The role of inflammasome activation in Triptolide-induced acute liver toxicity
The role of inflammasome activation in Triptolide-induced acute liver toxicity
复制标题
炎症小体激活在雷公藤甲素诱发的急性肝毒性中的作用
DOI：
10.1016/j.intimp.2019.105754
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发表时间：
2019
影响因子：
5.6
通讯作者：
Jiang Zhenzhou
中科院分区：
文献类型：
--
作者：
Yuan Ziqiao;Hasnat Muhammad;Liang Peishi;Yuan Zihang;Zhang Haoran;Sun Lixin;Zhang Luyong;Jiang Zhenzhou
雷公藤内酯醇（Triptolide，TP）是中药雷公藤（Tripterygium wilfordiiHook）的主要活性成分。F具有良好的免疫调节和抗肿瘤活性的药理学特征。然而，由于TP的治疗窗口较窄，且存在副作用，尤其是肝毒性，其应用受到限制。本研究旨在探讨炎性小体在TP急性肝毒性中的作用。以600 μg/kg的剂量给药12 h和24 h后，检测血清生化指标、肝脏组织病理学变化、肝脏炎症因子表达和NLRP 3炎性体活化情况。TP处理的小鼠表现出肝损伤，血清转氨酶和NLRP 3炎性体活化呈时间依赖性增加，伴有中性粒细胞浸润增加。进一步的结果提示，单次TP（600 μg/kg）诱导的TLR 4-Myd 88-NF-κB通路的激活和氧化应激可能参与了NLRP 3炎性体的激活。为了研究炎性小体的激活是否参与TP诱导的肝损伤，在TP给药前单剂量注射Ac-Yvad-Caspase（Caspase-1抑制剂）。Ac-Yvad-Caspase预处理可有效抑制Caspase-1活性的升高，抑制IL-1β的成熟。进一步的研究表明，Ac-Yvad-CsA预处理减少了中性粒细胞的募集，并抑制了大量促炎因子的产生。以上结果表明，炎症体的激活加重了TP的急性肝毒性。抑制炎性小体可能成为改善TP肝毒性的一个新的治疗靶点。
Triptolide (TP), the major active compound derived from the traditional Chinese medicineTripterygium wilfordiiHook. F, possesses an excellent pharmacological profile of immunomodulatory and anti-tumor activities. However, the application of TP was restricted due to its narrow therapeutic window and side effects, especially its hepatotoxicity. This study was designed to investigate the role of inflammasome in TP-induced acute liver toxicity. After the administration of TP at the dose of 600 μg/kg for 12 h or 24 h, we examined the serum biochemical parameters, liver histopathological changes, the expression of liver inflammatory factors, and the activation of NLRP3 inflammasome. Mice treated with TP displayed liver injury with a time-dependent increase of serum transaminases and activation of NLRP3 inflammasome, accompanied by the elevation of neutrophils infiltration. Further results implied that the activation of TLR4-Myd88-NF-κB pathway and oxidative stress induced by a single dose of TP (600 μg/kg) might participate in the activation of NLRP3 inflammasome. To investigate whether the activation of inflammasome participates in the liver damage induced by TP, a single dose of Ac-Yvad-Cmk (Caspase-1 inhibitor) was injected before TP administration. Ac-Yvad-Cmk pretreatment effectively prevented the increase of Cleaved Caspase-1 and inhibited the maturity of IL-1β. Additional studies revealed that Ac-Yvad-Cmk pretreatment decreased the recruitment of neutrophils and inhibited the production of massive pro-inflammatory factors. Taken together, our results revealed that activation of inflammasome aggravated the acute liver toxicity induced by TP. Inhibition of inflammasome could serve as a novel therapeutic target for the amelioration of TP-induced hepatotoxicity.