酒精性肝纤维化基质降解机制的研究

THE PATHOLOGICAL MECHANISM OF MATRIX DEGRADATION IN ALCOHOLIC HEPATIC FIBROSIS

为揭示酒精性肝病(ALD)肝纤维化基质降解的病理机制 ,2 8例ALD肝穿刺组织按其纤维化程度分为 3组 ,应用原位杂交技术分别检测各组肝组织内基质金属蛋白酶 1(MMP 1)、基质金属蛋白酶 2 (MMP 2 )、膜型基质金属蛋白酶 1(MT1 MMP)mRNA和基质金属蛋白酶抑制酶 1(TIMP 1)mRNA的表达。结果发现 ,MMP 1、MMP 2、MT1 MMP和TIMP 1mRNA阳性细胞主要位于纤维化的中央静脉、窦周及汇管区等部位周围 ,且MMP 2和MT1 MMPmRNA的表达细胞有重叠 ;MMP 2、MT1 MMP和TIMP 1mRNA表达阳性细胞数随肝纤维化程度的加重而增多 ,而MMP 1mRNA表达阳性细胞数减少 ,且以纤维化中期变化为著 ;MMP 1、MMP 2、MT1 MMP和TIMP 1mRNA表达阳性细胞主要为肝窦壁细胞 ,少数肝细胞亦呈阳性表达。提示MMP 1减少和TIMP 1增多可能是ALD肝纤维化过程中细胞外基质(ECM)沉积、尤其是I型胶原过量沉积的病理机制之一 ;MMP 2和MT1 MMP在基质降解过程中可能有协同作用 ,其表达增多可能对ALD时中央静脉纤维化、肝窦血管化起一定促进作用 ;肝窦壁细胞 (肝星状细胞等 )为肝组织内MMP 1、MMP 2、MT1 MMP和TIMP

To study the mechanism of matrix degradation in alcoholic liver disease (ALD), the liver tissues from 28 patients with ALD were divided into three groups according to their fibrosis degree. The mRNA expression of matrix metalloproteinase 1 (MMP 1), matrix metalloproteinase 2 (MMP 2), membrane type metalloproteinase (MT1 MMP), and tissue inhibitors of metalloproteinase (TIMP) was detected using in situ hybridization method. The results showed that the cells with positive MMP 1, MMP 2, MT1 MMP, and TIMP mRNA staining were mainly located around the fibrotic central veins, walls of sinusoids, and portal triads. These positive cells were the cells of hepatic sinusoidal walls and a few hepatocytes, meanwhile, some cells expressed both the MMP 2 and the MT 1MMP mRNA. The positive cells of the MMP 2, MT1 MMP, and TIMP mRNA increased in parallel with the severity of fibrosis, whereas the expression of MMP 1 mRNA decreased. These changes were observed predominantly in moderate fibrosis group. There findings demonstrated that down regulation of MMP 1 expression and up regulation of TIMP expression might be involved in excessive accumulation of extracellular matrix (ECM) in ALD. MMP 2 might collaborate with MT1 MMP in degradation of ECM. thereby contributing to fibrosis of central veins.Hepatic stellate cells might be the main cellular source of MMP 1, MMP 2, MT1 MMP and TIMP in ALD.