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Article(id=1317885673722462785, tenantId=1146029695717560320, journalId=1316781422847033486, issueId=1317885672153797495, articleNumber=null, orderNo=null, doi=10.12449/JCH260805, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1778688000000, receivedDateStr=2026-05-14, revisedDate=null, revisedDateStr=null, acceptedDate=1785859200000, acceptedDateStr=2026-08-05, onlineDate=1792138029746, onlineDateStr=2026-10-16, pubDate=1787587200000, pubDateStr=2026-08-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1792138029746, onlineIssueDateStr=2026-10-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1792138029746, creator=13701087609, updateTime=1792138029746, updator=13701087609, issue=Issue{id=1317885672153797495, tenantId=1146029695717560320, journalId=1316781422847033486, year='2026', volume='42', issue='8', pageStart='1745', pageEnd='2000', issueExtLink='null', onlineDate='null', pubDate='1787587200000', pubDateStr='2026-08-25', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=1, specialIssue=null, createTime=1792138029373, creator='13701087609', updateTime=1792138608261, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1317888100290900262, tenantId=1146029695717560320, journalId=1316781422847033486, issueId=1317885672153797495, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1317888100290900263, tenantId=1146029695717560320, journalId=1316781422847033486, issueId=1317885672153797495, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1766, endPage=1772, ext={EN=ArticleExt(id=1317885674095755842, articleId=1317885673722462785, tenantId=1146029695717560320, journalId=1316781422847033486, language=EN, title=Research advances in animal models of acute-on-chronic liver failure：From two-stage modeling to three-stage full-course simulation, columnId=1317885673009435512, journalTitle=Journal of Clinical Hepatology, columnName=Expert Forum, runingTitle=null, highlight=null, articleAbstract=

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.

, authors=Jia Lu, Jie Lu, Xiaogang Xiang, authorsList=Jia Lu, Jie Lu, Xiaogang Xiang, authorCompany=null, correspAuthors=Xiaogang Xiang, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1317885682895405640, articleId=1317885673722462785, tenantId=1146029695717560320, journalId=1316781422847033486, language=CN, title=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, columnId=1317885673185596282, journalTitle=临床肝胆病杂志, columnName=专家论坛, runingTitle=null, highlight=null, articleAbstract=

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。

, authors=陆嘉, 卢捷, 项晓刚, authorsList=陆嘉, 卢捷, 项晓刚, authorCompany=null, correspAuthors=项晓刚, authorNote=

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。

, correspAuthorsNote=
项晓刚， （ORCID：0000-0003-0999-2950）
Xiang Xiaogang，（ORCID：0000-0003-0999-2950）
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articleId=1317885673722462785, language=CN, orderNo=1, keyword=慢加急性肝功能衰竭), Keyword(id=1317885685508457057, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=CN, orderNo=2, keyword=模型，动物), Keyword(id=1317885685567177314, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=CN, orderNo=3, keyword=病理过程)], refs=[Reference(id=1317885686783525485, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, doi=null, pmid=null, pmcid=null, year=2026, volume=139, issue=8, pageStart=1110, pageEnd=1124, url=null, language=null, rfNumber=1, rfOrder=0, authorNames=Xu Y F, Liu J T, Shang D B, journalName=Chin Med J, refType=null, unstructuredReference=Xu Y F, Liu J T, Shang D B, et al. 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DOI: 10.1016/j.jcmgh.2024.101446., articleTitle=A novel multi-organ male model of alcohol-induced acute-on-chronic liver failure reveals NET-mediated hepatocellular death, which is prevented by RIPK3 inhibition, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1317885683373556297, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, xref=null, ext=[AuthorCompanyExt(id=1317885683386139210, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, companyId=1317885683373556297, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Infectious Diseases，Ruijin Hospital，Shanghai Jiao Tong University School of Medicine，Shanghai 200025，China), AuthorCompanyExt(id=1317885683398722123, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, companyId=1317885683373556297, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=上海交通大学医学院附属瑞金医院感染科，上海 200025)])], figs=[ArticleFig(id=1317885685818835555, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=EN, label=Figure 1, caption=Schematic illustration and characteristics of the three-stage ACLF mouse model, figureFileSmall=ZouQnb5/lDm7J46WS7YKWA==, figureFileBig=h3tS+IIeRkltxhBsmaTbYw==, tableContent=null), ArticleFig(id=1317885685873361508, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=CN, label=图1, caption=“ACLF三阶段”造模法示意图及模型特征

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。

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Classic ACLF animal models

, figureFileSmall=null, figureFileBig=null, tableContent=
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BDL28 d后给予1 mg/kg LPS［10］
SD大鼠BDL28 d后给予0.03 mg/kg LPS［13］
), ArticleFig(id=1317885686263431784, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=CN, label=表1, caption=

经典ACLF动物模型

, figureFileSmall=null, figureFileBig=null, tableContent=
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BDL28 d后给予1 mg/kg LPS［10］
SD大鼠BDL28 d后给予0.03 mg/kg LPS［13］
), ArticleFig(id=1317885686317957737, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=EN, label=Table 2, caption=

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

, figureFileSmall=null, figureFileBig=null, tableContent=
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
), ArticleFig(id=1317885686385066602, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=CN, label=表2, caption=

应用“ACLF三阶段”小鼠模型或造模理念的研究

, figureFileSmall=null, figureFileBig=null, tableContent=
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
), ArticleFig(id=1317885686590587499, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=EN, label=Table 3, caption=

Other ACLF animal models targeting specific etiologies or precipitating factors

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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
), ArticleFig(id=1317885686670279276, tenantId=1146029695717560320, journalId=1316781422847033486, articleId=1317885673722462785, language=CN, label=表3, caption=

针对特定病因或诱因的其他ACLF动物模型

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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
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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
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陆嘉 , 卢捷 , 项晓刚
临床肝胆病杂志 | 专家论坛 2026,42(8): 1766-1772
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临床肝胆病杂志 |专家论坛 2026 , 42 (8) : 1766 -1772
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
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陆嘉, 卢捷, 项晓刚
作者信息
  • 上海交通大学医学院附属瑞金医院感染科，上海 200025
通讯作者:
项晓刚， （ORCID：0000-0003-0999-2950）
Xiang Xiaogang，（ORCID：0000-0003-0999-2950）
作者简介:

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。

Research advances in animal models of acute-on-chronic liver failure：From two-stage modeling to three-stage full-course simulation
Jia Lu, Jie Lu, Xiaogang Xiang
Affiliations
  • Department of Infectious Diseases，Ruijin Hospital，Shanghai Jiao Tong University School of Medicine，Shanghai 200025，China
出版时间: 2026-08-25 doi: 10.12449/JCH260805
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摘要
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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

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
陆嘉, 卢捷, 项晓刚. 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. 临床肝胆病杂志, 2026 , 42 (8) : 1766 -1772 . DOI: 10.12449/JCH260805
Jia Lu, Jie Lu, Xiaogang Xiang. Research advances in animal models of acute-on-chronic liver failure：From two-stage modeling to three-stage full-course simulation[J]. Journal of Clinical Hepatology, 2026 , 42 (8) : 1766 -1772 . DOI: 10.12449/JCH260805
正文
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慢加急性肝衰竭（acute-on-chronic liver failure，ACLF）是一类在慢性肝病基础上发生，以肝内或肝外器官衰竭、短期高病死率及病程具有可逆性为特征的临床综合征［1-2］，其病因与发病机制复杂，目前尚无有效治疗措施。动物模型在疾病机制探索、诊断方法与治疗方案研究中发挥着不可或缺的作用，构建符合临床特征、高效稳定的ACLF动物模型，对阐明ACLF发病机制、建立早期诊断与有效治疗方案具有重要价值与现实意义。然而，由于ACLF的异质性与复杂性，相关动物模型的研发始终面临较大挑战。本文就目前ACLF动物模型的研究进展与相关创新干预策略进行综述。
1　经典ACLF动物模型
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目前，ACLF动物模型的建立主要遵循“两阶段”原则：（1）慢性肝损伤诱导肝纤维化或肝硬化；（2）急性打击。诱导肝损伤的方式可分为肝毒试剂、异种成分和手术方式。据此，现有ACLF动物模型可整理归类为3种类型：肝毒试剂诱导的ACLF模型、免疫反应诱导的ACLF模型和手术方式诱导的ACLF模型。
1.1　肝毒试剂诱导的ACLF模型
肝毒试剂诱导的ACLF模型是应用最广泛的ACLF动物模型。
1.1.1　四氯化碳（carbon tetrachloride，CCl4）+D-氨基半乳糖（D-galactosamine，D-GalN）/脂多糖（lipopolysaccharide，LPS）
CCl4中毒是诱导实验动物肝损伤的经典方式。对大鼠或小鼠经腹腔注射、皮下注射、灌胃或吸入CCl4 6～8周，可导致肝纤维化；但由于小鼠具有强大的自发肝再生能力，在实验条件下通常只能形成肝纤维化，难以自然或完全发展为人类典型的晚期肝硬化，且停止致毒物后，肝纤维化可能出现部分逆转［3］。相比之下，大鼠经8～12周CCl4处理则可诱导肝硬化［4-6］。在此基础上，使用D-GalN能够模拟急性打击，联合LPS可进一步促进全身性炎症反应。当前不同方案的差异主要体现在给药方式、剂量、频率及稀释比例等方面（表1）。CCl4联合D-GalN/LPS操作简便，且能较好地模拟ACLF病程的核心临床表现，但主要缺点是模型存活时间较短［14］。例如，Ni等［7］建立的模型中，SD大鼠在急性肝损伤后的平均存活时间<1 d，该时间窗对于临床前的干预研究稍偏短。
1.1.2　硫代乙酰胺（thioacetamide，TAA）+LPS
TAA可在大鼠体内诱导慢性肝损伤，并最终进展至肝硬化阶段，同时伴有典型的肝性脑病、凝血功能异常及肝内小叶中心性坏死等表现［15-16］。该模型操作简便（表1），且相较于CCl4模型，其诱导的肝损伤更加稳定持久，不易发生逆转。然而，TAA对人体具有较强的致癌性，故应用较少［17］。
1.2　免疫反应诱导的ACLF模型
免疫反应诱导的ACLF模型适用于研究在免疫介导慢性肝病基础上发生的ACLF。在实践中，针对啮齿类动物，异种成分的选择包括人血清白蛋白（human serum albumin，HSA）和猪血清，实验动物通常选用大鼠。目前，各方案的主要差异体现在白蛋白种类、给药剂量、给药途径以及给药时间等方面。
1.2.1　HSA+LPS/D-GalN
HSA+LPS/D-GalN是目前应用免疫诱导法构建ACLF动物模型最常见的方法，造模动物通常选用大鼠［18］。刘旭华等［19］最先提出将HSA诱导慢性肝损伤分为两个阶段。（1）免疫诱导阶段：将血清白蛋白以生理盐水稀释，并与等体积的完全福氏佐剂乳化，于第1、15、25、35天各皮下注射0.5 mL（内含白蛋白4 mg）；（2）免疫攻击阶段：尾静脉注射血清白蛋白4 mg，每周2次，持续6周。在急性肝损伤方面，常选择的方案是腹腔注射D-GalN 400 mg/kg联合LPS 100 μg/kg［20-22］。该模型的缺点为诱导期间死亡率高达23%［18］，动物模型存活时间较短，难以通过生存率判断干预效果。
1.2.2　猪血清+D-GalN/LPS
与HSA相比，猪血清造模具有操作简便、重复性高的优势。猪血清采用的给药途径为腹腔注射，相较于HSA采用的皮下注射、静脉注射更为安全，且成模率高。此外，猪血清诱导的ACLF模型更贴近人类ACLF的临床特点［18］。2017年，Li等［11］提出采用猪血清+D-GalN/LPS构建ACLF模型（表1），该模型造模后的ACLF时间窗可持续24 h；2022年，Hassan等［12］在此基础上对上述模型进行了优化（表1），改良后的ACLF时间窗延长至7 d，有利于后续干预研究的开展。
1.3　手术方式诱导的ACLF模型
手术方式诱导的慢性肝损伤模型主要用于模拟ACLF病程中的高胆红素血症。
1.3.1　胆管结扎术（bile duct ligation，BDL）+LPS
BDL诱导后的大鼠对内毒素的敏感性增强，故常以LPS作为急性肝损伤的诱因［17］。不同方案中LPS的给药剂量存在差异（表1）。该方法的不足之处在于手术操作复杂，难以掌握，且模型所致肝损伤不可逆，术后死亡率较高。
1.3.2　BDL+肝脏缺血再灌注/肝大部切除术
BDL+肝脏缺血再灌注/肝大部切除术首先采用BDL诱导高胆红素血症，构建肝纤维化或肝硬化模型；2周后再联合其他手术方式作为急性打击。该造模方式旨在模拟临床上接受肝脏手术的胆汁淤积性肝病患者发生ACLF的过程，能够较好地反映ACLF的病理生理过程和组织学特点［23］。然而，其缺点为手术操作复杂且难以掌握，限制了该方案的广泛应用。
2　ACLF动物模型研究新进展
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2.1　“ACLF三阶段”造模法
经典的ACLF动物模型遵循“两阶段”原则，但临床上多数ACLF患者的核心临床病程可分为3个阶段：（1）长期慢性肝损伤；（2）急性肝损伤；（3）细菌感染及全身性炎症反应与肝外器官损伤。据此，本课题组根据ACLF临床特征设计构建了一种“ACLF三阶段”小鼠模型。具体方法为：选择C57BL/6J小鼠，按体积比配制10% CCl4橄榄油溶液（v∶v），根据小鼠体重按照0.2 mL/kg计算CCl4总量，腹腔注射，每周2次，持续8周；第9周第1天使用双倍剂量CCl4诱发急性肝损伤，待急性肝损伤在24 h后达最高峰时，腹腔注射肺炎克雷伯菌（Klebsiella pneumoniae strain ATCC 43816）500～1 000菌落形成单位（colony forming unit，CFU）/只，ACLF小鼠可存活5～7 d（图1）。该模型能够完整模拟大多数ACLF患者的核心临床特征，并且能很好地呈现病程中出现的肝外器官损伤，尤其是肾损伤；同时，具有合适的生存周期可用于干预研究。应用此模型，本课题组发现肝内信号转导与转录激活因子1/3（signal transducer and activator of transcription 1/3，STAT1/3）激活失衡导致肝再生受抑是ACLF病程持续进展的重要机制，白细胞介素22（interleukin-22，IL-22）可以促进肝细胞内STAT3磷酸化，调控STAT1/3激活失衡，促进肝细胞再生，并针对这一靶点创建了以IL-22为核心的靶向促肝再生疗法，为ACLF提供了全新的救治方案。目前该疗法已进入临床转化阶段，且已完成IL-22治疗ACLF Ⅱa期研究［24］。
在“ACLF三阶段”小鼠模型的设计开发与探索过程中，第一阶段采用经典的8周CCl4诱导法，以模拟慢性肝损伤。ACLF造模第二阶段，课题组曾尝试多种肝毒试剂，均能成功诱导急性肝损伤；但研究发现，当CCl4剂量超过2倍后，小鼠急性肝损伤相关的丙氨酸氨基转移酶或天冬氨酸氨基转移酶水平升高至15 000～20 000 U/L时便不再继续上升；为提升造模便捷性，第二阶段最终采用双倍剂量CCl4诱导急性肝损伤。造模第三阶段，为模拟细菌感染及全身性炎症反应，课题组最初采用脓毒症研究领域经典的盲肠结扎穿孔术（cecal ligation and puncture，CLP）构建模型，发现该模型可有效模拟多重细菌感染及全身性炎症反应，且伴随肝外器官损伤，其中以肾损伤最为显著，与临床ACLF核心病程高度相似。但该模型存在明显不足：CLP手术难以精准控制盲肠内容物向腹腔的溢出量，导致感染程度不易调控；同时，CLP手术的创伤应激会对终末期肝衰竭的病程产生不良影响，且手术操作耗时较长，不同术者间的操作一致性较差。为解决上述问题，本课题组曾尝试盲肠泥来源的多重细菌注射法，但其模拟第三阶段细菌感染及全身性炎症反应远不及CLP手术，造模中小鼠死亡率极低。随后，课题组尝试单一细菌注射法，结合临床实践中肝衰竭患者腹水培养以革兰氏阴性细菌（主要为大肠埃希菌和克雷伯菌）为主的特征，采用单一细菌腹腔注射法替代CLP手术。探索过程中发现，给予小鼠腹腔注射大肠埃希菌时，即使细菌剂量超过108 CFU/只，仍不会造成小鼠死亡［18］；而在测试肺炎克雷伯菌时发现，腹腔注射500～1 000 CFU/只即可达到与CLP手术相当的效果。因此，第三阶段造模最终选用肺炎克雷伯菌，显著提升了ACLF造模的便捷性［1，14，24］。
Engelmann等［25］研究指出，临床上50%的ACLF患者即使初始诱因是非炎症因素，后续仍可继发细菌感染相关并发症。目前常用的两阶段ACLF动物模型无法反映这一复杂的临床特征，而“ACLF三阶段”小鼠模型在CCl4急性打击后使用肺炎克雷伯菌导致全身细菌感染，并成功诱导了广泛的肝肾损伤与7 d高死亡率（87.5%），更好地模拟了ACLF的临床特征。目前，已有多项研究应用该模型或造模理念（表2）。
2.2　针对特定病因或诱因的其他动物模型
ACLF的病因及诱因多样，决定了不同类型ACLF的异质性，因此建立基于特定病因或诱因的ACLF模型对于理解不同类型ACLF的病理生理机制具有重要意义。Kraus等［33］构建了一种非酒精性脂肪性肝炎（non-alcoholic steatohepatitis，NASH）相关ACLF（NASH-ACLF）大鼠模型，该模型被用于验证肥胖患者进展期NASH与ACLF发展的关系。当前常用的建模方法可以模拟化学性肝损伤、胆汁淤积性肝损伤与免疫性肝损伤，但无法模拟病毒性肝损伤。然而，乙型肝炎病毒（hepatitis B virus，HBV）相关ACLF（HBV-ACLF）是中国和亚太地区最为常见的ACLF类型，研发HBV-ACLF动物模型具有重要的现实意义。Zhang等［34］通过水溶性腺病毒/HBV 1.2质粒构建小鼠HBV复制模型，随后予以对乙酰氨基酚诱导急性肝损伤，最终构建的HBV-ACLF模型部分反映了HBV-ACLF的临床特点。浙江大学李君教授团队［35］则突破性地建立了双人源化乙型肝炎肝硬化小鼠模型，为后续HBV-ACLF动物模型的构建提供了研究基础。酒精相关ACLF是西方最为常见的ACLF类型，饮酒亦是西方最常见的ACLF诱因［36］。基于此，高斌教授团队［37］于2013年创建了经典的Binge酒精性肝病小鼠模型，该模型因其临床相关性与操作简便的特点，目前已被国际酒精性肝病研究领域广泛采用。Ortega-Ribera等［38］则结合手术方式构建了一种以胆汁淤积性肝硬化为基础、急性饮酒为诱因的ACLF模型。上述ACLF动物模型总结详见表3。
3　小结与展望
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理想的动物模型应当具备操作简便、稳定性强、可重复性高、生存期适中等特点，同时能够较好地模拟疾病的核心病程及临床特征。就ACLF动物模型而言，目前仍面临诸多亟待解决的困境与挑战。
首先，ACLF的病因、诱因及病理机制复杂多样，且在临床实践中，患者常同时或依次出现多种诱发因素和并发症［25］。传统的两阶段模型难以完整模拟人类ACLF的发生发展过程。“ACLF三阶段”造模法包括慢性肝损伤、急性肝损伤、细菌感染等3个阶段，能够完整地模拟大多数ACLF患者的核心病程，包括慢性肝损伤、急性肝损伤、细菌感染、肝外器官中的肾损伤、短期高病死率及病程可逆性等临床特征，且具有合适的生存期（5～7 d）用于干预研究。因此，该模型是目前相对而言能够完整模拟ACLF临床特征及全病程的理想动物模型。
其次，尽管在实际操作中，研究者可通过使用不同药物或手术方式、调整给药剂量等方法，在动物模型中模拟人类ACLF的病程、生存率、死亡率、并发症等一系列临床特点，但由于实验动物与人类之间的基因异质性，动物模型无法完全复制人类疾病的全貌。因此，未来仍需探索更贴近人类发病机制的动物模型、更佳的造模试剂类型及剂量，以尽可能接近人类ACLF的实际情况。
最后，针对不同病因和诱因的ACLF动物模型构建仍有待进一步探索。目前常用的诱导肝损伤与模拟细菌感染的造模方法，可模拟化学性肝损伤、胆汁淤积性肝损伤、免疫性肝损伤以及感染相关ACLF，但在临床实际中，ACLF的慢性肝病基础还包括慢性病毒性肝炎、脂肪性肝病及遗传代谢性肝病等多种类型，诱因除肝毒性物质和细菌感染外，还涉及HBV再激活、酗酒等常见因素。因此，经典的ACLF动物模型尚无法反映ACLF病理生理过程的多样性与异质性。
综上所述，随着对ACLF临床特征认识的不断深化，其动物模型体系亦在持续完善。理想的ACLF动物模型不仅为机制研究提供了可靠平台，更有助于深入阐释其发病的分子机制，进一步更新对疾病临床特征的认知，同时为新型靶向干预策略及创新治疗方案的研发奠定理论与实验基础。

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2026年第42卷第8期
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doi: 10.12449/JCH260805
  • 接收时间：2026-05-14
  • 首发时间：2026-10-16
  • 出版时间：2026-08-25
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  • 收稿日期：2026-05-14
  • 录用日期：2026-08-05
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    上海交通大学医学院附属瑞金医院感染科，上海 200025

通讯作者:

项晓刚， （ORCID：0000-0003-0999-2950）
Xiang Xiaogang，（ORCID：0000-0003-0999-2950）
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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