The role of proteolytic system on the liver regeneration : The analysis of gene deficient mice with transplantation of bone morrow

损伤后肝脏再生受多种生长因子和细胞因子的调控。这些生长因子的释放与细胞外基质（ECM）的降解密切相关。这种ECM降解是由纤溶酶原（Plg）和基质金属蛋白酶（MMP）系统的激活调节的。采用CCl_4注射模型，观察纤维蛋白溶解因子敲除小鼠（-/-）的肝脏再生情况。与野生型小鼠相比，α_2-antiplasmin (α_2-AP) -/-组肝脏再生能力显著增强，而Plg-/-、Plg-/-组肝脏再生能力显著降低。α_2-AP - / -。所有基因型小鼠肝损伤后血浆和肝组织提取物中Plg激活剂活性均有相似的升高。另一方面，肝损伤后Plg-/-肝组织提取物的蛋白水解活性低于α_2-AP-/-和WT，提示纤溶系统在肝修复中起重要作用。进一步，我们利用小鼠肝脏分离的肝细胞，分析了肝再生与纤溶系统的关系。没有注射CCl_4的小鼠肝细胞的增殖能力在所有基因型小鼠中都是相似的。另一方面，注射CCl_4后5 d的小鼠肝细胞α_2-AP-/-组的增殖能力较WT组明显增强，而Plg-/-组的增殖能力较WT组降低。从所有基因型小鼠中分离的肝细胞与固定的Plg相似地结合。在小鼠肝细胞存在的情况下，Plg的激活显著增加。小鼠肝细胞存在时α_2-AP对纤溶酶的抑制作用弱于无肝细胞时。另一方面，通过对骨移植基因缺陷小鼠肝脏再生的分析，探讨了蛋白水解系统在肝再生中的作用。用Plg+/+骨髓替代Plg-/-小鼠肝细胞，成功恢复了CCl_4损伤后的再生反应。这些结果表明，小鼠肝细胞表面的纤溶系统在肝脏再生中起重要作用。少

The liver regeneration after injury is regulated by variety of growth factors and cytokines. Release of these growth factors is deeply related to degradation of extracellular matrix (ECM). This ECM degradation is regulated by the activation of plasminogen (Plg) and matrix metalloproteinase (MMP) systems. The liver regenerations in knockout mice (-/-) for fibrinolytic factors were examined by using CCl_4 injection model. The ability of liver regeneration was significantly increased in the α_2-antiplasmin (α_2-AP) -/- as compared to the wild-type mice (WT), but was significantly decreased in the Plg-/-, or Plg-/-. α_2-AP-/-. Plg activator activity in the plasma and liver tissue extract after liver injury showed similar increase in all genotype mice. On the other hand, the proteolytic activity in liver tissue extract from Plg-/- after liver injury was lower than that α_2-AP-/- and WT. These results suggest that the fibrinolytic system playes an important role in the hepatic repair. Furthe … More r, we analyzed the relationship between the liver regeneration and fibrinolytic system by using the hepatocytes isolated from mouse liver. The proliferation ability of the hepatocytes isolated from mice without CCl_4 injection showed similar in all genotype mice. On the other hand, the proliferation ability of the hepatocytes from mice of 5 days after CCl_4 injection was significantly increased in the α_2-AP-/- as compared to the WT but was decreased in the Plg-/-. The hepatocytes isolated from all genotype mice similarly bound to the immobilized Plg. The activation of Plg was significantly increased in the presence of mouse hepatocytes. The plasmin inhibition by α_2-AP in the presence of mouse hepatocytes was weaker than that in the absence of mouse hepatocytes. On the other hand, The role of proteolytic system on the liver regeneration by the analysis of gene deficient mice with transplantation of bone morrow. Replacement of hepatocyte in Plg-/- mice with Plg+/+ bone marrow successfully restored the regeneration response after CCl_4 injure. These results indicate that the fibrinolytic system on the surfaces of mouse hepatocytes plays important roles in liver regeneration. Less