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New Strategy for Liver Failure by Regulating Hepatic Extracellular Matrix

Research Project

Project/Area Number 10470240
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

SHIMAHARA Yasuyuki  Kyoto University Medicine, Associate Professor, 医学研究科, 助教授 (30196498)

Co-Investigator(Kenkyū-buntansha) YAMAMOTO Maritaka  Kyoto University Medicine, Assistant Professor, 医学研究科, 助手 (30253298)
YAMAMOTO Yuzo  Kyoto University Medicine, lecturer, 医学研究科, 講師 (70281730)
YAMAOKA Yoshio  Kyoto University Medicine, Professor (Chairman), 医学研究科, 教授 (90089102)
KAWADA Norihumi  Osaka City University, Medicine, Assistant Professor, 医学部, 助手 (30271191)
IIMURO Yuji  Kyoto University Medicine, Assistant Professor, 医学研究科, 助手 (30252018)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 1999: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 1998: ¥10,400,000 (Direct Cost: ¥10,400,000)
KeywordsLiver Failure / liver Regeneration / Hepatocyte / Hepatic Extracellular Matrix / Hepatic Stellate Cell / Type IV Collagen / Cell Culture / Liver Fibrosis / 供培養 / 共培養
Research Abstract

(1) SIGNIFICANCE OF SERUM LEVELS OF TYPE IV COLLAGEN AND MICROSCOPICAL CHANGE IN LIVER TISSUE IN PATIENT WITH LIVER FAILURE : Type IV collagen, one of serum markers for hepatic fibrosis, was measured perioperatively in patients with and without chronic liver damage in order to investigate whether this parameter changes responding to acute stress to the liver and can predict surgical risk of hepatic resection. The serum type IV collagen level was significantly elevated in cases with liver cirrhosis. In cases with postoperative liver failure, serum type IV collagen levels were significantly higher both pre-and postoperatively as compared to those of uneventful cases. Microscopic findings of the liver obtained from autopsy indicated marked amount of deposition of type IV collagem in Disse space. Among several preoperative liver function tests, type IV collagen revealed to be an independent risk factor for postoperative liver failure. Thus, perioperative measurement of the serum type IV co … More llagen levels seemed to be useful for the prediction of the risk of hepatic resection in cases with chronic liver damage.
(2)INVESTIGATION OF INTERACTION WITH HEPATOCYTES AND STELLATE CELLS USING IN VITRO CO-CULTURE SYSTEM : Effect of stellate cells on proliferation and albumin synthesis of hepatocytes was investigated using co-culture models and conditioned mediums. When co-cultured with stellate cells, hepatocyte DNA synthesis was enhanced even under a serum-free condition. Conditioned medium, in which HGF concentration was below 6 ng/ml, stimulated the proliferation of hepatocytes. Cell contact between hepatocytes and stellate cells may be an additional factor for DNA synthesis of hepatocytes. Albumin production was not affected by co-culture. On the other hand, stellate cell proliferation was enhanced by co-culture with hepatocytes even under a serum-free status. Conditioned medium of hepatocytes and co-culture stimulated DNA synthesis of stellate cells. Such a mitogenic activity of conditioned medium was partially attenuated by anti-IGF-1 neutralizing antibody Thus, DNA synthesis of hepatocytes and stellate cells may be regulated by some factors derived from individual cells and cell-cell contact between hepatocytes and stellate cells may play a role in their proliferation and differentiation.
(3)ACTION OF NAC (N-ACETYL CYSTEINE) TO SUPPRESS PROLIFERATION OF HEPATIC STELLATE CELL AND LIVER FIBROSIS : N-acetyl-L-cysteine dose-dependently blocked platelet-derived growth factor-induced DNA synthesis and signal transduction, including MAPK and Akt, inprimary-cultured hepatic stellate cell. In vitro degradation assay with various protease inhibitors showed that reducing agents, including N-acetyl-L-cysteine, enhanced the catalytical activity of cathepsin B and triggered extracellular proteolysis of platelet-derived growth factor receptor, thereby leading to desensitization of the cell to platelet-derived growth factor-BB.Moreover, western blot showed that hepatic stellate cell secreted mature-cathepsin B into the culture medium, while vascular smooth muscle cell did not secrete cathepsin B.This mechanism was demonstrated in in vivo liver fibrosis models. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Iimuro-Y: "NFkappaB prevents apoptosis and liver dysfunction during liver regeneration"J-Clin-Invest. 101. 802-811 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawada-N: "Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells."Hepatology. 27. 1265-1274 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawada-N: "Expression of cyclins D1, D2 and E correlates with proliferation of rat stellate cells in culture."J-Hepatol. 30. 1057-1064 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shimahara-Y: "Significance of serum type IV collagen level of hepatectomized patients with chronic liver damage."World-J-Surg. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Okuyama-H: "N-acetyl cysteine inhibits PDGF-dependent proliferation of primary cultured of rat heptic stellate cells through degradation of PDGF receptor and attenuates progress of liver fibrosis in rat models."Kupffer Cell Symposium. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Uyama-N: "The interaction between hepatocytes and stellate cells on individual cell proliferation an differentiation"Kupffer Cell Symposium. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Iimuro-Y: "NFkappaB prevents apoptosis and liver dysfunction during liver regeneration"J-Clin-Invest. 101. 802-811 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawada-N: "Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells."Hepatology. 27. 1265-1274 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawada-N: "Expression of cyclins D1, D2 and E correlates with proliferation of rat stellate cells in culture."J-Hepatol. 30. 1057-1064 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shimahara-Y: "Significance of serum type IV collagen level of hepatectomized patients with chronic liver damage."World-J-Surg. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Okuyama-H: "N-acetyl cysteine inhibits PDGF-dependent proliferation of primary cultured of rat hepatic stellate cells through degradation of PDGF receptor and attenuates progress of liver fibrosis in rat models."Kupffer Cell Symposium. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Uyama-N: "The interaction between hepatocytes and stellate cells on individual cell proliferation an differentiation"Kupffer Cell Symposium. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shimahara Y.: "Usefulness and problems of total hepatic vascular exclusion in liver surgery"Nippon-Geka-Gakkai-Zasshi.. 100(5). 335-341 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamamoto Y.: "New simple technique for hepatic parenchymal resection using a Cavitron Ultrasonic Surgical Aspirator and bipolar cautery equipped with a channel for water dripping"World-J-Surg.. 23(10). 1032-1037 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Uesugi T.: "Evaluation of ammonia and lidocaine clearance, and galactose elimination capacity of xenoperfused pig livers using a pharmacokinetic analysis"Transplantation.. 68(2). 209-214 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Uehara T.: "Gene transfer to the rat biliary tract with the HVJ-cationic liposome method"J-Hepatol.. 30(5). 836-842 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Iimuro Y.: "The glutathione precursor L-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat"Hepatology.. 31(2). 391-398 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kawada N.: "Expression of cyclins D1, D2 and E correlates with proliferation of rat stellate cells in culture"J-Hepatol.. 30(6). 1057-1064 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shimahara-Y: "Nine-year survivor after resection of cholangiocellular carcinoma with tumor thrombi in the main portal trunk." J-Gastroenterol.33(5). 755-760 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 嶌原康行: "肝細胞癌外科治療の現況-肝移植手術の導入" 日本外科学会雑誌. 99. 208-213 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kanazawa-A: "The beneficial effect of phosphocreatine accumulation in the creatine kinase transgenic mouse liver endotocin-induced hepatic cell death." J-Surg-Res. 80(2). 229-235 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kinoshita-K: "Exposure of hepatic sinusoidal mononuclear cells to UW solution in situ but not ex vivo induces apoptosis." J-Hepatol.29(2). 300-305 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamamoto-Y: "Implications of heat shock proteins during liver surgery and liver perfusion." Recent-Results-Cancer-Res.147. 157-172 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamagami-K: "Heat shock preconditioning ameliorates liver injury following normothermic ischemia-reperfusion in steatotic rat livers." J-Surg-Res.79(1). 47-53 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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