肝巨噬细​​胞在肝纤维化：发病机理和潜在的治疗靶点

StephenW

BMJ Open Gastro 2016; 3:e000079 doi:10.1136/bmjgast-2016-000079
Hepatic macrophages in liver fibrosis: pathogenesis and potential therapeutic targets
Hai Li1, Hong You2, Xu Fan3, Jidong Jia2,
Author Affiliations
1Department of Hepatopancreatobiliary and Splenic Medicine, Affiliated Hospital, Logistics University of People's Armed Police Force, Tianjin, People's Republic of China
2Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, People's Republic of China
3State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
Received:
10 January 2016
Accepted:
18 April 2016
Published Online:
25 May 2016
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

  
Abstract

Hepatic macrophages account for the largest non-parenchymal cell population in the liver. Recent studies have found that hepatic macrophages have different functions in different stages of experimental liver fibrosis. Some studies found that there are different types of hepatic macrophages in the liver, although others have suggested that hepatic macrophages could switch to different phenotypes in different environments. Many studies demonstrated that while hepatic macrophages promoted fibrosis through the recruitment of proinflammatory immune cells, and the secretion of proinflammatory cytokines and chemokines in the early stages, these also promoted the resolution of hepatic fibrosis through the secretion of matrix metalloproteinases in the late stages. This article will review the current role played by hepatic macrophages in liver fibrosis and the potential therapeutic targets that modulate hepatic macrophages.
Keywords: HEPATIC FIBROSIS, MACROPHAGES, IMMUNOLOGY IN HEPATOLOGY


Potential targets of hepatic macrophages to treat liver fibrosis

Hepatic macrophages engage in close interactions with other non-parenchymal cells of the liver, especially HSCs.35 36 TGF-β1 and platelet derived growth factor (PDGF) secreted by hepatic macrophages can activate HSCs to fibroblasts, and the latter can proliferate and secrete abundant collagens and other ECM, thereby causing liver fibrosis.37

As hepatic macrophages have such great variability and huge numbers (10–15% of total liver cells), and also play important regulatory roles, these cells offer potential targets for treating liver fibrosis.

The first target involves preventing the infiltration of inflammatory mononuclear cells (Ly-6C+) through the inhibition of CCL2 (MCP-1) by RNA molecular technology,38 cleaning the intestinal tract with antibiotics to reduce the exposure of the liver to endotoxin, thereby reducing the infiltration of inflammatory cells.15 38–40

The second target involves antagonising the inflammatory cytokines released from hepatic macrophages, such as IL-1 and TNF-α,41 or promoting the apoptosis of activated HSCs, thereby attenuating hepatic fibrosis.42 43

The third target involves modulating the functional switch of hepatic macrophages via biological engineering of macrophages by nanoparticles44 45 or targeting drugs (dexamethasone vesicles) to control the functional transformation of hepatic macrophages.46

The fourth target involves promoting the functional restoration of macrophages by using CX3CL1 and IL-4 to accelerate the resolution of liver fibrosis.31 An ex vivo approach entails culturing peripheral blood monocytes in vitro under conditions favouring restorative hepatic macrophages47 or other desired subtypes48 and then intravenously infusing the cells back into patients to alleviate liver fibrosis.49

Hepatic macrophages play a key role in the progression and regression of fibrosis, although there are still many unanswered questions that need further investigation. Finally, tailored yet standardised methods for the purification and identification of functionally heterogeneous hepatic macrophages are urgently needed to yield reproducible and communicable results that shed light on the pathogenesis of liver fibrosis and offer novel potential therapeutic targets for liver fibrosis.3 30

StephenW

BMJ打开胃2016年; 3：e000079 DOI：10.1136 / bmjgast-2016-000079
肝巨噬细​​胞在肝纤维化：发病机理和潜在的治疗靶点
海丽1，香港You2，徐FAN3，冀东Jia2，
作者机构
肝胆胰脾医学附属医院，人民武装警察部队的后勤大学，天津，中国人民共和国教研室
2Liver研究中心，北京友谊医院，首都内侧大学，北京，中国人民共和国
蛋白质组学，北京蛋白质组研究中心，放射与辐射医学研究所，北京，中国人民共和国的3STATE重点实验室
收稿日期：
2016年1月10日
公认：
2016年4月18日
在线发布时间：
2016年5月25日
这是分布在符合知识共享署名非商业（CC BY-NC 4.0）的许可，允许他人分发，混音，改编，建立在这项工作的非商业化，并许可其在不同的衍生作品的开放存取文章方面，所提供的原始作品正确的引用和使用是非商业性。请参阅：http://creativecommons.org/licenses/by-nc/4.0/

  
抽象

肝的巨噬细胞占在肝脏中最大的非实质细胞群。最近的研究已经发现，肝巨噬细胞在实验性肝纤维化的不同阶段有不同的功能。一些研究发现，有不同类型的在肝脏的肝巨噬细胞的，虽然其他人认为肝的巨噬细胞可以切换到不同环境中的不同的表型。许多研究表明，尽管肝巨噬细胞，通过促炎免疫细胞的募集，并在早期阶段炎性细胞因子和趋化因子的分泌促进纤维化，这些也促进肝纤维化的分辨率通过基质金属蛋白酶在后期阶段的分泌。本文将回顾在肝纤维化肝巨噬细胞和肝脏调节的巨噬细胞潜在的治疗靶点发挥的当前角色。
关键词：肝纤维化，巨噬细胞，免疫学肝病


肝巨噬细​​胞治疗肝纤维化的潜在目标

肝的巨噬细胞参与同肝脏的其他非实质细胞密切的相互作用，尤其HSCs.35 36 TGF-β1和由肝巨噬细胞分泌能激活的HSC对成纤维细胞的血小板衍生的生长因子（PDGF），后者可以增殖并分泌丰富胶原和其他ECM，由此引起肝fibrosis.37

为肝的巨噬细胞具有如此大的变异性和巨大的数字（总肝细胞的10-15％），并且也发挥重要的调节作用，这些细胞提供潜在目标用于治疗肝纤维化。

第一目标涉及通过RNA分子技术预防炎性单核细胞的浸润（LY-6C +）通过CCL2（MCP-1）的抑制，38清洗肠道用抗生素以减少肝脏内毒素的曝光，从而降低炎性cells.15 38-40的浸润

第二目标涉及拮抗由肝巨噬细胞，如IL-1和TNF-α，41或促进活化的HSC的细胞凋亡，释放炎性细胞因子由此衰减肝fibrosis.42 43

第三个目标包括通过nanoparticles44 45通过调节巨噬细胞的生物工程肝巨噬细胞的功能开关或靶向药物（地塞米松囊泡）来控制肝macrophages.46职能转变

第四目标涉及使用CX3CL1和IL-4，加速肝fibrosis.31的离体方法的分辨率促进巨噬细胞的功能恢复嗣继承利于恢复肝macrophages47或其它所需subtypes48然后静脉内的条件下培养在体外外周血单核细胞注入细胞放回病人以减轻肝脏fibrosis.49

肝巨噬细​​胞发挥进展和纤维化的消退了关键作用，但仍有需要进一步调查许多悬而未决的问题。迫切需要用于纯化和功能多相肝巨噬细胞的识别最后，定制尚未标准化方法以产生对肝纤维化的发病机理阐明和肝fibrosis.3 30提供新的潜在的治疗靶标可再现和可通信的结果

StephenW

全文:
http://bmjopengastro.bmj.com/doi/full/10.1136/bmjgast-2016-000079