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基于中西医临床病证特点的胆汁淤积性肝病动物模型评价
DOI: 10.3969/j.issn.1001-5256.2023.12.031
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：朱正望负责论文撰写；朱平生负责指导论文修改并最后定稿；苗明三负责指导论文修改。
Evaluation of cholestatic liver disease animal model based on clinical syndrome characteristics of integrated traditional Chinese and Western medicine
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摘要: 胆汁淤积性肝病是一种临床常见的肝胆系统疾病，其病因及发病机制复杂，建立合适的胆汁淤积性肝病动物模型是深入研究其发病机制及防治的基础。本研究通过总结归纳现有的胆汁淤积性肝病动物模型造模方法、作用机制及模型特点，基于胆汁淤积性肝病的现代医学临床诊断标准、中医证候特点，分析其与中西医临床病证特点的吻合度，为建立规范的更符合中西医临床实际的胆汁淤积性肝病动物模型及评价方法提供参考。Abstract: Cholestatic liver disease is a common disease of the hepatobiliary system. Its etiology and pathogenesis are complex. The establishment of an appropriate animal model of cholestatic liver disease is the basis for further study of its pathogenesis and prevention. This study summarized the existing modeling methods， mechanisms， and characteristics of this model， and analyzed its alignment with the clinical disease and syndrome characteristics of integrated traditional Chinese and Western medicine based on the modern clinical diagnostic criteria and traditional Chinese medicine syndrome characteristics of cholestatic liver disease， so as to provide a reference for establishing standard animal models and evaluation methods for cholestatic liver disease that accord better with the clinical practice of integrated traditional Chinese and Western medicine.
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表 1 CLD诊断标准
Table 1. Diagnostic criteria for cholestatic liver disease
分类 表现 临床表现 （1）主要症状：黄疸、皮肤瘙痒、疲劳、脂肪泻、黄色瘤和骨质疏松 （2）非特异症状：乏力、纳差、恶心、上腹不适等 实验室检查 （3）肝生化检查ALP、GGT升高 影像学检查 （4）腹部超声或CT了解有无肝内、外胆管扩张 （5）磁共振胰胆管造影、超声内镜、经内镜逆行胰胆管造影了解胆道系统是否梗阻 组织病理学检查 （6）肝内胆汁淤积：肝细胞呈羽毛状变性，伴毛细胆管扩张胆栓形成；肝外胆汁淤积：门管区周边肝内胆汁湖伴胆汁肉芽肿形成 
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表 2 胆汁淤积性肝病中医辨证分型
Table 2. Traditional Chinese medicine syndrome differentiation of cholestatic liver disease
分类 证型 主症 次症 阳黄 湿热蕴结 身目俱黄，黄色鲜明 （1）发热口渴，口干而苦，小便短少黄赤 （2）头重身困，胸脘痞满或大便溏垢 胆腑郁热 身目发黄，黄色鲜明，上腹、右胁胀闷疼痛，牵引肩背 （1）身热不退，或寒热往来 （2）口苦咽干，呕吐呃逆 （3）尿黄赤，大便秘 阴黄 寒湿阻遏 身目俱黄，黄色晦暗，或如烟熏 （1）脘腹痞胀，纳谷减少，大便不实 （2）神疲畏寒，口淡不渴 脾虚湿滞 面目及肌肤淡黄，甚则晦暗不泽 （1）肢软乏力，心悸气短 （2）大便溏薄
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表 3 CLD动物模型评价
Table 3. Animal model evaluation of cholestatic liver disease
造模方式 造模对象 作用机制 模型特点 临床吻合度 胆总管结扎［18］ SD/Wistar大鼠 胆管结扎造成肝外胆道梗阻，引起胆管扩张和胆汁淤积 手术方法成熟、操作相对简单、建模周期短、成模率高、易于重复，可用于研究各类梗阻性原因导致的胆汁淤积 符合西医诊断1）（1）（2）（3）（5）（6），吻合度约75%；符合中医主症2）（1），次症（1）（5），吻合度约44% ANIT灌胃［19］ SD/Wistar大鼠 ANIT靶向胆管上皮细胞，使之变性、肿胀、坏死脱落，导致胆汁堵塞和淤积 操作简便可靠、重现性好，与人肝内胆汁淤积的病变相似度较高 符合西医诊断（1）（2）（3）（6），吻合度约50%；符合中医主症（1），次症（1）（5），吻合度约44% 苯甲酸雌二醇联合黄体酮注射［20］ SD大鼠 可能与破坏了肝细胞紧密连接结构，胆管的通透性增加，胆酸摄取减少，影响胆汁分泌有关 方法简单、成功率高，可用于特殊人群如孕妇的妊娠肝内胆汁淤积相关研究 符合西医诊断（3）（6），吻合度约30% 利福平灌胃［21］ Wistar大鼠 破坏肝细胞紧密连接蛋白的完整性，引起肝内胆汁淤积 可用于抗结核药引起胆汁淤积的相关研究 符合西医诊断（1）（3）（6），吻合度约40%；符合中医主症（1），次症（5），吻合度约32% DDC喂养［22］ C57BL/6小鼠 DDC可诱导胆管上皮细胞血管黏附分子、骨桥蛋白和肿瘤坏死因子α表达，胆卟啉分泌增加，导致胆管上皮细胞损伤、胆栓形成 成本较低、稳定可靠，可用于慢性胆汁淤积性疾病（如原发性硬化性胆管炎）的研究 符合西医诊断（3）（6），吻合度约30% LPS注射［23］ SD大鼠 LPS激活肝Kupffer细胞的增殖和分泌功能，生成和释放大量炎性介质，引起肝细胞弥漫性坏死 操作简便、模型稳定，适合中药预防给药研究模式 符合西医诊断（2）（6），吻合度约30%；符合中医次症（5），吻合度约12% 石胆酸LCA灌胃［24］ ICR小鼠 高浓度的LCA及其代谢物聚集在毛细胆管，导致节段性胆管阻塞，造成胆汁淤积 稳定可靠、重复性好，可用于研究药物对胆汁淤积基因的调控等研究 符合西医诊断（6），吻合度约20% CPZ注射［25］ SD大鼠 可能与CPZ干扰胆汁酸的合成、分泌，引起超敏反应有关 可用于药物因素引起的胆汁淤积性肝病研究 符合西医诊断（2）（3）（6），吻合度约40%；符合中医次症（5），吻合度约12% 全肠外营养［26］ C57BL/6小鼠 与肝脏发生氧化损伤启动线粒体介导的肝细胞凋亡有关 特异性强，适用于肠外营养相关性胆汁淤积症的研究 符合西医诊断（3）（6），吻合度约30% 注：1）西医诊断是指表1中内容；2）中医诊断是指前文2.2节“中医学诊断标准”中内容。本文根据CLD西医诊断标准及中医辨证分型，参考田硕等［15］的研究对其中西医诊断标准进行赋值，结合文献中模型建立后的表现及检测指标计算其吻合度。
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