Escape from Inhibition of Liver Regeneration in Fibrotic Liver through The Modulation of Extracellular Matrix.
| Project/Area Number |
07670637
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | University of Occupational and Environmental Health |
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Principal Investigator |
YAMADA Shinwa University of Occupational and Environmental Health Health Sciences, Professor, 産業保健学部, 教授 (60143426)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Yoshiya University of Occupational and Environmental Health Medicine, Assist. Professor, 医学部, 講師 (30248562)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1996: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1995: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | extracellular matrix / liver regeneration / liver fibrosis / hepatocyte growth factor / transforming growth factor / hepatic necrosis / 肝再生 / TGFβ / HGF |
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| Research Abstract |
Ithas been well known that the liver has a great potential to regenerate. The fibrotic liver, however, has been demonstrated to regenerate more slowly and to less extent that the healthy control. The mechanism of the attenuation was unclear. We have examined whether the inhibition of regeneration in fibrotic liver is due to hepatocyte growth factor (HGF) -trapping on the accumulated extracellular matrix by the action of transforming growth factor (TGF) -beta1.
We evaluated the spatial relationship between TGF-beta1 expression and liver regeneration in rat fibrotic liver with or without acute hepatocellular necrosis after partial hepatecomy. Male Fisher rats were given repeatedly pork serum (0.5 ml/100g WB) for 4 months until liver fibrosis was developed. A single dose of carbon tetrachloride (CCl4 : 0.1ml/100g BW) was injected to one group of the rats. When the expression of TGF-beta1 was observed with using the polyclonal antibody after tow-lobe hepatectomy, its expression around the s
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eptal fibrosis was enhanced and peaked at 48 h. The degree of its expression was significantly higher than regenerating liver of normal control rats. In the rats complicated with an acute hepatic necrosis (CCl4), TGF-beta1 was induced around the necrotic area and it was expressed on the stellate-shaped cells which were assessed as Kupffer cells. When the localization of S-phase hepatocytes in the hepatic lobule was evaluated with using BrdU,the regeneration around the septal fibrotic areas, except the area in close to the blood vessels, was assessed to be low. In the rats complicated with an acute hepatic necrosis, the BrdU labeling index and ^3H-thymidine uptake were significantly (P<0.05) lower as compared with those uncomplicated with the necrosis. These findings suggested that TGF-beta1 trapped on the extracellular matrix contributes at least as a part to the inhibition of regeneration in the fibrotic livers.
We are prompted to further investigate the extra-and intracellular signal transduction of this inhibitory action. Less
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Report
(3 results)
Research Products
(18 results)
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[Publications] Tanaka, Y., Kimata, K., Wake, A., Mine, S., Morimoto, I., Yamakawa, N., Habuchi, H., Ashikari, S., Yamamoto, H., Sakurai, K., Yoshida, K., Suzuki, S., Eto, S.: "Heparan sulfate proteoglycan on leukemic cells is primarily involved in integrin-triggering and its mediated adhesion to endothelial cells." J.Exp. Med.Vol. 184. 1987-1997 (1996)
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[Publications] Hisama, N., Yamaguchi, Y., Okajima, K., Uchida, M., Murakami, K., Mori, K., Yamada, S., Ogawa, M.: "Anticoagulant pretreatment attenuates production of cytokineinduced neutrophil chemoattractant following ischemiareperfusion of rat liver." Dig. Dis. Sci.Vol. 41 No. 7. 1481-1386 (1996)
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[Publications] Koyama, Y., Tanaka, Y., Saito, K., Abe, M., Nakatsuka, K., Morimoto, I., Auron, P.E., Eto, S.: "Cross-linking of intercellular adheson molecule-1 (CD54) induces AP-1 activation and interleukin-1b transcription." J.Immunol.Vol. 157. 5097-5103 (1996)
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[Publications] Tanaka, Y., Morimoto, I., Nakano, Y., Okada, Y., Hirota, S., Nomura, S., Nakamura, T., Eto, S.: "Osteoblasts are regulated by the cellular adhesion through ICAM-1 and VCAM-1." J.Bone Miner. Res.Vol. 10. 1462-1469 (1995)
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[Publications] Wake, A., Tanaka, Y., Nakatsuka, K., Misago, M., Oda, S., Morimoto, I., Eto, S.: "Calcium-dependent homotypic adhesion through LFA-1/ICAM-induces interleukin-1 and PTHrP production on adult T-cell leukemia cells in vitro." Blood. Vol. 86. 12257-2267 (1995)
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