胆管反应的发生机制及治疗策略

单佳燕; 徐华谦; 柏承志; 张亮; 杜超; 张勇; 汤善宏

doi:10.12449/JCH260332

胆管反应的发生机制及治疗策略

DOI: 10.12449/JCH260332

单佳燕^{1, 2},
徐华谦²,
柏承志²,
张亮²,
杜超²,
张勇²,
汤善宏^{1, 2, , ,}

1.
成都中医药大学医学与生命科学学院，成都 610075
2.
西部战区总医院消化内科，成都 610083

基金项目:

四川省自然科学基金 (2025ZNSFSC1902)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：单佳燕负责设计论文框架及撰写论文；汤善宏负责指导撰写文章并最后定稿；徐华谦、柏承志、张勇、杜超、张亮负责论文修改。

详细信息

通信作者:
汤善宏， shanhongtang@163.com （ORCID： 0000-0001-6652-2942）

计量
- 文章访问数: 6
- HTML全文浏览量: 3
- PDF下载量: 2
- 被引次数: 0
出版历程
- 收稿日期: 2025-07-04
- 录用日期: 2025-09-17
- 出版日期: 2026-03-25

Mechanism of ductular reaction and related treatment strategies

1.
School of Medical and Life Sciences，Chengdu University of Traditional Chinese Medicine，Chengdu 610075，China
2.
Department of Gastroenterology，The General Hospital of Western Theater Command，Chengdu 610083，China

Research funding:

Natural Science Foundation of Sichuan (2025ZNSFSC1902)

More Information

Corresponding author: TANG Shanhong， shanhongtang@163.com （ORCID： 0000-0001-6652-2942）

摘要

摘要: 胆管反应（DR）是肝胆损伤后发生的适应性病理改变，本质上是一种修复反应，涉及胆管上皮细胞增殖、纤维化和炎症反应。随着对胆管上皮细胞生物学功能的认识，DR在疾病预后和治疗中的潜在价值逐渐成为研究热点。本文系统综述了DR发生发展的分子机制、作为治疗靶点的潜力及未来发展方向，并探讨靶向分子机制提示新型疗法，为突破当前胆管疾病治疗的瓶颈提供新方向。
- 胆管疾病 /
- 纤维化 /
- 治疗学
Abstract: Ductular reaction （DR） refers to the adaptive pathological changes that occur after hepatobiliary injury， and it is essentially a repair response involving the proliferation， fibrosis， and inflammation of biliary epithelial cell （BEC）. With the understanding of the biological function of BEC， the potential value of DR in disease prognosis and treatment has gradually become a research hotspot. This article systematically reviews the molecular mechanism of DR， its potential as a therapeutic target， and future development directions， as well as novel therapies suggested by targeting these molecular mechanisms， in order to provide a new direction for overcoming current bottlenecks in the treatment of bile duct diseases.
- Bile Duct Diseases /
- Fibrosis /
- Therapeutics

HTML全文

表 1 胆管反应出现的病因、再生细胞来源及调控机制的差异

Table 1. Differences in etiology， source of regenerative cells， and regulatory mechanisms of DR occurrence

病因	再生细胞来源	调控机制
胆道梗阻	Hering管内HPC分化、原位BEC与肝细胞增殖^［1，10］	（1）Hedgehog通路促进HPC向BEC的转换^［2］（2）Notch/YAP和Wnt通路促进肝细胞向BEC转换^［1］（3）胆汁酸激活TGR5，介导EGFR和ERK通路激活促进BEC增殖^［10］
华支睾吸虫感染	BEC^［10］	BEC出现增殖可能与MAPK、PI3K/Akt等通路有关^［10］
原发性胆汁性胆管炎	Hering管的HPC、BEC增殖^［2，10］	（1）Hedgehog通路可以促进HPC向BEC的转换^［2］（2）Hippo-YAP可能通过调节Survivin（生存素）表达来促进BEC增殖^［10］（3）炎性因子IL-6等可通过激活PI3K、JAK/STAT和 MAPK通路等触发BEC增殖^［10］
原发性硬化性胆管炎	门静脉周围腺体HPC分化、BEC增殖^［2，13］	（1）VEGF、FGF和PDGF等激活胞内PI3K/Akt、MEK/ ERK、Smad等信号，促进BEC的增殖^［13］（2）Hedgehog通路可以促进HPC向BEC的转换^［2］（3）T细胞、B细胞等通过分泌IL-6等细胞因子促进 BEC增殖^［12］；（4）分泌素促使纤维化相关物质TGF-β1等的表达增加，导致BEC增殖^［14］
肝胆管细胞癌	肿瘤边缘分布着中间型肝细胞和HPC^［1］	慢性肝脏炎症和纤维化触发了HPC向BEC的转化^［1］
HBV/HCV	肝实质内的HPC^［1，13］	（1）HBV X蛋白和HCV核心蛋白可促进HPC向BEC 转化^［13］（2）Hedgehog通路促进HPC向BEC的转换^［1］
代谢相关脂肪性肝病	汇管区与肝实质处出现HPC、BEC增殖^［15］	（1）Notch 通路可能是HPC向BEC表型分化的关键通路^［15］（2）脂肪酸等脂质超载导致E2F转录因子的激活，促使成熟BEC向活化BEC转化并增殖^［14］
注：HPC，肝祖细胞；BEC，胆管上皮细胞；TGR5，G蛋白偶联胆汁酸受体5；EGFR，表皮生长因子受体；ERK，胞外信号调节激酶；MAPK，丝裂原活化蛋白激酶；PI3K，磷脂酰肌醇3-激酶；Akt，蛋白激酶B；JAK， Janus激酶；STAT，信号转导与转录激活因子；FGF，成纤维细胞生长因子；PDGF，血小板衍生生长因子；MEK，丝裂原活化蛋白激酶激酶；Smad，母系抗十五表态蛋白同源物；VEGF，血管内皮生长因子；IL-6，白细胞介素6；TGF-β1，转化生长因子β1；NF-κB，核因子κB；HBV，乙型肝炎病毒；HCV，丙型肝炎病毒；E2F，E2因子。

下载: 导出CSV

参考文献(35)

[1]	SORRENTINO G. Microenvironmental control of the ductular reaction: Balancing repair and disease progression[J]. Cell Death Dis, 2025, 16( 1): 246. DOI: 10.1038/s41419-025-07590-4.
[2]	HU YH, BAO XY, ZHANG Z, et al. Hepatic progenitor cell-originated ductular reaction facilitates liver fibrosis through activation of hedgehog signaling[J]. Theranostics, 2024, 14( 6): 2379- 2395. DOI: 10.7150/thno.91572.
[3]	GUPTA V, SEHRAWAT TS, PINZANI M, et al. Portal fibrosis and the ductular reaction: Pathophysiological role in the progression of liver disease and translational opportunities[J]. Gastroenterology, 2025, 168( 4): 675- 690. DOI: 10.1053/j.gastro.2024.07.044.
[4]	KAMIMOTO K, KANEKO K, KOK CY, et al. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling[J]. eLife, 2016, 5: e15034. DOI: 10.7554/eLife.15034.
[5]	ESPAÑOL-SUÑER R, CARPENTIER R, van HUL N, et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice[J]. Gastroenterology, 2012, 143( 6): 1564- 1575.e7. DOI: 10.1053/j.gastro.2012.08.024.
[6]	SACKETT SD, LI ZD, HURTT R, et al. Foxl1 is a marker of bipotential hepatic progenitor cells in mice[J]. Hepatology, 2009, 49( 3): 920- 929. DOI: 10.1002/hep.22705.
[7]	TARLOW BD, PELZ C, NAUGLER WE, et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes[J]. Cell Stem Cell, 2014, 15( 5): 605- 618. DOI: 10.1016/j.stem.2014.09.008.
[8]	FONT-BURGADA J, SHALAPOUR S, RAMASWAMY S, et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer[J]. Cell, 2015, 162( 4): 766- 779. DOI: 10.1016/j.cell.2015.07.026.
[9]	ZHAO JY, LIN YY, YUE P, et al. Pathogenesis, progression and treatment of biliary fibrosis[J]. Chin J Dig Surg, 2024, 23( 7): 989- 1000. DOI: 10.3760/cma.j.cn115610-20240417-00208. 赵进玉, 林延延, 岳平, 等. 胆道纤维化的发生发展与治疗[J]. 中华消化外科杂志, 2024, 23( 7): 989- 1000. DOI: 10.3760/cma.j.cn115610-20240417-00208.
[10]	ZHAO JY, YUE P, MI NN, et al. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: From molecular mechanisms to clinical implications[J]. Med Rev, 2024, 4( 4): 326- 365. DOI: 10.1515/mr-2024-0029.
[11]	BAEK EB, EUN HS, SONG JY, et al. Vitamin D supplementation ameliorates ductular reaction, liver inflammation and fibrosis in mice by upregulating TXNIP in ductular cells[J]. Nat Commun, 2025, 16( 1): 4420. DOI: 10.1038/s41467-025-59724-z.
[12]	JIANG XJ, OTTERDAL K, CHUNG BK, et al. Cholangiocytes modulate CD100 expression in the liver and facilitate pathogenic T-helper 17 cell differentiation[J]. Gastroenterology, 2024, 166( 4): 667- 679. DOI: 10.1053/j.gastro.2023.11.283.
[13]	GUICCIARDI ME, TRUSSONI CE, LARUSSO NF, et al. The spectrum of reactive cholangiocytes in primary sclerosing cholangitis[J]. Hepatology, 2020, 71( 2): 741- 748. DOI: 10.1002/hep.31067.
[14]	CAI XR, TACKE F, GUILLOT A, et al. Cholangiokines: Undervalued modulators in the hepatic microenvironment[J]. Front Immunol, 2023, 14: 1192840. DOI: 10.3389/fimmu.2023.1192840.
[15]	HE YH, PAN JX, XU LM, et al. Ductular reaction in non-alcoholic fatty liver disease: When Macbeth is perverted[J]. World J Hepatol, 2023, 15( 6): 725- 740. DOI: 10.4254/wjh.v15.i6.725.
[16]	YILDIZ E, ALAM G EL, PERINO A, et al. Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs[J]. eLife, 2023, 12: e81926. DOI: 10.7554/eLife.81926.
[17]	ZHENG LH, HAN Y. Personalized diagnosis and treatment strategies for primary biliary cholangitis[J]. J Clin Hepatol, 2025, 41( 7): 1270- 1274. DOI: 10.12449/JCH250707. 郑林华, 韩英. 原发性胆汁性胆管炎个性化诊疗策略[J]. 临床肝胆病杂志, 2025, 41( 7): 1270- 1274. DOI: 10.12449/JCH250707.
[18]	LI B, ZHANG J, CHEN Y, et al. Alterations in microbiota and their metabolites are associated with beneficial effects of bile acid sequestrant on icteric primary biliary cholangitis[J]. Gut Microbes, 2021, 13( 1): 1946366. DOI: 10.1080/19490976.2021.1946366.
[19]	DAI Z, SONG GQ, BALAKRISHNAN A, et al. Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells[J]. Gut, 2020, 69( 6): 1104- 1115. DOI: 10.1136/gutjnl-2019-318812.
[20]	CAO WL, LI M, LIU JY, et al. LGR5 marks targetable tumor-initiating cells in mouse liver cancer[J]. Nat Commun, 2020, 11( 1): 1961. DOI: 10.1038/s41467-020-15846-0.
[21]	CAROLINA E, KUSE Y, OKUMURA A, et al. Generation of human iPSC-derived 3D bile duct within liver organoid by incorporating human iPSC-derived blood vessel[J]. Nat Commun, 2024, 15( 1): 7424. DOI: 10.1038/s41467-024-51487-3.
[22]	OGAWA M, JIANG JX, XIA S, et al. Generation of functional ciliated cholangiocytes from human pluripotent stem cells[J]. Nat Commun, 2021, 12( 1): 6504. DOI: 10.1038/s41467-021-26764-0.
[23]	CHEN L, ELIZALDE M, DUBOIS LJ, et al. GAL3ST1 deficiency reduces epithelial-mesenchymal transition and tumorigenic capacity in a cholangiocarcinoma cell line[J]. Int J Mol Sci, 2024, 25( 13): 7279. DOI: 10.3390/ijms25137279.
[24]	CHAIYADET S, TANGKAWATTANA S, SMOUT MJ, et al. Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini[J]. PLoS Pathog, 2022, 18( 9): e1010839. DOI: 10.1371/journal.ppat.1010839.
[25]	PICARD FSR, LUTZ V, BRICHKINA A, et al. IL-17A-producing CD8⁺ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts[J]. Gut, 2023, 72( 8): 1510- 1522. DOI: 10.1136/gutjnl-2022-327855.
[26]	Society of Microecology, Chinese Preventive Medical Association. Evidence-based guideline for pediatric clinical application of probiotics(2023)[J]. Chin J Pract Pediatr, 2024, 39( 1): 1- 15, 20. DOI: 10.19538/j.ek2024010601. 中华预防医学会微生态学分会. 益生菌儿科临床应用循证指南(2023)[J]. 中国实用儿科杂志, 2024, 39( 1): 1- 15, 20. DOI: 10.19538/j.ek2024010601.
[27]	LIU YH, CHEN KF, LI FY, et al. Probiotic Lactobacillus rhamnosus GG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice[J]. Hepatology, 2020, 71( 6): 2050- 2066. DOI: 10.1002/hep.30975.
[28]	MOON SH. Advances in IgG4-related hepatobiliary disease[J]. Korean J Pancreas Biliary Tract, 2020, 25( 2): 100- 106. DOI: 10.15279/kpba.2020.25.2.100.
[29]	LIU XL, PAN Q, CAO HX, et al. Lipotoxic hepatocyte-derived exosomal microRNA 192-5p activates macrophages through rictor/Akt/forkhead box transcription factor O1 signaling in nonalcoholic fatty liver disease[J]. Hepatology, 2020, 72( 2): 454- 469. DOI: 10.1002/hep.31050.
[30]	BARRY-HAMILTON V, SPANGLER R, MARSHALL D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment[J]. Nat Med, 2010, 16( 9): 1009- 1017. DOI: 10.1038/nm.2208.
[31]	LIU HY, YIN G, FRANCO LEONARDI B, et al. Reactive cholangiocyte-derived ORM2 drives a pathogenic modulation of the injured biliary niche through macrophage reprogramming[J]. Gut, 2025, 74( 10): e334425. DOI: 10.1136/gutjnl-2024-334425.
[32]	WU N, ZHOU TH, CARPINO G, et al. Prolonged administration of a secretin receptor antagonist inhibits biliary senescence and liver fibrosis in Mdr2^-/- mice[J]. Hepatology, 2023, 77( 6): 1849- 1865. DOI: 10.1097/HEP.0000000000000310.
[33]	CHEN ZW, KANG FP, XIE CK, et al. A novel Trojan horse nanotherapy strategy targeting the cPKM-STMN1/TGFB1 axis for effective treatment of intrahepatic cholangiocarcinoma[J]. Adv Sci, 2023, 10( 32): 2303814. DOI: 10.1002/advs.202303814.
[34]	HU CL, WANG L. Advances in the treatment of liver injury based on mesenchymal stem cell-derived exosomes[J]. Stem Cell Res Ther, 2024, 15( 1): 474. DOI: 10.1186/s13287-024-04087-3.
[35]	KIM Y, KANG K, LEE SB, et al. Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells[J]. J Hepatol, 2019, 70( 1): 97- 107. DOI: 10.1016/j.jhep.2018.09.007.