内质网应激、自噬与凋亡在斑蝥素致大鼠肝毒性中的作用

何天目; 陈宽; 熊丽娟; 林可欣; 陆椗瑒; 李晓飞; 张建永

doi:10.13748/j.cnki.issn1007-7693.20232191

内质网应激、自噬与凋亡在斑蝥素致大鼠肝毒性中的作用

Liver Injury Induced by Cantharidin Through Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in Rat

摘要

摘要:
目的探讨斑蝥素(cantharidin，CTD)致大鼠药物性肝损伤(drug-induced liver injury，DILI)的毒理学机制。
方法采用不同剂量CTD(0.061 4，0.092 1，0.184 1 mg·kg⁻¹)连续灌胃SD大鼠 28 d，检测肝脏指数和血清肝功能指标，HE 染色评估肝脏病理变化。进一步采用免疫印迹法检测内质网应激(endoplasmic reticulum stress，ERS)、自噬和细胞凋亡通路蛋白。
结果 CTD 干预后肝脏指数显著升高，生化指标ALT、AST、LDH、ALP和T-Bil显著升高，且呈剂量依赖性，肝脏组织出现结构破坏和中央静脉扩张等病理变化；GRP78、CHOP、ATF4、Beclin-1、LC3、Caspase-3、Caspase-8和Bax/Bcl-2的蛋白表达水平显著升高。分子对接结果显示，GRP78、ATF4和Beclin-1与CTD对接结果良好。
结论 CTD可激活大鼠ERS，进一步激活自噬，诱导下游凋亡，研究结果可为CTD诱导的DILI提供新的科学依据。

Abstract:
OBJECTIVE To explore the toxicological mechanism of drug-induced liver injury(DILI) in rats induced by cantharidin(CTD).
METHODS SD rats were exposed to different doses of CTD(0.061 4, 0.092 1, 0.184 1 mg·kg⁻¹) by oral gavage for 28 d. Liver index and serum liver function indictors were detected. HE staining was used to evaluate the pathological changes of liver. Then the proteins in endoplasmic reticulum stress(ERS), autophagy, and apoptosis-pathway were detected by Western blotting.
RESULTS The liver index was increased in CTD groups. The ALT, AST, LDH, ALP and T-Bil were increased by CTD with a dose-dependent manner. Disrupted hepatic architecture and dilatation of central vein were observed after CTD intervention. The protein expression levels of GRP78, CHOP, ATF4, Beclin-1, LC3, Caspase-3, Caspase-8, and Bax/Bcl-2 were increased after CTD intervention. Molecular docking results revealed that GRP78, ATF4, and Beclin-1 could directly interconnect with CTD.
CONCLUSION CTD can activate ERS, autophagy and synergistically inducing downstream apoptosis in rat, providing a novel insight into the mechanism of CTD-induced DILI.

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