Alimujiang·Abudureyimu,Lin Feng,Wang Haojie,et al.Activation of Notch signaling pathway collaborated with macrophages for promoting liver fibrosis in biliary atresia[J].Journal of Clinical Pediatric Surgery,,20():376-381.[doi:10.12260/lcxewkzz.2021.04.014]
Activation of Notch signaling pathway collaborated with macrophages for promoting liver fibrosis in biliary atresia
- Keywords:
- Biliary Atresia/ET; Liver Cirrhosis/CO; Liver Cirrhosis/ET; Notch Signaling Pathway; Macrophages
- CLC:
- R726;R657.4+4
- Abstract:
- Objective To explore the relationship of activation of Notch signaling pathway with related inflammatory molecular mechanisms in fibrotic progression of children with biliary atresia (BA).Methods From January 2019 to November 2020, 20 children of biliary malformation were recruited from Tianjin Children’s Hospital.The causes were BA (n=15) and congenital biliary dilatation (CBD, n=5).Intraoperative liver biopsy samples were collected.HES-1, an effector molecule of Notch signaling pathway, and M2 macrophage marker CD163, cytokines IL-6 and PDGF-AA in liver tissue were detected by immunohistochemistry.Results As compared with CBD, the expression of HES-1, CD163, IL-6 and PDGF-AA in the liver tissues of children with BA markedly increased (0.044±0.017 vs.0.143±0.027) (0.089±0.020 vs.0.259±0.111) (0.070±0.007 vs.0.216±0.028) (0.155±0.019 vs.0.220±0.044).The expression of HES-1 was positively correlated with the expression of CD163 (r=0.687, P<0.01).And HES-1, CD163, IL-6 and PDGF-AA were positively correlated with the extent of liver fibrosis (rs=0.791, rs=0.912, rs=0.920, rs=0.887, P<0.001). Conclusion Involved in the process of hepatic fibrosis in biliary atresia, Notch signaling pathway has a synergistic effect with M2 macrophages.
References:
1 詹江华,余晨.胆道闭锁发病机制研究概述与启示[J].临床小儿外科杂志,2018,17(11):801-804.DOI:10.3969/j.issn.1671-6353.2018.11.001. Zhan JH,Yu C.Overview of the pathogenesis of biliary atresia and its implication[J].J Clin Ped Sur,2018,17(11):801-804.DOI:10.3969/j.issn.1671-6353.2018.11.001.
2 郑珊.胆道闭锁患儿获得长期生存需要关注的问题[J].临床小儿外科杂志,2020,19(6):469-472.DOI:10.3969/j.issn.1671-6353.2020.06.001. Zheng S.Several outstanding issues in long-term survival of children with biliary atresia[J].J Clin Ped Sur,2020,19(6):469-472.DOI:10.3969/j.issn.1671-6353.2020.06.001.
3 詹江华,夏强.规范Kasai手术为肝移植做准备[J].中华小儿外科杂志,2019,40(5):385-387.DOI:10.3760/cma.j.issn.02533006.2019.05.001. Zhan JH,Xia Q.Standardizing Kasai’s procedure for preparing for liver transplantation[J].Chin J Pediatr Surg,2019,40(5):385-387.DOI:10.3760/cma.j.issn.02533006.2019.05.001.
4 Zheng Q,Zhang S,Ge L,et al.Investigation into multi-centre diagnosis and treatment strategies of biliary atresia in mainland China[J].Pediatr Surg Int,2020,36(7):827-833.DOI:10.1007/s00383-020-04679-z.
5 贾金富,詹江华,余晨,等.Notch-1、Jagged-1、Hes-1在胆道闭锁患儿肝纤维化中的表达及意义[J].中华小儿外科杂志,2019,40(5):399-403.DOI:10.3760/cma.j.issn.0253-3006.2019.05.004. Jia JF,Zhan JH,Yu C,et al.Expression and significance of Notch-1,Jagged-1 and Hes-1 in liver fibrosis of children with biliary atresia[J].Chin J Pediatr Surg,2019,40(5):399-403.DOI:10.3760/cma.j.issn.0253-3006.2019.05.004.
6 Nakano T,Fukuda D,Koga J,et al.Delta-Like Ligand 4-Notch Signaling in Macrophage Activation[J].Arterioscler Thromb Vasc Biol,2016,36(10):2038-2047.DOI:10.1161/ATVBAHA.116.306926.
7 Nakano T,Katsuki S,Chen M,et al.Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation via the interplay of OATP2B1 and Dll4-Notch signaling[J].Circulation,2019,139(1):78-96.DOI:10.1161/CIRCULATIONAHA.118.034588.
8 Wang L,Yang Y,Chen Y,et al.Early differential diagnosis methods of biliary atresia:a meta-analysis[J].Pediatr Surg Int,2018,34(4):363-380.DOI:10.1007/s00383-018-4229-1.
9 Ge L,Zhan J,Gao W,et al.Relevant factors for early liver transplantation after Kasai portoenterostomy[J].BMC Pediatr,2020,20(1):484.DOI:10.1186/s12887-020-02355-8.
10 Wang J,Xu Y,Chen Z,et al.Liver immune profiling reveals pathogenesis and therapeutics for biliary atresia[J].Cell,2020.DOI:10.1016/j.cell.2020.10.048.
11 彭琴,赵绅君,李武.肝纤维化相关信号转导通路研究进展[J].临床肝胆病杂志,2017,33(5):954-958.DOI:10.3969/j.issn.1001-5256.2017.05.035. Peng Q,Zhao SJ,Li W.Research advances in signaling pathways involved in the development of hepatic fibrosis[J].J Clin Hepatol,2017,33(5):954-958.DOI:10.3969/j.issn.1001-5256.2017.05.035.
12 朱倩仪,王立,詹江华.Notch信号通路在胆道闭锁中的研究进展[J].中华小儿外科杂志,2018,39(4):317-320.DOI:10.3760/cma.j.issn.0253-3006.2018.04.017. Zhu QY,Wang L,Zhan JH.Research advances of Notch signaling pathway in biliary atresia[J].J Chin Pediatr Surg,2018,39(4):317-320.DOI:10.3760/cma.j.issn.0253-3006.2018.04.017.
13 Mitchell E,Gilbert M,Loomes KM.Alagille Syndrome[J].Clin Liver Dis,2018,22(4):625-641.DOI:10.1016/j.cld.2018.06.001.
14 Zhang K,Zhang YQ,Ai WB,et al.Hes1,an important gene for activation of hepatic stellate cells,is regulated by Notch1 and TGF-beta/BMP signaling[J].World J Gastroenterol,2015,21(3):878-887.DOI:10.3748/wjg.v21.i3.878.
15 Tacke F,Zimmermann HW.Macrophage heterogeneity in liver injury and fibrosis[J].Journal of hepatology,2014,60(5):1090-1096.DOI:10.1016/j.jhep.2013.12.025.
16 Krenkel O,Tacke F.Liver macrophages in tissue homeostasis and disease[J].Nat Rev Immunol,2017,17(5):306-321.DOI:10.1038/nri.2017.11.
17 Yang Y,Dong R,Zheng C,et al.Infiltration of polarized macrophages associated with liver fibrosis in infants with biliary atresia[J].J Pediatr Surg,2017,52(12):1984-1988.DOI:10.1016/j.jpedsurg.2017.08.045.
18 Palaga T,Buranaruk C,Rengpipat S,et al.Notch signaling is activated by TLR stimulation and regulates macrophage functions[J].Eur J Immunol,2008,38(1):174-183.DOI:10.1002/eji.200636999.
19 Pradere JP,Kluwe J,De Minicis S,et al.Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice[J].Hepatology,2013,58(4):1461-1473.DOI:10.1002/hep.26429.
20 Tacke F.Targeting hepatic macrophages to treat liver diseases[J].J Hepatol,2017,66(6):1300-1312.DOI:10.1016/j.jhep.2017.02.026.
21 Vannella KM,Wynn TA.Mechanisms of organ injury and repair by macrophages[J].Annu Rev Physiol,2017,79:593-617.DOI:10.1146/annurev-physiol-022516-034356.
22 Kazlauskas A.PDGFs and their receptors[J].Gene,2017,614:1-7.DOI:10.1016/j.gene.2017.03.003.
23 Fielding CA,Jones GW,McLoughlin RM,et al.Interleukin-6 signaling drives fibrosis in unresolved inflammation[J].Immunity,2014,40(1):40-50.DOI:10.1016/j.immuni.2013.10.022.
24 Wilasco MIA,Uribe-Cruz C,Santetti D,et al.IL-6,TNF-α,IL-10,and nutritional status in pediatric patients with biliary atresia[J].J Pediatr (Rio J),2017,93(5):517-524.DOI:10.1016/j.jped.2016.11.009.
25 杨森,慕永平,张珏.原发性胆汁性肝硬化患者外周血单核巨噬细胞中Notch受体表达情况[J].胃肠病学和肝病学杂志,2020,29(3):332-335.DOI:10.3969/j.issn.1006-5709.2020.03.020. Yang S,Mu YP,Zhang Y.Expression of Notch receptor on mononuclear macrophages in patients with primary biliary cirrhosis[J].Chin J Gastroenterol Hepatol,2020,29(3):332-335.DOI:10.3969/j.issn.1006-5709.2020.03.020.
Memo
收稿日期:2020-12-31。
基金项目:新疆维吾尔自治区自然科学基金（编号：2019D01A12）
作者简介:阿里木江·阿不都热依木,Email:alm0223@163.com