目的 探讨大黄素甲醚（physcion，PHY）对对乙酰氨基酚（acetaminophen，APAP）诱导小鼠药物性肝损伤的保护作用及其机制。方法 C57BL/6小鼠采用随机数字表法分为5组，分别为对照组，模型组，阳性对照组，大黄素甲醚低、高剂量（20、40 mg/kg）组，采用ip APAP（300 mg/kg）建立药物性肝损伤小鼠模型，观察大黄素甲醚对小鼠肝脏形态及病理学的影响，检测小鼠血清中天冬氨酸转移酶（aspartate aminotransferase，AST）、丙氨酸转移酶（alanine aminotransferase，ALT）及肝组织谷胱甘肽（glutathione，GSH）、丙二醛（Malondialdehyde，MDA）水平；采用Western blotting及反转录酶-聚合酶链锁反应（reverse transcription-polymerase chain reaction，RT-PCR）检测小鼠肝组织高迁移率族蛋白B1（high mobility group protein B1，HMGB1）、核苷酸结合寡聚化结构域样受体家族pyrin结构域蛋白3（nucleotide binding oligomerization domain-like receptor family pyrin domain protein 3，NLRP3）、半胱氨酸天冬氨酸特异性蛋白酶-1（cysteinyl aspartate specific proteinase-1，Caspase-1）蛋白及mRNA水平，同时检测白细胞介素-1β（interleukin-1β，IL-1β）及IL-18 mRNA表达水平。结果 与模型组相比，大黄素甲醚低、高剂量组小鼠血清AST、ALT水平及肝组织MDA水平，HMGB1、NLRP3、Caspase-1蛋白和mRNA表达量，IL-1β、IL-18 mRNA表达量显著降低（P＜0.01），肝组织GSH活性显著升高（P＜0.01）。病理学染色结果显示，与模型组相比，大黄素甲醚可明显改善小鼠肝组织坏死、细胞炎性浸润，且呈剂量相关性。结论 大黄素甲醚对APAP诱导的药物性肝损伤有一定的保护作用，其机制可能与其抗氧化应激、减少炎性反应，抑制HMGB1-NLRP3炎性小体信号通路有关。

Objective To investigate the protective effect of physcion (PHY) on drug-induced liver injury in mice induced by acetaminophen (APAP) and its possible mechanism. Methods C57BL/6 mice were divided into five groups by random number table method: control group, model group, positive control group, low-dose and high-dose PHY groups (20 and 40 mg/kg). The drug-induced liver injury model was established by intraperitoneal injection of APAP, the effects of PHY on liver morphology and pathology in mice were observed, the levels of aspartate transferase (AST), alanine transferase (ALT) in serum, glutathione (GSH) and malondialdehyde (MDA) in liver tissue were detected. The protein and mRNA expression of high mobility group protein B1 (HMGB1), nucleotide binding oligomerization domain-like receptor family pyrin domain protein 3 (NLRP3), cysteinyl aspartate specific proteinase-1 (Caspase-1) in liver tissue were detected by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR); Then the interleukin-1β (IL-1β) and IL-18 mRNA levels were detected by RT-PCR. Results Compared with model group, the serum AST and ALT levels, liver MDA levels, HMGB1, NLRP3, Caspase-1 protein and mRNA expression levels, IL-1β and IL-18 mRNA expression levels of mice in low and high doses of PHY groups were significantly decreased (P < 0.01), and the liver GSH activity was significantly increased (P < 0.01). The HE staining results indicated that PHY could obviously improve the liver necrosis and inflammatory cell infiltration in dose-dependent manner, and were better than those in model group. Conclusion PHY has a protective effect on APAP induced drug-induced liver injury, and its mechanism may related to anti-oxidant response effect, reducing inflammatory response and inhibiting HMGB1-NLRP3 inflammasomes signal pathway.

R285

国家自然科学基金项目(81900532);国家自然科学基金项目(81700523);中央引导地方科技发展资金自由探索类基础研究项目(负责人杨勇);辽宁省自然科学基金指导计划项目(2019-ZD-0570)