S1P1调节剂IMMH002对自身免疫性肝炎的治疗作用及机制研究  

The S1P1 regulator IMMH002 and its therapeutic effect and mechanism on autoimmune hepatitis

作　　者：张春雨 向楠 李树颖 陈晓光 金晶 梁泰刚[1] ZHANG Chun-yu;XIANG Nan;LI Shu-ying;CHEN Xiao-guang;JIN Jing;LIANG Tai-gang(School of Pharmaceutical Science,Medicinal Basic Research Innovation Center of Chronic Kidney Disease,Ministry of Education,Shanxi Medical University,Taiyuan 030001,China;State Key Laboratory of Bioactive Substances and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University),Ministry of Education,Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,Yantai University,Yantai 264005,China)

机构地区：[1]山西医科大学药学院,慢性肾脏疾病药物基础研究教育部创新中心,山西太原030001 [2]中国医学科学院、北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050 [3]烟台大学,分子药理学与药物评价教育部重点实验室,先进给药系统与山东高校生物技术药物协同创新中心,山东烟台264005

出　　处：《药学学报》2023年第12期3608-3618,共11页Acta Pharmaceutica Sinica

基　　金：国家重点研发计划-政府间国际科技创新合作重点专项基金(2019YFE0111800);山西省基础研究计划(20210302123300);国家重点研发计划(2019YFC1710803);山西省“黄芪”资源产业化与产业国际化协同创新中心项目(HQXTCXZXX2016-021).

摘　　要：本研究采用植物凝集素刀豆球蛋白A (concanavalin A, ConA)诱导的自身免疫性肝炎(autoimmune hepatitis,AIH)小鼠模型,评价和探索选择性鞘氨醇-1-磷酸1型受体(sphingosine-1-phosphate receptor subtype 1, S1P1)调节剂IMMH002{2-氨基-2-(2-(4'-(2-乙基噁唑-4-基)-[1,1'-联苯]-4-基)乙基)丙烷-1,3-二醇}的药效及作用机制。实验方案按照中国医学科学院、北京协和医学院药物研究所实验动物伦理委员会指导政策严格执行(批准号:00004046)。雄性ICR小鼠预防性给予药物4天后,尾静脉注射ConA蛋白诱导自身免疫性肝炎,对小鼠肝功能、肝组织病理及外周血五分类进行检测,并对免疫球蛋白G (immunoglobulin G, IgG)、炎症因子、T细胞分布和炎症通路等进行研究。结果显示, IMMH002可以明显降低谷丙转氨酶、谷草转氨酶等肝功能指标,减轻肝脏组织炎症和损伤性坏死程度,降低血清中IgG含量,并降低白介素6 (interleukin 6, IL-6)、肿瘤坏死因子α (tumor necrosis factor α, TNF-α)、白介素1β(interleukin 1β, IL-1β)、干扰素γ (interferon γ, IFN-γ)等炎症因子的表达,促进T淋巴细胞归巢,下调肝脏组织和细胞炎症模型中核因子κB (nuclear factor kappa-B, NF-κB)、IκB激酶β (IκB kinase β, IKKβ)及核因子抑制蛋白α (nuclear factor inhibitor protein-α, IκBα)磷酸化蛋白的表达。综上, IMMH002可以显著缓解ConA蛋白诱导的小鼠自身免疫性肝炎,具有广泛的抗炎、抗损伤坏死的作用,为临床治疗AIH奠定理论基础。This study assessed and explored the pharmacological effects and mechanisms of action of IMMH002(2-amino-2-(2-(4'-(2-ethyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl)propane-1,3-dio),a selective sphingosine-1-phosphate receptor subtype 1(S1P1)modulator,in a concanavalin A(ConA)-induced autoimmune hepatitis(AIH)mouse model.The experimental protocol strictly adhered to the guidelines of the Ethics Committee for Animal Research of the Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College(Approval No.:00004046).Male ICR mice were pre-treated with the drug for four days,followed by induction of AIH through tail vein injection of ConA protein.Liver function,hepatic tissue pathology,peripheral blood parameters,as well as immunoglobulin G(IgG),inflammatory cytokines,T cell distribution,and inflammatory pathways were evaluated in mice.Results demonstrated that IMMH002 significantly reduced liver function indicators such as alanine aminotransferase(ALT)and aspartate aminotransferase(AST),alleviated hepatic tissue inflammation and necrotic damage,decreased serum IgG levels,and lowered the expression of inflammatory mediators including interleukin 6(IL-6),tumor necrosis factor α(TNF-α),interleukin 1β(IL-1β),and interferon(IFN-γ).Additionally,it facilitated T lymphocyte homing,downregulated the phosphorylation of nuclear factor kappa-B(NF-κB),IB kinaseβ(IKKβ)and nuclear factor inhibitor protein-α(IκBα)proteins in hepatic tissue and cellular inflammation models.Collectively,IMMH002 effectively ameliorated ConA-induced autoimmune hepatitis in mice,exhibiting extensive anti-inflammatory and anti-necrotic effects,thereby laying a theoretical foundation for AIH clinical treatment.

关 键 词：自身免疫性肝炎 鞘氨醇-1-磷酸1型受体 2-氨基-2-(2-(4'-(2-乙基噁唑-4-基)-[1 1'-联苯]-4-基)乙基)丙烷-1 3-二醇 肝损伤 淋巴细胞归巢 

分 类 号：R967[医药卫生—药理学]