1999 Fiscal Year Final Research Report Summary
New Strategy for Liver Failure by Regulating Hepatic Extracellular Matrix
| Project/Area Number |
10470240
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SHIMAHARA Yasuyuki Kyoto University Medicine, Associate Professor, 医学研究科, 助教授 (30196498)
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| 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)
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| Project Period (FY) |
1998 – 1999
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| Keywords | Liver Failure / liver Regeneration / Hepatocyte / Hepatic Extracellular Matrix / Hepatic Stellate Cell / Type IV Collagen / Cell Culture / Liver Fibrosis |
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| 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
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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
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Research Products
(12 results)
