富马酸二甲酯抑制NLRP3/AIM2炎性小体防治脾脏组织辐射损伤  

Dimethyl fumarate inhibits NLRP3/AIM2 inflammasomes to prevent spleen radiation injury

作　　者：张亮亮 胡昌坤 吴泽坤 闫梓乔 廖泽彬 高月 ZHANG Liang-liang;HU Chang-kun;WU Ze-kun;YAN Zi-qiao;LIAO Ze-bin;GAO Yue(School of Pharmacy,Guangdong Pharmaceutical University,Guangzhou 510006,China;Institute of Radiation Medicine,Academy of Military Medical Sciences,Academy of Military Sciences,Beijing 100850,China;School of Pharmacy,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;Dept of Traditional Chinese Medicine,the Sixth Medical Center of Chinese People's Liberation Army(PLA)General Hospital,Beijing 100089,China)

机构地区：[1]广东药科大学药学院,广东广州510006 [2]军事科学院军事医学研究院辐射医学研究所,北京100850 [3]天津中医药大学药学院,天津301617 [4]中国人民解放军总医院第六医学中心中医科,北京100089

出　　处：《中国药理学通报》2024年第3期521-528,共8页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金青年科学基金项目(No82103776);国家自然科学基金重大项目(No82192911)。

摘　　要：目的探讨富马酸二甲酯(dimethyl fumarate,DMF)对γ射线辐射所致小鼠脾脏损伤的防护作用及机制。方法将C57BL/6J小鼠随机分为空白对照组、辐射模型组、DMF给药组,于辐照前12 h,辐照后0.5、12、24、48 h各给药一次。检测经60Coγ射线一次性全身照射(8 Gy)后,小鼠30 d存活率、体质量变化及照射后小鼠脾脏病理损伤;TUNEL染色法检测脾脏细胞凋亡;酶联免疫吸附法(ELISA)检测脾脏中TNF-α、IL-1β、IL-6、IL-18、NLRP3及AIM2含量变化;Western blot实验和免疫荧光染色实验验证辐照后脾脏组织中NLRP3、AIM2含量变化。结果DMF能明显提高辐照后小鼠的存活率,改善照射后小鼠体质量降低情况,减轻脾脏病理损伤,并抑制辐照后脾脏细胞凋亡;ELISA实验结果显示DMF可以显著抑制照射导致的脾脏炎症因子TNF-α、IL-1β、IL-6、IL-18和炎性小体组分NLRP3、AIM2升高;Western blot实验和组织免疫荧光染色也证实,DMF能抑制辐照导致的NLRP3、AIM2炎性小体蛋白水平升高,同时NLRP3激动剂、AIM2激动剂能拮抗DMF对脾脏细胞的辐射防护作用。结论DMF对^(60)Coγ射线损伤小鼠脾脏损伤有明显改善作用,其机制与NLRP3/AIM2炎性小体密切相关,可作为辐射损伤防护药物潜在研究对象。Aim To investigate the protective effect of dimethyl fumarate on spleen injury induced by gamma radiation in mice and the related mechanism.Methods C57BL/6 mice were randomly divided into the blank control group,radiation model group and DMF administration group,which were administered once at 12 h before irradiation and once at 0.5 h,12 h,24 h and 48 h after irradiation.The 30-day survival rate,body weight and pathological injury of spleen were measured after a one-time total body irradiation of 60Coγrays(8 Gy).TUNEL staining was used to detect apoptosis of spleen cells.Enzyme-linked immunoassay(ELISA)was applied to detect the contents of TNF-α,IL-1β,IL-6,IL-18,NLRP3 and AIM2 in spleen.Western blot test and immunofluorescence staining test was employed to verify the changes of NLRP3 and AIM2 contents in spleen tissue after irradiation.Results DMF could obviously improve the survival rate of irradiated mice,improve the weight loss of irradiated mice,reduce the pathological injury of spleen,and inhibit the apoptosis of spleen cells after irradiation.ELISA results showed that DMF could significantly inhibit the increase of spleen inflammatory cytokines TNF-α,IL-1β,IL-6,IL-18 and inflammasome components NLRP3 and AIM2 induced by irradiation.Western blot and tissue immunofluorescence staining also confirmed that DMF could inhibit the increase of NLRP3 and AIM2 inflammasome protein levels caused by irradiation.Meanwhile,NLRP3 agonist and AIM2 agonist could antagonize the radiation protection effect of DMF on spleen cells.Conclusion DMF can ameliorate spleen injury of ^(60)Coγ-ray injured mice,and its mechanism is closely related to NLRP3/AIM2 inflammasomes,which can be used as a potential protective drug for radiation injury.

关 键 词：富马酸二甲酯 电离辐射 炎性小体 炎症因子 辐射损伤 脾脏损伤 

分 类 号：R-332[医药卫生] R322.21R364.5R818R916.4