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摘要
胆道上皮细胞(即胆管细胞)的持续暴露于诸如无序免疫、遗传改变、缺血、有毒化合物或者感染因子等不同因素中会导致慢性门静脉炎症反应最终会导致胆道纤维化。该阶段的特点是增加形成瘢痕的细胞外基质蛋白(ECM)的产生和沉淀,特别是I型和III型原纤维胶原蛋白,但包括弹性纤维的两种成分的其他ECM成分如弹性蛋白和纤维蛋白-1。负责胶原蛋白沉积的主要细胞介质是活化的肝星状细胞(HSC),并且在较小程度上是通过可溶性炎症介质(即细胞因子,生长因子)和细胞外基质组分活化的门静脉成纤维细胞。除非能够有效治疗胆汁性损伤的根本原因,否则这些过程可能最终导致失代偿性肝硬化,也可为原发性肿瘤的发展和生长提供理想的微环境。最近的证据表明纤维化是一个动态和潜在的可逆过程。由于大多数慢性胆汁性疾病的疗效仍然局限于移植,因此急需澄清胆道纤维化发展所涉及的分子途径,并确定新的治疗靶点。在本综述中,我们描述了协调胆管细胞/肌成纤维细胞串扰的细胞和分子调节因子,并确定最有希望进行治疗靶向的信号过程。
关键词: 胆道纤维化,导管反应,肌成纤维细胞,反应性胆管细胞,治疗靶点
Current Drug Targets
Title:New Advances in the Molecular Mechanisms Driving Biliary Fibrosis and Emerging Molecular Targets
Volume: 18 Issue: 8
关键词: 胆道纤维化,导管反应,肌成纤维细胞,反应性胆管细胞,治疗靶点
摘要: Persistent exposure of biliary epithelial cells (i.e., cholangiocytes) to diverse factors such as disordered immunity, genetic alterations, ischemia, toxic compounds and/or infectious agents leads to a chronic portal inflammatory response which eventually progresses to biliary fibrosis. This stage is characterized by increased production and deposition of scar-forming extracellular matrix proteins (ECM), in particular fibrillar collagen types I and III, but including other ECM constituents such as elastin and fibrillin-1, both components of elastic fibers. The major cellular mediators responsible for collagen deposition are activated hepatic stellate cells (HSCs) and to a lesser extent, portal myofibroblasts, which are activated by soluble inflammatory mediators (i.e., cytokines, growth factors) and extracellular matrix components. Unless the underlying cause of biliary injury can be effectively treated, these processes may ultimately lead to decompensated cirrhosis and can also provide ideal microenvironments for the development and growth of primary tumors. Recent evidence indicates that fibrosis is a dynamic and potentially reversible process. As the curative options for most chronic biliary diseases remain limited to transplantation, there is an urgent need to clarify the molecular pathways involved in the development of biliary fibrosis and identify new therapeutic targets. In this review we describe the cellular and molecular regulators that orchestrate the cholangiocyte /myofibroblast cross-talk and identify the signaling processes that are most promising for therapeutic targeting.
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Cite this article as:
New Advances in the Molecular Mechanisms Driving Biliary Fibrosis and Emerging Molecular Targets, Current Drug Targets 2017; 18 (8) . https://dx.doi.org/10.2174/1389450116666150427155035
DOI https://dx.doi.org/10.2174/1389450116666150427155035 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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