Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia
Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia
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DOI：
10.2119/molmed.2015.00076
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发表时间：
2015-01-01
影响因子：
5.7
通讯作者：
Nadler, Evan P.
中科院分区：
文献类型：
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作者：
Iordanskaia, Tatiana;Malesevic, Miroslav;Nadler, Evan P.
胆道闭锁（BA）是一种病因不明的破坏性肝病，通常影响出生后3个月内的儿童。该疾病表现为炎症和随后的肝外胆管阻塞、纤维化和肝功能衰竭。负责疾病发病机制尚未完全理解，但SMAD信号通路控制的许多因素已被牵连。在这项研究中，我们使用恒河猴轮状病毒（RRV）小鼠模型研究了已知的促炎症因子细胞外亲环素A（CypA）在胆道闭锁发病机制中的作用。我们使用了一种独特的环孢菌素A衍生物，MM 284，它不进入细胞，因此完全灭活细胞外亲环蛋白，作为一种潜在的治疗。我们证明了RRV感染小鼠血浆中CypA水平显著增加，并且在RRV感染引发疾病之前或之后一天用MM 284治疗小鼠显著改善了具有实验BA的小鼠的状态：体重增加恢复，胆红素尿消失，炎症细胞对肝脏的浸润减少，SMAD通路和SMAD控制的纤维化介质和金属蛋白酶组织抑制剂（TIMP）的激活。4、基质金属蛋白酶（MMP-7）的表达明显减轻。此外，用重组亲环蛋白处理人肝星状细胞重现了SMAD 2/3活化，其也被MM 284处理抑制。我们的数据提供了第一个证据表明，细胞外亲环素激活SMAD途径，并促进炎症实验BA，并表明，MM 284可能是一个有前途的治疗剂，用于治疗BA和其他肝内慢性疾病。
Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders.