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第45卷第5期
·628 · 南 京 医 科 大 学 学 报 2025年5月

（BDL）and α⁃naphthylisothiocyanate（ANIT）respectively，and to explore the applicability of these models in cholestatic liver injury
research. Methods：Male C57BL/6 mice were randomly divided into six groups：control，sham，BDL，BDL + short ⁃ chain fatty acid
（SCFA），ANIT，and ANIT+SCFA groups. BDL and BDL+SCFA groups underwent BDL surgery on day 1，while ANIT and ANIT+
SCFA groups were administered 100 mg/kg ANIT via gavage weekly starting from day 1 to induce liver injury，BDL+SCFA and ANIT+
SCFA groups received water containing SCFA（67.5 mmol/L sodium acetate，25.9 mmol/L sodium propionate，and 40 mmol/L sodium
butyrate）for 14 days. After the collection of liver tissues and serum samples from mice of each group，liver histopathology was assessed
by hematoxylin and eosin（HE）staining. Serum levels of alanine aminotransferase（ALT），aspartate aminotransferase（AST），alkaline
phosphatase（ALP），and total bilirubin（TBIL）were measured using biochemical assay kits，while the concentrations of inflammatory
cytokines interleukin（IL）⁃6，IL⁃1β，and monocyte chemoattractant protein⁃1（MCP⁃1）were determined by ELISA. Results：Mice in
the BDL group exhibited marked jaundice and continuous weight loss within the first week，progressing to severe jaundice by the
second week. In contrast，the ANIT group displayed mild jaundice in the early stage，which gradually worsened，with only slight initial
weight loss and minimal subsequent change. Both models shared common gross and histopathological features，including partial
hepatic cirrhosis，hepatocellular necrosis，portal fibrosis，inflammatory cell infiltration，and bile duct proliferation. However，these
features appeared earlier and were more pronounced in the BDL group，whereas the ANIT group showed milder early changes that
progressively intensified as the study progressed. Serum biochemical analysis revealed significant elevations in hepatic transaminase
levels in both groups（P < 0.05）. In the BDL group，early ALP and TBIL levels were significantly higher than those in the control group
（P < 0.05）and markedly exceeded those in the ANIT group（P < 0.05）. In the ANIT group，ALP and TBIL levels were only mildly
elevated in the early stage but gradually increased in later stage（P < 0.05）. Analysis of serum inflammatory cytokines showed that IL⁃1β，
IL⁃6，and MCP⁃1 levels were significantly higher in the BDL group than in the control group in the early stage（P < 0.05），while in the
ANIT group，cytokine levels increased only slightly at first and then gradually rose to levels comparable to those of the BDL group by
the later stages（P > 0.05）. After two weeks of SCFA treatment，no significant improvement was observed in jaundice，weight loss，
serum liver function markers（ALT，AST，ALP，and TBIL），or inflammatory cytokine levels（IL⁃6 and MCP⁃1）in the BDL group（P > 0.05）.
Conversely，SCFA treatment in the ANIT group significantly alleviated jaundice and weight loss（P < 0.05）and reduced ALT，AST，
and TBIL levels（P < 0.05）. Furthermore，SCFA intervention markedly decreased IL⁃1β，IL⁃6，and MCP⁃1 levels in the ANIT group
（P < 0.05）. Conclusion：The BDL model，characterized by rapid onset and severe liver injury，is suitable for studying acute
cholestatic liver injury，whereas the ANIT model，with its gradual onset and progressively worsening liver damage，is more appropriate
for simulating chronic cholestatic liver injury.
［Key words］ cholestatic liver injury；bile duct ligation；α⁃naphthylisothiocyanate；short⁃chain fatty acids
［J Nanjing Med Univ，2025，45（05）：627⁃636］

胆汁淤积性肝损伤是指由于胆汁生成或排泄 型，分别代表了机械性和化学性病因导致的胆汁淤
［9］
功能受损引起的胆汁淤积和毒性胆酸蓄积的一类 积性肝损伤 。
疾病，随病程进展可导致肝纤维化甚至终末期肝 BDL 模型通过手术部分或全部阻断肝外胆管，
病 ［1-2］ 。胆汁淤积的病因复杂多样，包括肝内胆汁淤 造成胆汁流出受阻，从而引发急性胆汁淤积、胆管
积，如妊娠期胆汁淤积、病毒性肝炎、药物性肝损伤、 细胞增生及显著的纤维化反应 ［10］ 。该模型主要表
酒精性肝病、原发性胆汁性肝硬化（primary biliary 现为肝外胆道梗阻，重复性高，实验周期短，已被广
cholangitis，PBC）和原发性硬化性胆管炎（primary 泛应用于研究胆汁淤积导致的肝脏形态和功能改
sclerosing cholangitis，PSC）等 ［3-4］ ；肝外胆汁淤积，如 变，如胆管细胞增殖、纤维化形成 ［11-13］ 。
［5］
胆总管结石、胰管癌和胆道闭锁等 。胆汁淤积性 ANIT 作为一种由肝细胞代谢后进入胆汁的毒
［6］
肝损伤发病率在世界范围内呈上升趋势 ，而目前 性物质，通过化学性损伤作用于肝内胆管细胞，诱
治疗手段有限 ［7-8］ 。为研究胆汁淤积性肝损伤的发 导胆管细胞坏死，促进胆管增生和炎症反应，最终导
［14］
病机制，探索新的治疗药物及方法，目前发明众多 致肝纤维化 。ANIT模型肝外胆管大多不受影响，
动物模型，其中常用两种小鼠胆汁淤积性肝损伤模 主要作用于肝内胆管，与人类自身免疫性胆汁淤积
［15］
型——胆管结扎（bile duct ligation，BDL）和α⁃萘基异 性疾病（如PSC）在某些病理特征上较为相似 。
硫氰酸酯（α⁃naphthylisothiocyanate，ANIT）诱导模 短链脂肪酸（short⁃chain fatty acid，SCFA）是肠