Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.
Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.
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DOI：
10.3389/fphar.2016.00033
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发表时间：
2016
影响因子：
5.6
通讯作者：
Weiskirchen R
中科院分区：
文献类型：
--
作者：
Schon HT;Bartneck M;Borkham-Kamphorst E;Nattermann J;Lammers T;Tacke F;Weiskirchen R
肝星状细胞（hepatic stellate cells，HSC）的活化和转分化为具有收缩性、基质生成性的肌成纤维细胞（myofibroblasts，MFB）是肝纤维化发生的中心环节。这些过程由自分泌和旁分泌作用的可溶性因子（即，细胞因子和趋化因子）。过去几十年的概念验证研究表明，肝MFB的失活和去除以及拮抗促纤维化因子原则上都适合于减弱正在进行的肝纤维化。尽管几种药物在肝纤维化的实验模型中显示出有效的抗纤维化活性，但目前还没有专门批准用于治疗肝纤维化的有效药物干预。药物干预通常由于对患病肝组织的药物供应不足和/或由于影响非靶细胞而产生的不良反应而受到阻碍。因此，迫切需要特异性结合仅在活化的HSC或转分化的MFB上表达的受体的靶向递送系统和通常可以改善药物向肝脏分布的递送系统。在这篇综述中，我们总结了当前将药物靶向输送到肝脏，特别是促纤维化肝细胞的策略。螯合分子，选择性蛋白质载体，脂质为基础的药物载体，病毒载体，转录靶向方法，治疗性肝和HSC特异性纳米颗粒，和基于miRNA的策略的适用性和有效性进行了讨论。这些递送系统中的一些已经在正在进行的肝纤维化的实验动物模型中成功测试，预计将转化为特异性靶向HSC的临床有用的治疗剂。
The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.