胆道纤维化狭窄的机制及其治疗研究进展
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1.中南大学湘雅医学院附属海口医院 肝胆胰外科,海南 海口 570208;2.海口市消化病临床研究与转化重点实验室,海南 海口 570208

作者简介:

张潇予,中南大学湘雅医学院附属海口医院硕士研究生,主要从事肝胆疾病基础和临床方面的研究。

基金项目:

海南省科技计划基金资助项目(ZDYF2021SHFZ053,YSPTZX202027);国家自然科学基金资助项目(82260136);海口市重点科技计划基金资助项目(2022-032)。


Research progress on the mechanism and treatment of fibrotic biliary stricture
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1.Department of Hepatobiliary and Pancreatic Surgery, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, China;2.Haikou Key Laboratory of Clinical Research and Transformation of Digestive Diseases, Haikou 570208, China

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    摘要:

    胆道狭窄,特别是腹腔镜胆囊切除及肝移植术引起的纤维化狭窄,是临床面临的难题之一。各种原因(如损伤、缺血、炎症和免疫疾病等)所致的细胞外基质过度沉积和上皮-间充质转化均可引起胆道纤维化,随后胆管上皮细胞增生、管壁变厚、胆道内腔逐渐纤维化狭窄。胆道狭窄后胆汁流通不畅、淤积,可导致化脓性胆管炎、胆道硬化,甚至肝衰竭,影响患者生活质量以及总体生存率。TGF-β、Wnt及Notch信号通路等是引起胆道纤维化的重要机制,其中非经典Wnt信号通路的Wnt/PCP信号通路在胆管上皮细胞增殖和纤维化进程中的作用最显著。成纤维细胞生长因子(FGF)可通过促进或抑制上述信号通路调控纤维化进程,且不同量的FGF对于纤维化过程的作用截然相反,然而其具体作用机制研究较少。经内镜逆行胰胆管造影及经皮经肝胆道造影下支架植入是胆道狭窄的首选治疗方法,内镜下支架植入受限及难治性胆道狭窄的患者则选择手术治疗,其他治疗方式还包括磁压榨吻合、胆管内射频消融、光动力疗法等。基于3D打印的组织工程支架具有仿生结构及良好的机械性能,可部分恢复或替代受损组织,实现胆道的再生修复,具有巨大应用前景。此外,胆道类器官在疾病建模、药物筛选和机制研究等方面也为胆道纤维修复提供了新途径。然而,尽管研究者使用不同活性材料制备的“人工胆管”在动物体内获得了较好的治疗效果,但目前均停留在实验阶段,而且未充分探索合成材料及支架上负载生物活性因子对胆道纤维化分子机制的影响。本文主要就胆道纤维化狭窄的可能机制,及其治疗方法进行综述,为临床胆道狭窄研究和诊疗提供借鉴。

    Abstract:

    Biliary stricture, particularly fibrotic stricture caused by laparoscopic cholecystectomy and liver transplantation, is one of the clinical challenges. Excessive deposition of extracellular matrix and epithelial-mesenchymal transition resulting from various causes (such as injury, ischemia, inflammation, and immune diseases) can lead to biliary fibrosis. This fibrosis subsequently causes biliary epithelial cell proliferation, thickening of the duct wall, and gradual fibrotic narrowing of the bile duct lumen. Biliary stricture leads to poor bile flow and stasis, which can result in conditions such as suppurative cholangitis, biliary sclerosis, and even liver failure, affecting patients' quality of life and overall survival rate. The TGF-β, Wnt, and Notch signaling pathways are important mechanisms leading to biliary fibrosis, with the Wnt/PCP signaling pathway of the non-canonical Wnt pathway playing a significant role in biliary epithelial cell proliferation and the fibrosis process. Fibroblast growth factors (FGF) can regulate the fibrosis process by promoting or inhibiting these signaling pathways, and different amounts of FGF have opposing effects on fibrosis; however, the specific mechanisms of their action are not well studied. Endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography with stent placement are the first-line treatments for biliary stricture. Surgical treatment is reserved for patients with refractory biliary strictures or those where endoscopic stent placement is limited. Other treatment options include magnetic compression anastomosis, intraductal radiofrequency ablation, and photodynamic therapy. Tissue-engineered stents based on 3D printing, which have a biomimetic structure and good mechanical properties, show promise in partially restoring or replacing damaged tissue, enabling the regeneration and repair of the bile ducts, and thus have significant potential for clinical application. Additionally, bile duct organoids offer new avenues for biliary fibrosis repair in disease modeling, drug screening, and mechanism studies. However, these studies are still experimental despite the promising therapeutic outcomes of "artificial bile ducts" made from different active materials in animal models. Moreover, the impact of synthetic materials and bioactive factor-coated stents on the molecular mechanisms of biliary fibrosis has not been fully explored. This review focuses on the potential mechanisms of fibrotic biliary stricture and its treatment options to provide insights for clinical research and treatment of biliary stricture.

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张潇予,向杨,张剑权.胆道纤维化狭窄的机制及其治疗研究进展[J].中国普通外科杂志,2024,33(8):1320-1329.
DOI:10.7659/j. issn.1005-6947.2024.08.013

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  • 收稿日期:2023-12-11
  • 最后修改日期:2024-03-20
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  • 在线发布日期: 2024-09-05