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

蛋白水解系统对肝脏再生的作用：骨髓移植基因缺陷小鼠的分析

基本信息

批准号：
15590197
负责人：
OKADA Kiyotaka
金额：
$ 1.92万
依托单位：
Kinki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

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

肝损伤后的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降解受纤溶酶原（Plg）和基质金属蛋白酶（MMP）系统的激活调节。用CCl_4注射模型观察纤溶因子基因敲除小鼠（-/-）肝脏再生情况。α_2-抗纤溶酶（α_2-AP）-/-小鼠的肝再生能力显著高于野生型小鼠（WT），而Plg-/-或Plg-/-小鼠的肝再生能力显著低于野生型小鼠（WT）。α_2-AP-/-。肝损伤后血浆和肝组织提取物中Plg激活物活性在所有基因型小鼠中显示相似的增加。肝损伤后Plg-/-肝组织提取液中蛋白水解活性低于α_2-AP-/-和WT。提示纤溶系统在肝损伤修复中起重要作用。富特 ...更多信息 r，分析了肝再生与纤溶系统的关系。未注射CCl_4的小鼠肝细胞的增殖能力在所有基因型小鼠中相似。另一方面，注射CCl_4后5天，α_2-AP-/-组小鼠肝细胞的增殖能力显著高于WT组，而Plg-/-组小鼠肝细胞的增殖能力低于WT组。从所有基因型小鼠分离的肝细胞类似地结合到固定化的Plg。在小鼠肝细胞的存在下，Plg的活化显著增加。α_2-AP对纤溶酶的抑制作用在有肝细胞存在时较无肝细胞存在时弱。另一方面，通过对骨髓移植基因缺陷小鼠的分析，探讨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，成功地恢复了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再生中起重要作用。少