急性胰腺炎肝损伤的分子机制

徐文倩; 郭敏; 王晓; 吴瑶麒; 张近远; 李合国

doi:10.3969/j.issn.1001-5256.2022.11.045

急性胰腺炎肝损伤的分子机制

DOI: 10.3969/j.issn.1001-5256.2022.11.045

徐文倩¹,
郭敏²,
王晓²,
吴瑶麒¹,
张近远¹,
李合国^2, , ,

1.
河南中医药大学第一临床医学院，郑州 450000
2.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450000

基金项目:

河南省特色骨干学科中医学学科建设项目 (STG-ZYX02-202116);

河南省中医药科学研究重大专项课题 (2018ZYZD06);

国家自然科学基金 (81904161)

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：徐文倩、郭敏对研究的思路或设计有关键贡献，参与研究数据的获取分析解释过程；吴瑶麒、张近远参与撰写及修改文章；李合国、王晓对文章关键内容进行指导与修改。

详细信息

通信作者:
李合国，lhg1964@163.com

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出版历程
- 收稿日期: 2022-04-05
- 录用日期: 2022-05-07
- 出版日期: 2022-11-20

Molecular mechanism of liver injury in acute pancreatitis

1.
The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou 450000, China
2.
Department of Hepatology and Spleen-Stomach, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China

Research funding:

Henan Characteristic Backbone Discipline Construction Project of Traditional Chinese Medicine (STG-ZYX02-202116);

Major Special Project of Scientific Research of Traditional Chinese Medicine in Henan Province (2018ZYZD06);

National Natural Science Foundation of China (81904161)

More Information

Corresponding author: LI Heguo, lhg1964@163.com(ORCID: 0000-0002-5289-868X)

摘要

摘要: 急性胰腺炎进展十分迅速，如不及时控制，可能引发多脏器损伤，更有甚者会因器官功能衰竭而死亡。目前因肝衰竭而死亡的急性胰腺炎患者比例仍较大。肝脏与胰腺在生理上相互联系，在病理上相互影响。本文通过胰腺与肝脏的生理联系、细胞因子、炎症反应、氧化应激、微循环障碍及肠道菌群移位等6个方面对急性胰腺炎肝损伤的分子机制进行阐述。
- 急性胰腺炎 /
- 肝损伤 /
- 细胞因子类
Abstract: Acute pancreatitis often progresses rapidly, and if it is not controlled in time, it may lead to multiple organ injury and even death due to organ failure. At present, there is still a high proportion of patients with acute pancreatitis who died due to liver failure. The liver and the pancreas are interrelated physiologically and affect each other pathologically. This article elaborates on the molecular mechanism of liver injury in acute pancreatitis from the six aspects of the physiological relationship between the pancreas and the liver, cytokines, inflammatory response, oxidative stress, microcirculation disturbance, and intestinal flora translocation.
- Acute Pancreatitis /
- Liver Injury /
- Cytokines

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图 1 急性胰腺炎肝损伤中炎症反应分子机制

注：AcCoA，乙酰辅酶A；ATP，三磷酸腺苷；TAC cycle，三羧酸循环；LA，乳酸。

Figure 1. Molecular mechanism of inflammatory response in acute pancreatitis liver injury

下载: 全尺寸图片幻灯片

图 2 急性胰腺炎肝损伤中氧化应激分子机制

Figure 2. Molecular mechanism of oxidative stress in acute pancreatitis liver injury

下载: 全尺寸图片幻灯片

表 1 急性胰腺炎过程中细胞因子对肝脏的作用

Table 1. Effect of cytokines on liver during acute pancreatitis

细胞因子	对肝脏的作用机制
IL-17	促进Kupffer细胞极化为M1巨噬细胞，加重肝脏的炎症反应^[9]，IL-17可增强炎症反应过程中ERK的活性，诱导、加重肝损伤^[10]
IL-18	激活MAPK和PI3K/AKT信号通路诱导大量细胞因子产生，加重肝脏炎症损伤^[11]。同时，还能够刺激IFNγ的产生，并增强T淋巴细胞和NK细胞的能力
IL-1β	诱导炎性细胞产生IL-6、IL-18、TNFα、ICAM-1、Es及趋化因子等，介导炎症反应、肝细胞凋亡等过程^[12]
NLRP-3	NLRP-3作为炎症反应的核心环节，其活化有利于半胱天冬酶原-1、IL-1β、IL-18等中下游促炎因子的活化^[13]，还能够通过阻碍肝脏炎症反应过程中线粒体自噬来加重肝缺血/再灌注过程中的损伤^[14]
IL-6	诱导STAT3磷酸化，CXCL1与G蛋白结合后传递损伤部位信息，促使白细胞向损伤部位移动^[15]。作为CRP上游的炎症因子参与炎症和免疫反应，IL-6通过其信号转导因子gp130发挥功能，进而激活MAPK，启动JAK/STAT信号通路，促进急性胰腺炎肝损伤的发生^[16]
TNFα	激活T淋巴细胞，促进IL-1、IL-2、IL-6的分泌，诱发炎症反应，在高浓度时会破坏机体的免疫平衡，在炎症级联反应中起放大作用，释放具有单核细胞抑制作用的蛋白HMGB、HSP，继而激活单核细胞/巨噬细胞表达的TLR，释放细胞因子和趋化因子激活促炎反应^[17]
MIF	通过激活P38-MAPK和NF-κB信号传导途径促进巨噬细胞分泌IL-1、IL-6、IL-12、TNFα等炎症因子加重急性胰腺炎过程中的肝内胆管损伤和炎症反应^[18]
MCP-1	趋化单核细胞且激活单核细胞与免疫应答，与肝损伤的严重程度有关，反映肝巨噬细胞活化的程度^[19]
ICAM-1	参与白细胞和血管内皮细胞的黏附和聚集，使肝脏微血管通透性增加，血管内皮损伤，造成肝脏微循环障碍^[20]
MIP-2	激活Kupffer细胞释放，趋化和激活中性粒细胞释放多种炎症介质导致肝脏炎性损伤^[21]
ROS	参与蛋白酪氨酸磷酸化，激活NF-κB、JNK、MAPK、TXNIP/NLRP-3信号通路等炎性通路，下调PPARγ信号，促进炎性因子如IL-1、IL-6、TNFα、iNOS的产生。增加血清AST、ALT、TBil含量，加重肝损伤^[22]
注：ERK，细胞外信号调节激酶；MAPK，丝裂原活化蛋白激酶；PI3K/AKT，磷脂酰肌醇3-激酶/蛋白激酶B；NK细胞，自然杀伤细胞；ICAM-1，细胞间黏附分子；Es，E-选择素；NLRP-3，核苷酸结合寡聚化结构域样受体蛋白3；STAT3，信号传导与转录激活因子3；CXCL1，趋化因子(CXC基序)配体1；JAK，非受体酪氨酸激酶；CRP，C反应蛋白；gp130，糖蛋白130；HSP，热休克蛋白；TLR，Toll样受体；MCP-1，单核细胞趋化因子1；MIP-2，巨噬细胞炎性蛋白2；ROS，活性氧；JNK，蛋白激酶；TXNIP，硫氧还蛋白互作蛋白；PPARγ，过氧化物酶体增殖物激活受体γ；iNOS，诱导型一氧化氮合酶。

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