“二次打击”在酒精性肝病动物模型中的应用

刘萌思; 谢艳迪

doi:10.12449/JCH250932

“二次打击”在酒精性肝病动物模型中的应用

DOI: 10.12449/JCH250932

刘萌思¹,
谢艳迪^2, , ,

1.
北京大学人民医院，教育处，北京 100044
2.
北京大学人民医院，肝病科，北京 100044

基金项目:

国家自然科学基金 (82000557)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：刘萌思负责设计论文框架，起草论文，绘制图表；谢艳迪负责论文修改，拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
谢艳迪， xieyandee@163.com （ORCID： 0000-0001-5002-341X）

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出版历程
- 收稿日期: 2025-01-04
- 录用日期: 2025-03-21
- 出版日期: 2025-09-25

Application of the “two-hit” hypothesis in animal models of alcoholic liver disease

Mengsi LIU¹,
Yandi XIE^{2
, ,
,}

1.
Department of Education, Peking University People’s Hospital，Beijing 100044，China
2.
Department of Hepatology, Peking University People’s Hospital，Beijing 100044，China

Research funding:

National Natural Science Foundation of China (82000557)

More Information

Corresponding author: XIE Yandi， xieyandee@163.com （ORCID： 0000-0001-5002-341X）

摘要

摘要: 酒精性肝病（ALD）严重威胁全球饮酒者的健康，构建合适的ALD动物模型是开展疾病相关研究的重要基础。由于啮齿动物与人类在生理和病理生理方面存在差异，单纯饲喂酒精难以诱导出与人类疾病表现高度吻合的模型，因此“二次打击”（即联合采用酒精与另一种肝损伤因素以诱导预期肝损伤状态）得到广泛应用。本文将“二次打击”中较为常用且有效的方案划分为特殊饮食、化学物质、基因工程等3大类，并进一步细分为高脂饮食、高铁饮食、四氯化碳、脂多糖和基因工程5个部分进行综述。这5类“二次打击”模型虽各有优劣，但已能较完整地覆盖ALD疾病谱。未来ALD动物模型的开发可更多聚焦于缩小动物与人类酒精性肝损伤的病理生理差异，以及模拟更为复杂的人类饮酒模式等方向。
- 肝疾病，酒精性 /
- 模型，动物 /
- 二次打击
Abstract: Alcoholic liver disease （ALD） poses a serious threat to the health of drinkers worldwide， and establishing appropriate animal models of ALD is an important foundation for conducting disease-related research. Due to the physiological and pathophysiological differences between rodents and humans， alcohol feeding alone is difficult to induce a model that closely matches the disease manifestations in humans， and therefore， the “two-hit” hypothesis （ combining alcohol with another liver injury factor to induce the expected state of liver injury） has been widely used. This article classifies the more commonly used and effective “two-hit” regimens into three major categories of special diets， chemical substances， and genetic engineering， which are divided into high-fat diet， high-iron diet， carbon tetrachloride， lipopolysaccharide， and genetic engineering for further analysis. Although these five “two-hit” models have their own advantages and disadvantages， they can nearly cover the disease spectrum of ALD. In the future， the development of ALD animal models can focus on narrowing the pathophysiological differences in alcohol-induced liver injury between animals and humans and simulating more complex drinking patterns in humans.
- Liver Diseases， Alcoholic /
- Models， Animal /
- Second Hit

HTML全文

表 1 ALD啮齿动物“二次打击”模型的建模方法及应用效果

Table 1. Modeling method and application effect of "second-hit" model in rodents with ALD

项目	高脂饮食	高铁饮食	CCl₄	LPS	基因工程
建模方法
动物类型	C57BL/6J小鼠	雄性Sprague-Dawley 大鼠；雄性Wistar大鼠； C57BL/6J小鼠	BALB/c小鼠； C57BL/6小鼠	雄性Sprague-Dawley大鼠；雄性Wistar大鼠；雌性C57BL/6小鼠	C57BL/6小鼠； SV129小鼠； GR floxed小鼠
时间（周）	7～24	8～26	1～10	4	3～8
剂量		0.04～0.87 mg/mL	剂量差异较大，与给药方式有关	0.5～2 mg/kg体质量
酒精摄入	灌胃； Ad libitum	Lieber-Decarli液体饮食	灌胃； Ad libitum	NIAAA模型； Lieber-DeCarli液体饮食	NIAAA模型；灌胃；Ad libitum
应用效果
病理表现	肝脂肪变；肝炎；细胞周纤维化	肝脂肪变；肝纤维化；微小结节性肝硬化	肝脂肪变；肝炎；肝纤维化	肝脂肪变；肝炎；局灶性坏死及胶原沉积	与涉及的具体基因相关
适用疾病	脂肪肝	肝纤维化	肝纤维化	肝炎	与涉及的具体基因相关
优点	更生活化地模拟酒精性肝损伤；更灵活地诱导不同程度的ALD	能引起较严重的损伤，如肝硬化	建模时间成本低；能引起较严重的损伤，如肝纤维化	更贴合人类ALD病理生理机制；实验动物死亡率低；建模时间成本低	直接、明确地通过某种机制致病；能更自由地诱导各类疾病
缺点	建模时间较长	建模方法较复杂；不太贴合人类ALD的病理生理机制	可能增加实验动物死亡率	无法造成严重的肝损伤	更加昂贵、复杂；存在脱靶、转基因细胞发育不良等风险

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