Matrilysin (MMP-7) is a major matrix metalloproteinase upregulated in biliary atresia-associated liver fibrosis
Matrilysin (MMP-7) is a major matrix metalloproteinase upregulated in biliary atresia-associated liver fibrosis
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DOI：
10.1038/modpathol.3800374
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发表时间：
2005-07-01
期刊：
影响因子：
7.5
通讯作者：
Tai, MH
中科院分区：
文献类型：
--
作者：
Huang, CC;Chuang, JH;Tai, MH
基质金属蛋白酶（MMPs）是在包括胆道闭锁在内的各种疾病引起的肝纤维化过程中负责组织重塑的蛋白酶。然而，关于这些蛋白酶对肝纤维化的相对作用的信息仍然有限。我们研究了在葛西手术时的早期胆道闭锁、肝移植时伴有晚期纤维化的晚期胆道闭锁以及无肝纤维化的正常对照的肝脏组织中基质金属蛋白酶 - 2（MMP - 2）、 - 7、 - 9和 - 13的mRNA表达。实时定量逆转录聚合酶链反应分析结果显示，只有MMP - 2和 - 7的表达在各组之间存在显著差异。肝移植组的MMP - 2显著高于对照组（P = 0.010）和葛西手术组（P = 0.001），而对照组和葛西手术组之间MMP - 2表达的差异不显著。然而，当比较对照组、葛西手术组和肝移植组时，MMP - 7的相对表达水平依次升高，并且在比较对照组和肝移植组时有显著差异（P = 0.019）。此外，各组之间MMP - 7 mRNA的倍数差异远高于MMP - 2 mRNA的倍数差异。通过琼脂糖凝胶电泳和蛋白质印迹法进一步证实了MMP - 7的表达。免疫组织化学分析显示，MMP - 7免疫染色评分与肝纤维化分期呈显著正相关。原位杂交表明胆管上皮细胞、枯否细胞和肝细胞是肝脏中基质金属蛋白酶 - 7的主要产生细胞。我们的结果表明，MMP - 7是与胆道闭锁肝纤维化进展过程中的组织重塑相关的主要MMP。
Matrix metalloproteinases ( MMPs) are the proteases responsible for tissue remodeling during liver fibrosis caused by various disorders including biliary atresia. However, information regarding the relative contribution of these proteases to liver fibrosis is still limited. We studied matrix metalloproteinase- 2 ( MMP- 2), - 7, - 9 and - 13 mRNA expressions in the liver tissue of early- stage biliary atresia at the time of Kasai's procedure, late-stage biliary atresia at the time of liver transplantation with advanced fibrosis and nondiseased control without liver fibrosis. The results of real-time quantitative reverse transcriptase-PCR analysis revealed that only MMP- 2 and - 7 expressions were significantly different between groups. MMP- 2 was significantly higher in Liver Transplantation group than both in Control ( P = 0.010) and in Kasai's Procedure ( P = 0.001) groups, whereas the difference of MMP- 2 expression between Control and Kasai's Procedure was not significant. However, the relative expression level of MMP- 7 was sequentially elevated when comparing Control, Kasai's Procedure and Liver Transplantation groups, and there was significant ( P = 0.019) difference when comparing Control and Liver Transplantation groups. Moreover, the fold difference in MMP- 7 mRNA was much higher than that in MMP- 2 mRNA between groups. The expressions of MMP- 7 were further confirmed by agarose gel electrophoresis and Western blotting. Immunohistochemical analysis revealed a significant positive correlation of the scores of MMP- 7 immunostaining with the stages of liver fibrosis. In situ hybridization demonstrated that the bile ductular epithelial cells, Kupffer cells and hepatocytes were the major producers of matrix metalloproteinase-7 in the liver. Our results imply that MMP- 7 is a major MMP associated with the tissue remodeling during the progression of liver fibrosis in biliary atresia.