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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

引用本文:
Citation:

急性胰腺炎肝损伤的分子机制

DOI: 10.3969/j.issn.1001-5256.2022.11.045
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

Molecular mechanism of liver injury in acute pancreatitis

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: 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。

     

  • 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

    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

    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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