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

众所周知，肝脏有很大的再生潜力。然而，与健康对照组相比，纤维化肝的再生速度更慢，程度也更小。衰减的机制尚不清楚。我们研究了纤维化肝再生的抑制是否由于肝细胞生长因子（HGF）在转化生长因子(TGF) - β 1的作用下捕获了积累的细胞外基质。我们评估了部分肝切除后伴有或不伴有急性肝细胞坏死的大鼠纤维化肝中tgf - β 1表达与肝再生的空间关系。雄性Fisher大鼠连续4个月给予猪血清（0.5 ml/100g WB），直至肝纤维化形成。一组大鼠注射单剂量四氯化碳（CCl4: 0.1ml/100g BW）。在肝双叶切除后用多克隆抗体观察tgf - β 1的表达时，其在肝周周围的表达增强，并在48 h达到峰值，其表达程度明显高于正常对照的再生肝。在合并急性肝坏死（CCl4）的大鼠中，tgf - β 1在坏死区域周围被诱导，并在星状细胞上表达，被鉴定为Kupffer细胞。当使用BrdU评估肝小叶s期肝细胞的定位时，除了靠近血管的区域外，间隔纤维化区域周围的再生被评估为低。合并急性肝坏死大鼠的BrdU标记指数和^ 3h -胸苷摄取明显低于未合并肝坏死大鼠（P<0.05）。这些发现表明，被困在细胞外基质上的tgf - β 1至少在一定程度上抑制了纤维化肝脏的再生。我们被提示进一步研究这种抑制作用的细胞外和细胞内信号转导。少

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