Escape from Inhibition of Liver Regeneration in Fibrotic Liver through The Modulation of Extracellular Matrix.

通过细胞外基质的调节摆脱纤维化肝脏中肝脏再生的抑制。

• 批准号: 07670637
• 负责人: YAMADA Shinwa
• 金额: $ 1.34万
• 依托单位: University of Occupational and Environmental Health
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670637/
• 关键词: extracellular matrix; liver regeneration; liver fibrosis; hepatocyte growth factor; transforming growth factor; hepatic necrosis; 肝再生; TGFβ; HGF

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 … More 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

众所周知，肝脏具有很大的再生潜力。然而，纤维化的肝脏已经被证明比健康对照再生得更慢并且程度更低。其衰减机制尚不清楚。我们研究了肝纤维化肝再生的抑制是否是由于肝细胞生长因子（HGF）通过转化生长因子（TGF）-β 1的作用而捕获在积累的细胞外基质上。我们评估了部分肝切除后伴或不伴急性肝细胞坏死的大鼠肝纤维化肝中TGF-β 1表达与肝再生之间的空间关系。雄性Fisher大鼠反复给予猪血清（0.5ml/100 g WB）4个月，直至肝纤维化形成。其中一组大鼠一次性注射四氯化碳（CCl_4：0.1ml/100 g BW）。当使用多克隆抗体观察两叶肝切除术后TGF-β 1的表达时， ...更多信息 间隔纤维化增强，48 h达高峰。其表达程度明显高于正常对照组大鼠再生肝。在伴有急性肝坏死（CCl 4）的大鼠中，在坏死区域周围诱导TGF-β 1，并在星状细胞上表达，这些细胞被评估为枯否细胞。当使用BrdU评价肝小叶中S期肝细胞的定位时，除靠近血管的区域外，间隔纤维化区域周围的再生被评估为低。急性肝坏死组大鼠BrdU标记指数和^3 H-胸苷摄取量均显著低于无坏死组（P<0.05）。这些结果表明，TGF-β 1被困在细胞外基质有助于至少作为一部分的再生抑制在纤维化肝。我们提示进一步研究这种抑制作用的细胞外和细胞内的信号转导。少

项目成果

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