猪胆汁性肝纤维化的形成机制研究

The changes in expression of matrix metalloproteinase-2 and urokinase plasminogen activator in pig liver fibrosis model

目的 研究猪胆汁性肝纤维化时尿激酶型纤维蛋白酶原激活物 (uPA)和基质金属蛋白酶 2 (MMP 2 )的表达 ,分析其在肝纤维化形成初始阶段的作用。方法 2 0只普通猪行胆总管结扎制作胆汁性肝纤维化模型 ,术前和术后取其肝组织作样本自身对照 ,用原位杂交法研究uPA和MMP 2的mRNA表达改变。结果 术后 4周肝细胞呈灶状坏死 ;胆管扩张 ,淤胆 ,部分胆管充满脓性胆汁 ;正常纤维塌陷 ,纤维组织增生 ,连接成片 ,胆管周围纤维增多。原位杂交显示肝星状细胞(HSC)细胞增多 ,增生 ,向肝细胞坏死区聚集 ,uPA和MMP 2表达胞浆呈强阳性。经图像分析术前和术后两者平均吸光度差异有非常显著性 (P <0 .0 1)。结论 MMP 2和uPA在肝纤维化的早期参与ECM的重塑和肝小叶的改建。

Objective To observe the expression of the matrix metalloproteinase-2 (MMP-2) and urokinase plasminogen activator (uPA) in the early stage of liver fibrosis.Methods 20-pig models of hepatic fibrosis induced by common bile duct ligation (BDL) were used.Expression of the MMP-2 and uPA was detected by in situ hybridization in liver tissue after hepatic fibrosis developed or the tissue obtained before BDL.Results In situ hybridization showed that hepatic stellate cells were accumulated in the necrotic lesion area.Disruption of the lobular structure was also found.Bile duct were dilated,filled with pus,and were surrounded with fibroid tissue.Proliferating hepatic stellate cells with strong expression of uPA and MMP-2 were found.Imaging analysis reveated that there was statistically significant difference in mean optical density before and after operation (P<0.01).Conclusion Activated MMP-2 may remodel liver parenchyma during the process of liver fibrosis,and hepatic stellate cells may play a central role in the pathogenesis of liver fibrosis.It is possible that up-regulation of MMP-2 and uPA and the increase in gelatinolytic activity of MMP-2 may take part in the remodeling process of ECM and hepatic lobule.