留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

YAP在肝脏缺血-再灌注损伤中的作用及其机制

杨文杰 成峰 王学浩 吕凌 张峰 饶建华

杨文杰, 成峰, 王学浩, 等. YAP在肝脏缺血-再灌注损伤中的作用及其机制[J]. 器官移植, 2020, 11(1): 54-59. doi: 10.3969/j.issn.1674-7445.2020.01.008
引用本文: 杨文杰, 成峰, 王学浩, 等. YAP在肝脏缺血-再灌注损伤中的作用及其机制[J]. 器官移植, 2020, 11(1): 54-59. doi: 10.3969/j.issn.1674-7445.2020.01.008
Yang Wenjie, Cheng Feng, Wang Xuehao, et al. Effect and mechanism of YAP in hepatic ischemia-reperfusion injury[J]. ORGAN TRANSPLANTATION, 2020, 11(1): 54-59. doi: 10.3969/j.issn.1674-7445.2020.01.008
Citation: Yang Wenjie, Cheng Feng, Wang Xuehao, et al. Effect and mechanism of YAP in hepatic ischemia-reperfusion injury[J]. ORGAN TRANSPLANTATION, 2020, 11(1): 54-59. doi: 10.3969/j.issn.1674-7445.2020.01.008

YAP在肝脏缺血-再灌注损伤中的作用及其机制

doi: 10.3969/j.issn.1674-7445.2020.01.008
基金项目: 

国家自然科学基金 81871259

国家自然科学基金 81400650

江苏省“六大人才高峰”高层次人才项目 WSW-019

详细信息
    作者简介:

    杨文杰,男,1995年生,硕士,研究方向为肝移植与移植免疫,Email:1789503880@qq.com

    通讯作者:

    张峰,男,1958年生,教授,博士生导师,研究方向为肝移植的临床与基础研究,Email: zhangfeng1958@hotmail.com

    饶建华,男,1983年生,博士后,主治医师,研究方向为肝移植的临床与基础研究,Email: raojh@njmu.edu.cn

  • 中图分类号: R617

Effect and mechanism of YAP in hepatic ischemia-reperfusion injury

More Information
  • 摘要:   目的  探究Yes相关蛋白(YAP)在小鼠肝脏缺血-再灌注损伤(IRI)中的作用及机制。  方法  雄性C57BL/6小鼠40只,按随机数字表法分为假手术组(Sham组)、溶血磷脂酸(LPA)+Sham组、IRI组、LPA+IRI组,每组10只。缺血-再灌注6 h后,收集肝组织和血清标本。检测血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的水平,苏木素-伊红(HE)染色、免疫组织化学(免疫组化)染色检测肝组织病理学改变和巨噬细胞浸润情况,蛋白印迹法分析肝组织YAP的蛋白表达水平,逆转录聚合酶链反应(RT-PCR)法评估炎症因子肿瘤坏死因子(TNF)-α、诱生型一氧化氮合酶(iNOS)、白细胞介素(IL)-1和IL-6的信使核糖核酸(mRNA)表达水平。  结果  蛋白印迹结果显示,LPA+IRI组YAP的蛋白表达水平较IRI组明显升高。与Sham组相比,IRI组ALT和AST显著增高(均为P < 0.05);LPA+IRI组较IRI组血清ALT和AST显著降低(均为P < 0.05)。HE染色显示,Sham组和LPA+Sham组肝细胞形态正常;LPA+IRI组和IRI组出现肝脏淤血、肝细胞肿胀和肝小叶结构异常等病理改变;LPA+IRI组相较于IRI组病理改变程度减轻。RT-PCR提示,LPA+IRI组中炎症因子TNF-α、iNOS、IL-1和IL-6的mRNA表达水平较IRI组降低(均为P < 0.05)。免疫组化显示,LPA部分抑制了IRI后缺血组织巨噬细胞浸润。  结论  YAP能明显缓解肝脏IRI,其作用机制与调控巨噬细胞募集和活化相关。

     

  • 图  1  各组小鼠肝组织YAP蛋白表达水平的比较

    注:与Sham组比较,aP < 0.001;与IRI组比较,bP < 0.001。

    Figure  1.  Comparison of YAP protein expression level in liver tissue in each group of mice

    图  2  各组小鼠血清ALT和AST的比较

    注:与Sham组比较,aP < 0.01;与IRI组比较,bP < 0.01。

    Figure  2.  Comparison of ALT and AST in serum in each group of mice

    图  3  各组小鼠肝组织病理学改变及评分的比较

    注:A~D图分别为Sham组、LPA+Sham组、IRI组、LPA+IRI组(HE,×100);E图为病理学评分的比较,与IRI组比较,aP < 0.01。

    Figure  3.  Comparison of the pathological changes and the scores of liver tissue in each group of mice

    图  4  各组小鼠肝组织中炎症因子mRNA表达水平的比较

    注:与Sham组比较,aP < 0.05;与IRI组比较,bP < 0.05。

    Figure  4.  Comparison of the expression of inflammatory factor mRNA in liver tissue in each group of mice

    图  5  各组小鼠肝组织巨噬细胞浸润程度的比较

    注:A~D图分别为Sham组、LPA+Sham组、IRI组、LPA+IRI组(免疫组化,×200);E图为各组巨噬细胞浸润数量的比较,与Sham组比较,aP < 0.05,与IRI组比较,bP < 0.05。

    Figure  5.  Comparison of macrophage infiltration in liver tissue in each group of mice

  • [1] DATTA G, FULLER BJ, DAVIDSON BR. Molecular mechanisms of liver ischemia reperfusion injury: insights from transgenic knockout models[J]. World J Gastroenterol, 2013, 19(11):1683-1698. DOI: 10.3748/wjg.v19.i11.1683.
    [2] ZHAI Y, PETROWSKY H, HONG JC, et al. Ischaemia-reperfusion injury in liver transplantation--from bench to bedside[J]. Nat Rev Gastroenterol Hepatol, 2013, 10(2):79-89. DOI: 10.1038/nrgastro.2012.225.
    [3] WOOLBRIGHT BL, JAESCHKE H. The impact of sterile inflammation in acute liver injury[J]. J Clin Transl Res, 2017, 3(Suppl 1):170-188. DOI: 10.18053/jctres.03.2017S1.003.
    [4] PLOUFFE SW, MENG Z, LIN KC, et al. Characterization of Hippo pathway components by gene inactivation[J]. Mol Cell, 2016, 64(5):993-1008. DOI: 10.1016/j.molcel. 2016.10.034.
    [5] YIMLAMAI D, FOWL BH, CAMARGO FD. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer[J]. J Hepatol, 2015, 63(6):1491-1501. DOI: 10.1016/j.jhep.2015.07.008.
    [6] PATEL SH, CAMARGO FD, YIMLAMAI D. Hippo signaling in the liver regulates organ size, cell fate, and carcinogenesis[J]. Gastroenterology, 2017, 152(3):533-545. DOI: 10.1053/j.gastro.2016.10.047.
    [7] PARK JA, KWON YG. Hippo-YAP/TAZ signaling in angiogenesis[J]. BMB Rep, 2018, 51(3):157-162. doi: 10.5483/BMBRep.2018.51.3.016
    [8] KANG LI, MARS WM, MICHALOPOULOS GK. Signals and cells involved in regulating liver regeneration[J]. Cells, 2012, 1(4):1261-1292. DOI: 10.3390/cells1041261.
    [9] WANG Y, YU A, YU FX. The Hippo pathway in tissue homeostasis and regeneration[J]. Protein Cell, 2017, 8(5): 349-359. DOI: 10.1007/s13238-017-0371-0.
    [10] RAO J, YUE S, FU Y, et al. ATF6 mediates a pro-inflammatory synergy between ER stress and TLR activation in the pathogenesis of liver ischemia-reperfusion injury[J]. Am J Transplant, 2014, 14(7):1552-1561. DOI: 10.1111/ajt.12711.
    [11] JAESCHKE H, WOOLBRIGHT BL. Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species[J]. Transplant Rev (Orlando), 2012, 26(2):103-114. DOI: 10.1016/j.trre.2011.10.006.
    [12] FRANCIS A, BAYNOSA R. Ischaemia-reperfusion injury and hyperbaric oxygen pathways: a review of cellular mechanisms[J]. Diving Hyperb Med, 2017, 47(2):110-117. http://cn.bing.com/academic/profile?id=1668a9239048b784c5994d9f77ad3841&encoded=0&v=paper_preview&mkt=zh-cn
    [13] MUKHOPADHYAY P, HORVÁTH B, ZSENGELLĖR Z, et al. Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia-reperfusion: therapeutic potential of mitochondrially targeted antioxidants[J]. Free Radic Biol Med, 2012, 53(5):1123-1138. DOI: 10.1016/j.freeradbiomed.2012.05.036.
    [14] JU C, TACKE F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies[J]. Cell Mol Immunol, 2016, 13(3):316-327. DOI: 10.1038/cmi.2015.104.
    [15] LU L, ZHOU H, NI M, et al. Innate immune regulations and liver ischemia-reperfusion injury[J]. Transplantation, 2016, 100(12):2601-2610. doi: 10.1097/TP.0000000000001411
    [16] LU TF, YANG TH, ZHONG CP, et al. Dual effect of hepatic macrophages on liver ischemia and reperfusion injury during liver transplantation[J]. Immune Netw, 2018, 18(3):e24. DOI: 10.4110/in.2018.18.e24.
    [17] LV Y, KIM K, SHENG Y, et al. YAP controls endothelial activation and vascular inflammation through TRAF6[J]. Circ Res, 2018, 123(1):43-56. DOI: 10.1161/CIRCRESAHA.118.313143.
    [18] LEE KK, YONEHARA S. Identification of a mechanism that couples multisite phosphorylation of Yes-associated protein (YAP) with transcriptional coactivation and regulation of apoptosis[J]. J Biol Chem, 2016, 291(9): 4844-4845. DOI: 10.1074/jbc.A111.296954.
    [19] FENG J, LI H, ZHANG Y, et al. Mammalian STE20-like kinase 1 deletion alleviates renal ischaemia-reperfusion injury via modulating mitophagy and the AMPK-YAP signalling pathway[J]. Cell Physiol Biochem, 2018, 51(5):2359-2376. DOI: 10.1159/000495896.
    [20] COSSET É, ILMJÄRV S, DUTOIT V, et al. Glut3 addiction is a druggable vulnerability for a molecularly defined subpopulation of glioblastoma[J]. Cancer Cell, 2017, 32(6):856-868. DOI: 10.1016/j.ccell.2017.10.016.
    [21] LI X, YAO W, YUAN Y, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma[J]. Gut, 2017, 66(1):157-167. DOI: 10.1136/gutjnl-2015-310514.
    [22] BAECK C, WEHR A, KARLMARK KR, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury[J]. Gut, 2012, 61(3):416-426. DOI: 10.1136/gutjnl-2011-300304.
    [23] PYONTECK SM, AKKARI L, SCHUHMACHER AJ, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression[J]. Nat Med, 2013, 19(10): 1264-1272. DOI: 10.1038/nm.3337.
    [24] HUANG YJ, YANG CK, WEI PL, et al. Ovatodiolide suppresses colon tumorigenesis and prevents polarization of M2 tumor-associated macrophages through YAP oncogenic pathways[J]. J Hematol Oncol, 2017, 10(1):60. DOI: 10.1186/s13045-017-0421-3.
    [25] LI C, JIN Y, WEI S, et al. Hippo signaling controls NLR family pyrin domain containing 3 activation and governs immunoregulation of mesenchymal stem cells in mouse liver injury[J]. Hepatology, 2019, 70(5):1714-1731. DOI: 10.1002/hep.30700.
  • 加载中
图(5)
计量
  • 文章访问数:  291
  • HTML全文浏览量:  139
  • PDF下载量:  21
  • 被引次数: 0
出版历程
  • 收稿日期:  2019-11-02
  • 网络出版日期:  2021-01-19
  • 刊出日期:  2020-01-15

目录

    /

    返回文章
    返回