基质金属蛋白酶/基质金属蛋白酶水解酶对肝纤维化的调控及相关治疗药物研究进展

黄倩; 杨燕; 曾锐; 姚孟林; 孙琴

doi:10.3969/j.issn.1001-5256.2022.06.042

基质金属蛋白酶/基质金属蛋白酶水解酶对肝纤维化的调控及相关治疗药物研究进展

DOI: 10.3969/j.issn.1001-5256.2022.06.042

黄倩^1a,
杨燕^1b,
曾锐^1b,
姚孟林^1b,
孙琴^{1b, 2, , ,}

1a.
西南医科大学药学院，四川泸州 646000
1b.
西南医科大学中西医结合学院，四川泸州 646000
2.
西南医科大学附属中医医院中西医结合药物研究中心，四川泸州 646000

基金项目:

四川省科学技术厅项目 (2021YFH0150);

泸州市人民政府-西南医科大学高层次人才引进专项资助项目 (2017RC-002);

西南医科大学-西南医科大学附属中医医院联合项目 (Southwest Medical University〔2018〕 No.6-51)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：黄倩、杨燕对研究的思路或设计有同等的关键贡献；曾锐、张馨月、姚孟林参与了研究数据的获取分析解释过程；孙琴起草或修改文章关键内容。

详细信息

通信作者:
孙琴，zxyjhsq@swmu.edu.cn

黄倩、杨燕对本文贡献等同，为共同第一作者

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出版历程
- 收稿日期: 2021-10-11
- 录用日期: 2021-11-16
- 出版日期: 2022-06-20

Regulation of liver fibrosis by matrix metalloproteinase/tissue inhibitor of metalloproteinase and research advances in related therapeutic drugs

Qian HUANG^1a,
Yan YANG^1b,
Rui ZENG^1b,
Menglin YAO^1b,
Qin SUN^{1b, 2
, ,
,}

1a.
School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
1b.
School of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China
2.
Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China

Research funding:

Project of Science and Technology Department of Sichuan Province (2021YFH0150);

Luzhou People's Government-Southwest Medical University High-level Talents Introduction Special funding project (2017RC-002);

Southwest Medical University-Southwest Medical University Affiliated Hospital of Traditional Chinese Medicine Joint Project (Southwest Medical University〔2018〕 No.6-51)

More Information

Corresponding author: SUN Qin, zxyjhsq@swmu.edu.cn(ORCID: 0000-0002-6208-150X)

摘要

摘要: 肝纤维化是多种慢性肝损伤的共同后果，其主要特征是细胞外基质(ECM)产生与降解不平衡，导致间质胶原及其他基质成分积聚。而基质金属蛋白酶(MMP)及其特异性抑制剂[金属蛋白酶的组织抑制剂，基质金属蛋白酶水解酶(TIMP)]在胶原生成和溶解中起着关键作用。本文通过文献综述，整合基于MMP/TIMP的肝纤维化实验研究，并总结可能通过影响MMP/TIMP表达或活性发挥抗肝纤维化作用的组分，尝试阐明MMP/TIMP调控胶原平衡的机制，以期为抗肝纤维化药物的开发提供支持。
- 肝硬化 /
- 基质金属蛋白酶类 /
- 金属蛋白酶类组织抑制剂
Abstract: Liver fibrosis is the common consequence of various chronic liver injuries and is mainly characterized by the imbalance between the production and degradation of extracellular matrix, which leads to the accumulation of interstitial collagen and other matrix components. Matrix metalloproteinases (MMPs) and their specific inhibitors, i.e., tissue inhibitors of metalloproteinases (TIMPs), play a crucial role in collagen synthesis and lysis. Through a literature review, this article reviews the experimental studies of liver fibrosis based on MMPs/TIMPs, summarizes the components that may exert an anti-liver fibrosis effect by affecting the expression or activity of MMPs/TIMPs, and attempts to clarify the mechanism of MMPs/TIMPs in regulating collagen homeostasis, so as to provide support for the development of anti-liver fibrosis drugs.
- Liver Cirrhosis /
- Matrix Metalloproteinases /
- Tissue Inhibitor of Metalloproteinases

HTML全文

图 1 现已知结构的MMP分类图

注：信号肽、前肽及具有活化锌的催化结构是MMP的共性结构。

Figure 1. Classification diagram of MMP with known structure

下载: 全尺寸图片幻灯片

表 1 MMP主要功能分类表

Table 1. Main function classification table of MMP

种类	包含的MMP
胶原酶	MMP-1、8、13
明胶酶	MMP-2、9
基质降解酶	MMP-3、7、10、11、26
巨噬细胞弹性酶	MMP-12
膜型基质金属蛋白酶	MMP-14、15、16、17、24、25
其他	MMP-20、23、27、28

下载: 导出CSV

表 2 近5年基于TIMP与MMP发挥抗肝纤维化的天然产物研究情况

Table 2. Research on natural products of anti-liver fibrosis based on TIMP and MMP in recent 5 years

序号	组分名称	模型	MMP/TIMP	其他指标变化
1	全反式维甲酸^[32]	E	MMP2↓，TIMP1↓	TGFβ1、Smad2/3↓
2	白果内酯^[33]	C	MMP1↑，TIMP1↓	IL-1/6、TNFα
3	阿魏酸^[34]	E	MMP2、MMP9↑	TGFβ、Smad3↓
4	葫芦茶苷^[35]	A	MMP2↓，TIMP1/2↓	TGFβ1、COLⅠ↓
5	改性果胶^[36]	A	TIMP1↓	COL Ⅰα1、α-SMA、SOD↓
6	甜菜碱^[37]	A+C	MMP2↓，TIMP1/2↓	HYP、α-SMA↓
7	水飞蓟^[38]	A	MMP9↑	TGFβ、α-SMA↓
8	β-香树脂醇^[39]	A	TIMP1↓	TNFα、caspase 3↓
9	褪黑素^[40]	A	MMP13↑	TGFβ1、SOD↓
10	柴胡皂苷D^[41-42]	E	MMP2↑，TIMP1/2↓	TGFβ1↓
11	硫辛酸^[43]	A	MMP13↑	NF-κB↓
12	潘多汀A^[44]	D	MMP2↓，TIMP1↓	PDGF、TGFβ1↓
13	异绿原酸^[45]	C	TIMP1↓	LOX、TGFβ1、MCP-1、COL Iα1↓
14	二氢杨梅素^[46]	A	MMP1↑，TIMP1↓	CoL-1α1、α-SMA↓
注：COL Ⅰ，Ⅰ型胶原；COL Ⅰα1，Ⅰ型胶原α1亚型；HYP，羟脯氨酸；α-SMA，平滑肌动蛋白；caspase3，胱天蛋白酶3；SOD，超氧化物歧化酶；NF-κB，核因子κB；PDGF，血小板衍生生长因子；LOX，脂氧合酶；MCP-1，单核细胞趋化蛋白-1。A表示CCl₄诱导的体内纤维化模型；B表示DMN诱导的体内纤维化模型；C表示MCD诱导的体内肝纤维化模型；D表示硫代乙酰胺诱导的体内纤维化模型；E表示体外肝纤维化模型。

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