慢加急性肝衰竭动物模型的研究进展：从两阶段构建到三阶段全病程模拟

陆嘉; 卢捷; 项晓刚

doi:10.12449/JCH260805

慢加急性肝衰竭动物模型的研究进展：从两阶段构建到三阶段全病程模拟

DOI: 10.12449/JCH260805

上海交通大学医学院附属瑞金医院感染科，上海 200025

基金项目:

国家自然科学基金 (82570730);

国家自然科学基金 (82170619);

国家自然科学基金 (81970544);

上海市东方英才计划拔尖人才项目 (BJJY2024072);

上海市公共卫生体系建设三年行动计划（2023—2025年）学科带头人项目 (GWVI-11.2-XD03)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：陆嘉负责检索和整理文献，撰写论文；项晓刚、卢捷负责设计撰写思路及修改论文。

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通信作者:
项晓刚， shine-xxg@163.com （ORCID： 0000-0003-0999-2950）

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出版历程
- 收稿日期: 2026-05-14
- 录用日期: 2026-08-05
- 出版日期: 2026-08-25

Research advances in animal models of acute-on-chronic liver failure: From two-stage modeling to three-stage full-course simulation

Department of Infectious Diseases，Ruijin Hospital，Shanghai Jiao Tong University School of Medicine，Shanghai 200025，China

Research funding:

National Natural Science Foundation of China (82570730);

National Natural Science Foundation of China (82170619);

National Natural Science Foundation of China (81970544);

Shanghai Oriental Talents Program Top-notch Talent Project (BJJY2024072);

Project for Discipline Leaders in the Three-year Action Plan （2023—2025） for Strengthening the Construction of Public Health System in Shanghai (GWVI-11.2-XD03)

More Information

Corresponding author: Xiang Xiaogang， shine-xxg@163.com（ORCID： 0000-0003-0999-2950）

摘要

摘要: 慢加急性肝衰竭（ACLF）是一种以急性肝功能失代偿、肝外器官损伤和短期高病死率为主要特征的严重临床综合征，其发病机制复杂，目前尚未完全阐明。ACLF动物模型在该疾病的研究中至关重要，不仅能为机制研究提供良好的基础，也能为临床实践提供实验依据，有助于推动疾病诊治的进步。本文系统总结了目前常用的ACLF动物模型，比较不同模型的构建方法、病理生理特点及优缺点，并综述该领域内动物模型研究的最新进展与创新干预策略，以期为ACLF动物模型的优化、标准化及进一步应用提供参考。
- 慢加急性肝功能衰竭 /
- 模型，动物 /
- 病理过程
Abstract: Acute-on-chronic liver failure （ACLF） is a severe clinical syndrome characterized by acute decompensation of liver function， extrahepatic organ injury， and a high short-term mortality rate， with a complex pathogenesis that has not yet been fully clarified. Animal models of ACLF play a crucial role in disease research， since they not only provide a solid foundation for mechanistic studies， but also offer experimental evidence for clinical practice， thereby helping to promote advances in diagnosis and treatment. This article systematically reviews the commonly used animal models of ACLF， compares the establishment methods， pathophysiological characteristics， advantages， and limitations of different models， and discusses the latest research advances in animal models and innovative therapeutic strategies in the field， in order to provide a reference for further optimization， standardization， and application of animal models for ACLF.
- Acute-On-Chronic Liver Failure /
- Models， Animal /
- Pathologic Processes

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注： a，“ACLF三阶段”小鼠模型构建流程时间示意图；b，“ACLF三阶段”小鼠模型生存率及血清ALT水平变化。ACLF，慢加急性肝衰竭；CCl₄，四氯化碳；K.P，肺炎克雷伯菌；ALT，丙氨酸氨基转移酶；CFU，菌落形成单位。

图 1 “ACLF三阶段”造模法示意图及模型特征

Figure 1. Schematic illustration and characteristics of the three-stage ACLF mouse model

下载: 全尺寸图片幻灯片

表 1 经典ACLF动物模型

Table 1. Classic ACLF animal models

实验动物	慢性肝损伤	急性肝损伤
SD大鼠	CCl₄按体积比（v∶v）1∶1溶于花生油中，腹腔注射2个月，每3 天1次，第1个月1.5 mL/kg体重，第2个月2.0 mL/kg体重	腹腔注射500 mg/kg体重的D-GalN和80 μg/kg体重的LPS^［7］
C57BL/6小鼠（8～10周）	CCl₄溶于橄榄油中，配制终浓度为0.5 mL/mL（v∶v）的溶液， 0.5 mL/kg体重灌胃，每周2次，持续6周	腹腔注射4 mg/kg的LPS或1 000 mg/kg的D-GalN^［8］
C57BL/6小鼠	12%体积浓度将CCl₄溶解于橄榄油中，每周2次，每次5 μL/g 体重，腹腔注射，持续8周	腹腔注射LPS 10 μg/kg联合D-GalN 600 mg/kg^［9］
SD大鼠	TAA 250 mg/kg腹腔注射，每周2次，持续10周	LPS 1 mg/kg腹腔注射^［10］
Wistar大鼠	腹腔注射0.5 mL/kg猪血清，每周2次，持续11周	腹腔注射D-GalN 600 mg/kg，皮下注射LPS 50～ 100 μg/kg^［11］
SD大鼠	腹腔注射2 mL/kg猪血清，每周2次，持续12周	腹腔注射D-GalN 800 mg/kg，皮下注射LPS 100 μg/kg^［12］
SD大鼠	BDL	28 d后给予1 mg/kg LPS^［10］
SD大鼠	BDL	28 d后给予0.03 mg/kg LPS^［13］
注：ACLF，慢加急性肝衰竭；CCl₄，四氯化碳；D-GalN，D-氨基半乳糖；LPS，脂多糖；TAA，硫代乙酰胺；BDL，胆管结扎术。

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表 2 应用“ACLF三阶段”小鼠模型或造模理念的研究

Table 2. Articles that apply the “ACLF three-stage” animal model or its conceptual framework

研究者团队	运用模型	研究内容	优点	缺点
张继明教授团队^［26-27］	“ACLF三阶段”造模法	B细胞和T细胞衰减因子通过诱导CD4⁺ T细胞耗竭，促进 ACLF病程中感染的发生并导致死亡率增加，阻断B细胞和 T细胞衰减因子可有效改善 ACLF小鼠生存率
肖佳教授团队^［28］	“ACLF三阶段”造模法	过表达核转录因子红系2相关因子2和Dickkopf相关蛋白 1能够提高间充质干细胞对 ACLF的治疗效果
陈鹏教授团队^［29］	第三阶段重新采用CLP 手术	潘糖可通过减少小鼠细菌感染预防ACLF发生
Nautiyal等^［30］	CCl₄+APAP+LPS		模拟进展性肝坏死、肝衰竭、肝再生抑制、门静脉高压及多器官衰竭，且生存期明显延长，适用于进行干预研究	未能体现ACLF患者短期高死亡率的特点
Flores-Costa等^［31］	CCl₄+CLP		模拟多重细菌自发性腹膜炎诱导的ACLF，并展现出完整的肝外器官衰竭	CLP手术操作具有复杂性及不稳定性，且仅以CLP手术模拟急性打击和细菌感染也存在不足
Elias等^［32］	TAA+CLP	脓毒症导致的内皮功能障碍可通过血管生成素2-肝细胞生长因子-CCAAT/增强子结合蛋白β通路促进ACLF病程进展		CLP手术操作具有复杂性及不稳定性，且仅以CLP手术模拟急性打击和细菌感染也存在不足
注：ACLF，慢加急性肝衰竭；CLP，盲肠结扎穿孔术；CCl₄，四氯化碳；APAP，对乙酰氨基酚；LPS，脂多糖；TAA，硫代乙酰胺。

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表 3 针对特定病因或诱因的其他ACLF动物模型

Table 3. Other ACLF animal models targeting specific etiologies or precipitating factors

实验动物	造模方式	应用场景
SD大鼠	高脂西方饮食联合CCl₄每周2次腹腔注射，同时予以苯巴比妥饮水，持续7周，随后反复LPS腹腔注射及经鼻粪便接种模拟细菌易位及感染^［33］	NASH-ACLF
C57BL/6小鼠	5～8 s内尾静脉注射总体积8%～10%小鼠体重的水溶性腺病毒/HBV 1.2质粒，总量6 μg，随后在第 21天予以360 mg/kg APAP腹腔注射^［34］	HBV-ACLF
Fah^-/-Rag2^-/-IL-2Rγc^-/-SCID （FRGS）小鼠	将人骨髓间充质干细胞移植至FRGS小鼠体内，生成肝脏和免疫细胞双人源化小鼠，再感染HBV^［35］	双人源化乙型肝炎肝硬化小鼠模型，为后续 HBV-ACLF动物模型构建提供了研究基础
C57BL/6小鼠	10 d 5%乙醇液体饲料喂养，联合第11天清晨单次 5 g/kg乙醇灌胃^［37］	模拟临床患者慢加急性酒精性肝损伤
C57BL/6小鼠	BDL术后28 d予以5 g/kg酒精灌胃^［38］	模拟胆汁淤积性肝硬化基础上急性饮酒导致的ACLF
注：ACLF，慢加急性肝衰竭；CCl₄，四氯化碳；LPS，脂多糖；NASH，非酒精性脂肪性肝炎；HBV，乙型肝炎病毒；APAP，对乙酰氨基酚；BDL，胆管结扎术。

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