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髓系细胞在肝纤维化中的作用及其机制
DOI: 10.12449/JCH260123
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：崔承杰负责文献阅读及综述撰写；赵珍珍负责设计论文框架、绘制机制图；崔静、臧淑娴负责绘制机制图；付娜负责拟定写作思路，指导撰写综述并最后定稿。
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摘要: 肝纤维化是由多种慢性致病因素引起的以肝脏细胞外基质过度沉积、肝脏结构和功能异常为特征的复杂动态过程。若不及时进行抗纤维化治疗，可进展为肝硬化乃至肝癌。肝纤维化的发病机制复杂，既往研究多集中于肝星状细胞活化。而近年研究发现，髓系细胞因具有多向分化的潜能，亦可参与肝纤维化的发生发展。本文系统综述了髓系细胞在肝纤维化中的作用及调控机制，以期为临床诊断及靶向治疗提供科学参考依据。Abstract: Hepatic fibrosis is a complex dynamic process caused by multiple chronic pathogenic factors， characterized by excessive accumulation of liver extracellular matrix and abnormal liver structure and function. If anti-fibrotic treatment is not performed in time， it can progress to liver cirrhosis and even liver cancer. Hepatic fibrosis has a complex pathogenesis， and previous studies mainly focused on the activation of hepatic stellate cells. Recent studies have shown that myeloid cells have the potential of multi-directional differentiation and can also participate in the development and progression of hepatic fibrosis. This article systematically reviews the role and regulatory mechanism of myeloid cells in hepatic fibrosis， in order to provide a reference for clinical diagnosis and targeted therapy.
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Key words:
- Hepatic Fibrosis /
- Myeloid Cells /
- Mechanism
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注： MerTK，原癌基因酪氨酸激酶；Erk，外细胞质信号调节激酶；TGF，转化生长因子；PDGF，血小板衍生生长因子；ROS，活性氧；NLRP3，NOD样受体热蛋白结构域相关蛋白3；TNF，肿瘤坏死因子；TLR，Toll样受体；LPS，脂多糖；IL，白细胞介素；LOXL，赖氨酰氧化酶样蛋白；CCL，C-C趋化因子配体；CXCL，C-X-C基序趋化因子配体；HSC，肝星状细胞；ECM，细胞外基质；DC，树突状细胞；IDO1，吲哚胺2，3-双加氧酶1；PI3K，磷脂酰肌醇3激酶；AKT，蛋白激酶B；FoxO1，叉头盒O1；PD-L1，程序性死亡-配体1；PD-1，程序性死亡蛋白受体-1；IFN，干扰素；IL-1Ra，IL-1受体拮抗剂。
图 1 Kupffer细胞及DC在肝纤维化中的作用机制
Figure 1. Mechanism of Kupffer cells and dendritic cells in hepatic fibrosis
注： MDM，单核细胞来源巨噬细胞；LPS，脂多糖；iNOS，诱导型一氧化氮合酶；NO，一氧化氮；PGE2，前列腺素E2；IFN-γ，干扰素γ；TSP1，血小板反应蛋白1；Erk，外细胞质信号调节激酶；mTOR，雷帕霉素靶蛋白；SYK，脾酪氨酸激酶；HIF1α，缺氧诱导因子1α；PDGF，血小板衍生生长因子；HSC，肝星状细胞；BMDM，骨髓来源巨噬细胞；MMP，基质金属蛋白酶；HGF，肝生长因子；NK细胞，自然杀伤细胞；TRAIL，TNF相关凋亡诱导配体；SMPDL3B；鞘磷脂磷酸二酯酶样3B；IL，白细胞介素；TNF，肿瘤坏死因子；CSF1，集落刺激因子1；CCL，C-C驱化因子配体；CXCL，C-X-C基序驱化因子配体；OSM，抑瘤素M；VEGF，血管内皮生长因子；TGF-β，转化生长因子β；FGF21，成纤维细胞生长因子21；C3ar1，肝脏补体3a受体1；α-SMA，α平滑肌肌动蛋白；collagen Ⅰ，胶原蛋白Ⅰ；GRP78，葡萄糖调节蛋白78；IRE1α，肌醇需求酶1α；PDI，蛋白二硫键异构酶。
图 2 髓系巨噬细胞在肝纤维化中的作用机制
Figure 2. Mechanism of myeloid macrophages in hepatic fibrosis
注： JNK，c-Jun氨基末端激酶；TGF-β，转化生长因子-β；IL，白细胞介素；MMP，基质金属蛋白酶；PDGF，血小板衍生生长因子；α-SMA，α平滑肌肌动蛋白；PGE2，前列腺素E2；NLRP3，NOD样受体热蛋白结构域相关蛋白3；SMPDL3B，鞘磷脂磷酸二酯酶样3B；TLR：Toll样受体；ROS，活性氧；MPO，髓过氧化物酶；TAZ，具有PDZ结合序列的转录共激活因子；IHH，印度刺猬蛋白；GLI2，GLI锌指2；NET，中性粒细胞外陷阱；Col1A1，Ⅰ型胶原蛋白α1链；COX2，环氧化酶2；MDM，单核细胞来源巨噬细胞；HSC，肝星状细胞；ECM，细胞外基质；GM-CSF，粒细胞-巨噬细胞集落刺激因子；Erk，外细胞质信号调节激酶。
图 3 中性粒细胞在肝纤维化中的作用机制
Figure 3. Mechanism of neutrophils in hepatic fibrosis
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