated VEGF receptor, fit-1. Exogenous VEOF may attenuate microcirculatory disturbance in fulminant hepatic failure patients through inhibition of stellate cell contraction. Less

  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [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 carbon tetrachloride intoxication : A possible factor for macrophage migration into hepatic necrotic areas." Biochem Biophys Res Commun. 印刷中.

    • Description
      「研究成果報告書概要(和文)」より
  • [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 hepatectomized rats." Hepatology. 印刷中.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Arai S,Mochida S,Ohno A,et al.: "Decreased expressions of receptors for vascular endothelial growth factor and sinusoidal endothelial cell damage in cold preserved rat liver." Transplant Proc. 印刷中.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mashiba S,Mochida S,Ishikawa K,et al.: "Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with uprgulation of FLT tyrosine kinase receptor family,flt-1." Biochem Biophys Res Commun. 印刷中.

    • Description
      「研究成果報告書概要(和文)」より
  • [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. 印刷中.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishikawa K,Mochida S,Mashiba s,et al.: "Expressions 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)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Arai M,Mochida S,Ohno A,et al.: "Selective bowel decontamination of recipients for prevention against liver injury following orthotopic liver transplantation : Evaluation with rat models." Hepatology. 27. 123-127 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Toshima K,Mochida S,Ishikawa K,et al: "Contribution of CD14 to endotoxin-induced liver injury may depend on types of macrophage activation in rats." Biochem Biophys Res Commun. 246. 731-735 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mochida S,Ishikawa K,Toshima K et al: "The mechanisms of hepatic sinujsoidal endothelial cell regeneration: A possible communication system associated with vascular endothelial growth factor in liver cells." J Gastroenterol Hepatol. 13. S1-S5 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Toshima K,Mochida S,Arai S,et al.: "Effects of FK506 on the activation state of hepatic macrophages in Propionibacterium acnes-treated rats." J Gastroenterol Hepatol. 13. S51-S54 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamaoka M,Hirata K,Ogata I,et al.: "Enhancement of albumin production by hepatocyte growth factor in rat hepatocytes: Distinction in mode of action from stimulation of DNA synthesis." Liver. 18. 52-59 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mochida S,Arai S,Yamanobe F,et al.: "Anticoagulant targeting for hepatic sinusoidal walls in prevention of hypercoagulopathy in cold preserved rat livers." Transplant Proc. 30. 45-48 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mochida S,Fujiwara K.: "The role of hepatic sinusoidal cells in the development of massive liver necrosis. In “Liver Disease and Hepatic Sinusoidal Cells"" Tanikawa K and Ueno T(eds),Springer-Verlag Inc,Tokyo, 101-113 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fujiwara K,Mochida S.: "Hepatic sinusoidal endothelial cells in liver regeneration. In “Liver Disease and Hepatic Sinusoidal Cells"" Tanikawa K and Ueno T(eds),Springer-Verlag Inc,Tokyo, 114-123 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mochida S,Ishikawa K,et al.: "Regeneration of sinusoidal endothelial cells: A possible communication system through vascular endothelial growth factor among liver cells. In “The Cells of The Hepatic Sinusoids Vol 9)"" Wisse E,et al.(eds),Kupffer Cell Foundation, Netherlands 印刷中, (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kawashima R,Mochida S,Matsui A,YouLuTuZ Y,Ishikawa K,Toshima K,Yamanobe F,Inao M,Ikeda H,Ohno A,Nagoshi S,Uede T,Fujiwara K.: "Expression of osteopontin in Kupffer cells and hepatic macrophages and stellate cells in rat liver after carbon tetrachloride intoxication : A possible factor for macrophage migration into hepatic necrotic areas." Biochem Biophys Res Commun. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mochida S,Arai M,Ohno A,Yamanobe F,Ishikawa K,Matsui A,Maruyama I,Kato H,Fujiwara K.: "Deranged blood coagulation equilibrium as a factor of massive liver necrosis following endotoxin administration in partially hepatectomized rats." Hepatology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Arai S,Mochida S,Ohno A,Ishikawa K,Matsui A,Arai M,Shibuya M,Fujiwara K.: "Decreased expressions of receptors for vascular endothelial growth factor and sinusoidal endothelial cell damage in cold preserved rat liver." Transplant Proc. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mashiba S,Mochida S,Ishikawa K,Inao M,Matsui A,Ohno A,Ikeda H,Nagoshi S,Shibuya M,Fujiwara K.: "Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with uprgulation of FLT tyrosine kinase receptor family, flt-1." Biochem Biophys Res Commun. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mashimo Y,Mochida S,Inao M,Yamaoka M,Nagoshi S,Matsui A,Fujiwara K.: "Decreased expression of smooth muscle alpha actin in activated rat hepatic stellate cells at the S-phase of the cell cycle in vitro." Hepatology Res. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishikawa K,Mochida S,Mashiba S,Inao M,Matsui A,Ikeda H,Ohno A,Shibuya M,Fujiwara K.: "Expressions 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)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Arai M,Mochida S,Ohno A,Arai S,Fujiwara K.: "Selective bowel decontamination of recipients for prevention against liver injury following orthotopic liver transplantation : Evaluation with rat models." Hepatology. 27. 123-127 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toshima K,Mochida S,Ishikawa K,Matsui A,Arai M,Ogata I,Fujiwara K.: "Contribution of CD14 to endotoxin-induced liver injury may depend on types of macrophage activation in rats." Biochem Biophys Res Commun. 246. 731-735 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mochda S,Ishiakwa K,Toshima K,Inao M,Ikeda H,Matsui A,Shibuya M,Fujiwara K.: "The mechanisms of hepatic sinusoidal endothelial cell regeneration : A possible communication system associated with vascular endothelial growth factor in liver cells." J Gastroenterol Hepatol. 13. S1-5 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toshima K,Mochida S,Arai S,Ishikawa K,Matsui A,Fujiwara K.: "Effect of FK506 on the activation state of hepatic macrophages in Propionibacterium acnes-treated rats." J Gastroenterol Hepatol. 13. S51-54 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamaoka M,Hirata K,Ogata I,Tomiya T,Nagoshi S,Mochida S,Fujiwara K.: "Enhancement of albumin production by hepatocyte growth factor in rat hepatocytes : Distinction in mode of action from stimulation of DNA synthesis" Liver. 18. 52-59 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mochida S,Arai S,Yamanobe F,Ohno A,Kamikubo Y,Kato H,Fujiwara K.: "Anticoagulant targeting for hepatic sinusoidal walls in prevention of hypercoagulopathy in cold preserved rat livers." Transplant Proc. 30. 45-48 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mochida S,Ohno A,Fujiwara K.: "Pitfall in the implication of intracellular adhesion molecule-1 expression on isolated hepatocytes." Hepatology. 25. 1546-1547 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamanobe F,Mochida S,Ohno A,Ishikawa K,Fujiwara K.: "Recombinant human tissue factor pathway inhibitor as a possible anticoagulant targeting hepatic sinusoidal walls." Thromb Res. 85. 493-501 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mochida S,Arai M,Ohno A,Fujiwara K.: "Bacterial translocation from gut to portal blood as a factor of hypercoagulopathy in the hepatic sinusoids following orthotopic liver transplantation in rats." Transplant Proc. 29. 874-875 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Inao M,Mochida S,Ikeda H,Awaya A,Fujiwara K.: "Effect of neurotropic pyrimidine heterocyclic compound, MS-430, on cultured hepatic parenchymal and stellate cells." Life Sciences. 61. 273-282 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mochida S,Fujiwara K.: The role of hepatic sinusoidal cells in the development of massive liver necrosis. "Liver Disease and Hepatic Sinusoidal Cells". Tanikawa K and Ueno T (eds), Springer-Verlag Inc, Tokyo, 101-113 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fujiwara K,Mochida S.: Hepatic sinusoidal endothelial cells in liver regeneration. "Liver Disease and Hepatic Sinusoidal Cells". Tanikawa K and Ueno T (eds), Springer-Verlag Inc, Tokyo, 114-123 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mochida S,Ishikawa K,Mashiba S,Toshima K,Inao M,Ikeda H,Ohno A,Matsui A,Shibuya M,Fujiwara K.: Regeneration of sinusoidal endothelial cells : A possible communication system through vascular endothelial growth factor among liver cells. "The Cells of The Hepatic Sinusoids (Vol 9) ". Wisse E,et al. (eds), Kupffer Cell Foundation, Netherlands. (in press),

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-12-08  

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