胺碘酮通过诱发免疫紊乱加剧小鼠肝毒性

Amiodarone Aggravates Liver Toxicity in Mice by Inducing Immune Dysregulation

胺碘酮(amiodarone)是临床上广泛使用的第三类抗心律失常药物,临床研究已经发现长期服用胺碘酮会对人体造成副作用,包括肝毒性。鉴于人体与共生微生物形成了一个复杂的共生生态系统,口服胺碘酮对机体的影响,从药物吸收到直接或间接的药物作用,反映了药物与机体以及共生生态系统相互作用的结果。然而,胺碘酮对肝功能的影响及其潜在机制仍然知之甚少。本研究为探讨胺碘酮对肝脏的影响,建立了胺碘酮诱导小鼠模型,采用Lieber-Decarli液体饲料,分别设置200 mg·kg^(-1)的低剂量组和600 mg·kg^(-1)的高剂量组。研究发现胺碘酮处理28 d后,诱发小鼠肝脏转录谱发生改变,与对照组相比,胺碘酮处理组有1 634个差异基因表达显著变化,差异基因富集的KEGG信号通路包括PPAR信号通路、脂肪酸代谢信号通路、胆汁酸分泌、代谢外源物质的细胞色素P450信号通路等。此外,胺碘酮处理组肝脏结构和功能受到损伤,组织病理学分析显示肝脏出现微泡型脂肪肝,脂质新生相关的基因Acaca、Fasn和Srebf1表达上调。血清生化检测结果表明丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)水平升高,并有浓度依赖性。进一步研究发现胺碘酮引起小鼠肝脏免疫紊乱,促发Th17细胞和Th1细胞比例上调,相应的炎症因子TNF-α、TGF-β1、IL-17等也显著增加。胺碘酮也诱发脾脏Treg细胞比例下调,CD8阳性细胞比例上调。由此可知,胺碘酮可以诱导小鼠肝脏转录组发生改变,同时造成肝毒性,诱发小鼠自身免疫紊乱,进一步引发炎症反应。

Amiodarone,a commonly used ClassⅢantiarrhythmic drug in clinical practice,has been associated with various side effects on the human health,including liver toxicity.Given that the human body and commensal microbes form a complex symbiotic ecosystem,the impact of oral amiodarone on the body,from drug absorption to direct or indirect drug effects,reflects the outcome of interactions between the drug and organism as well as symbiotic ecosystems.However,the effects of amiodarone and its underlying mechanism on liver functions remain poorly understood.In this study,our objective was to investigate the influence of amiodarone on liver function using an amiodarone-induced mouse model.Two groups of mice were administered with Lieber-Decarli liquid diets containing 200 mg·kg^(-1)(low-dose group)or 600 mg·kg^(-1)(high-dose group)amiodarone.We found that after 28 d of amiodarone treatment,there were significant changes in the mice’s liver transcriptome compared to the control group.A total of 1634 different genes exhibited altered expression in response to amiodarone treatment,involving with enriched KEGG signaling pathways including PPAR signaling,fatty acid metabolism,bile acid secretion,and the cytochrome P450 signaling pathway in exogenous substance metabolism.Additionally,histopathological analysis revealed microvesicular steatosis and upregulation of genes related to lipid biosynthesis such as Acaca,Fasn,and Srebf1,indicating compromised liver structure and function in the amiodarone-treated group.Serum bio-chemical tests indicated elevated levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST),which demonstrated concentration-dependent changes.Further investigation revealed that amiodarone induced immune dysregulation in the liver tissue,leading to an upregulation of Th17 and Th1 cells proportions,accompanied by a significant elevation of inflammatory factors such as TNF-α,TGF-β1,and IL-17.Furthermore,amiodarone also caused a reduction in Treg cells proportion in the spleen and an increase in CD8+cells.Collectively,these findings provide compelling evidence for the potency of amiodarone to induce alterations in the mouse liver transcriptome,causing hepatotoxicity and triggering autoimmune disturbances followed by an inflammatory response.