Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis.
Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis.
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DOI：
10.2174/187152811798104890
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
H. Zimmermann;F. Tacke
中科院分区：
文献类型：
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作者：
H. Zimmermann;F. Tacke
尽管对慢性肝病发病机制中的分子途径的了解越来越多，但选择性治疗选择很少，特别是在以肝脏瘢痕形成（称为纤维化）甚至完全肝硬化为特征的晚期疾病中。由于各种类型的损伤（例如，丙型肝炎、非酒精性脂肪性肝炎）通常被认为是纤维形成的关键先决条件。肝脏炎症的特征在于肝脏和循环中不同趋化因子途径的激活，允许不同的免疫细胞群通过窦状隙和窦后小静脉进入肝脏。最近的研究揭示了纤维化肝星状细胞（HSC）和浸润免疫细胞之间的密切相互作用，这从根本上推动了肝脏瘢痕形成。实验性纤维化和炎症模型已经证明，通过靶向单核细胞和巨噬细胞、T细胞群或NKT细胞，趋化因子途径如CCL 2（MCP-1）或其受体CCR 2、CCL 5（RANTES）或CCR 1/CCR 5等的破坏可以有效地防止胶原沉积。然而，某些单核细胞的迁移在纤维化过程中甚至可能是有益的。浸润的NK细胞和单核细胞衍生的巨噬细胞亚群可以促进细胞外基质的溶解。这强调了肝纤维化不是一个单向的过程，而是可以逆转到一定程度。本综述旨在总结免疫细胞浸润以及相关趋化因子系统对实验性肝纤维化的贡献，并将讨论可能的治疗应用于人类，特别强调单核细胞/巨噬细胞谱系及其相关趋化因子途径。
Despite increasing knowledge about molecular pathways in pathogenesis of chronic liver disease, selective therapeutic options are scarce, especially in advanced diseases characterized by scarring of the liver (termed fibrosis) or even complete cirrhosis. Sustained hepatic inflammation as a result to various types of injury (e.g., hepatitis C, nonalcoholic steatohepatitis) is generally accepted to represent the key prerequisite for fibrogenesis. Liver inflammation is characterized by an activation of distinct chemokine pathways in the liver and the circulation allowing distinct immune cell populations to enter the liver via sinusoids and postsinusoidal venules. Recent investigations have shed light on the intimate interactions between the fibrogenic hepatic stellate cell (HSC) and infiltrating immune cells, which fundamentally drive liver scarring. Experimental fibrosis and inflammation models have demonstrated that disruption of chemokine pathways such as CCL2 (MCP-1) or its receptor CCR2, CCL5 (RANTES) or CCR1 / CCR5 and others may efficiently prevent collagen deposition, by targeting monocytes and macrophages, T-cell populations or NKT cells. However, immigration of certain mononuclear cells may even be beneficial in the course of fibrosis. Infiltrating NK cells and monocyte-derived macrophage subsets can promote resolution of extracellular matrix. This emphasizes that hepatic fibrosis is not a unidirectional process, but can be reverted up to a certain point. The present review aims at summarizing the contribution of immune cell infiltration as well as related chemokine systems to experimental liver fibrosis and will discuss possible therapeutic applications in humans, with a special emphasis on the monocyte/macrophage lineage and their related chemokine pathways.