Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia.
Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia.
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DOI：
10.1002/cjp2.50
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Pakarinen MP
中科院分区：
文献类型：
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作者：
Kerola A;Lampela H;Lohi J;Heikkilä P;Mutanen A;Hagström J;Tervahartiala T;Sorsa T;Haglund C;Jalanko H;Pakarinen MP
胆道闭锁（BA）手术治疗后进行性肝纤维化的分子机制仍不清楚。我们的目的是研究肝门肠吻合术（PE）成功后肝脏基因和蛋白质表达以及基质金属蛋白酶（MMPs）及其组织抑制剂（TIMPs）的血清水平，并将它们与肝损伤的组织学征象、临床随访数据和肝功能的生化标志物相关联。从25名肝门肠吻合术成功的儿童（中位年龄3.3岁）获取肝脏活检和血清样本。通过酶联免疫吸附测定法测定血清MMP浓度。使用实时逆转录聚合酶链反应分析MMPs和TIMPs的肝脏基因表达。使用免疫组织化学研究MMP - 7和细胞角蛋白 - 7的肝脏表达。尽管肝门肠吻合术后生化和组织学胆汁淤积得到有效清除，但与对照组相比，胆道闭锁患者肝脏中MMP - 7（29倍，p < 0.001）、MMP - 2（3.1倍，p < 0.001）、MMP - 14（1.7倍，p = 0.007）和TIMP - 1（1.8倍，p < 0.001）的基因表达增加。与胆管上皮标志物细胞角蛋白 - 7相似，MMP - 7的表达定位于胆管的胆管上皮和胆管增生以及门周肝细胞，且与对照组相比增加（p < 0.001）。胆道闭锁患者血清MMP - 7水平高6倍（p < 0.001），其与肝脏MMP - 7基因（r = 0.548，p = 0.007）和蛋白质（r = 0.532，p = 0.007）表达呈正相关。患者胆管MMP - 7表达与Metavir纤维化分期（r = 0.605，p = 0.001）和门脉纤维化分级（r = 0.606，p = 0.001）呈正相关。在肠道衰竭相关肝病且Metavir分期相当的患者中，未观察到MMP - 7表达类似增加以及与肝纤维化的相关性。总之，我们的研究结果支持MMP - 7肝脏表达改变在肝门肠吻合术成功后肝纤维化进展中的独特作用，并引入了一个潜在的治疗靶点，即通过抑制MMP - 7过度活性来药物性延长原生肝脏的存活。血清MMP - 7可能是胆道闭锁术后有价值的预后工具。
The molecular mechanisms underlying progressive liver fibrosis following surgical treatment of biliary atresia (BA) remain unclear. Our aim was to address hepatic gene and protein expression and serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) after successful portoenterostomy (PE), and relate them to histological signs of liver injury, clinical follow‐up data and biochemical markers of hepatic function. LIver biopsies and serum samples were obtained from 25 children after successful PE at median age of 3.3 years. Serum MMP concentrations were determined by enzyme‐linked immune sorbent assay. Hepatic gene expression of MMPs and TIMPs was analyzed using real‐time reverse‐transcription PCR. Liver expression of MMP‐7 and cytokeratin‐7 was studied using immunohistochemistry. Despite effective clearance of biochemical and histological cholestasis following PE, BA patients showed increased hepatic gene expression of MMP‐7 (29‐fold, p < 0.001), MMP‐2 (3.1‐fold, p < 0.001), MMP‐14 (1.7‐fold, p = 0.007), and TIMP‐1 (1.8‐fold, p < 0.001), when compared to controls. Similar to a biliary epithelial marker cytokeratin‐7, expression of MMP‐7 localized in biliary epithelium of bile ducts and ductal proliferations and periportal hepatocytes and was increased (p < 0.001) in relation to controls. BA patients had 6‐fold higher serum levels of MMP‐7 (p < 0.001), which correlated positively with hepatic MMP‐7 gene (r = 0.548, p = 0.007) and protein (r = 0.532, p = 0.007) expression. Patients showed a positive correlation between biliary MMP‐7 expression and Metavir fibrosis stage (r = 0.605, p = 0.001) and portal fibrosis grade (r = 0.606, p = 0.001). Neither similarly increased MMP‐7 expression nor correlation with liver fibrosis was observed in patients with intestinal failure‐associated liver disease and comparable Metavir stage. In conclusion, our findings support an unique role of altered hepatic expression of MMP‐7 in the progression of liver fibrosis after successful PE and introduce a potential therapeutic target to pharmacologically extend native liver survival by inhibiting MMP‐7 hyperactivity. Serum MMP‐7 may be a valuable postoperative prognostic tool in BA.