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《中国科学—生命科学》发表本组类风湿关节炎最新研究论文
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青蒿素和雷帕霉素阻遏一氧化氮爆发性缺氧激发的小鼠急性关节滑膜炎
吴佩①†, 鲍飞②†, 郑青③, 肖娜①, 汪大婷①, 曾庆平①*
① 广州中医药大学热带医学研究所, 广州 510405;
② 中山大学附属第一医院放射治疗科, 广州 510080;
③ 暨南大学药学院, 广州 510632
† 同等贡献
投稿日期: 2012-03-31; 接受日期: 2012-08-15
广东省自然科学基金(批准号: 9145624536-4000003)和广东省高校师资队伍建设专项经费(2008)资助项目
doi: 10.1360/052012-148
摘要 为探讨类风湿性关节炎(RA)的发病原因并揭示青蒿素及雷帕霉素抗RA的作用机理, 本研究建立了完全弗氏佐剂(CFA)诱导的急性关节炎(CIAA)小鼠模型. 从炎症形态学及组织病理学上与经典的胶原诱导关节炎(CIA)的比较表明, CIAA能完全模拟CIA的关节红肿、滑膜增生和炎性浸润, 而且造模时间大大缩短(从28天缩短到3天). 关节腔CFA注射使促炎症细胞因子基因全面上调, 一氧化氮(NO)急剧爆发, 缺氧诱导因子-1(HIF-1)和血管内皮生长因子(VEGF)过表达, 最终导致滑膜血管新生及细胞增殖. 用NO供体化合物硝普钠(SNP)注射小鼠关节腔也能引起关节红肿, 而CFA与NO合成抑制剂NG-单甲基-L-精氨酸(L-NMMA)共同给药则无关节炎症发生. SNP先激活促炎症细胞因子表达, 然后阻遏诱导型NO合酶表达, 再进一步促进HIF-1和VEGF表达. 在CIAA小鼠造模前后注射青蒿琥酯和/或雷帕霉素, 可逆转缺氧诱导的HIF-1和VEGF表达、滑膜血管形成、肿瘤样增生和淋巴细胞炎性浸润. 青蒿琥酯不能完全抑制CFA诱导的免疫激活, 而雷帕霉素可显著下调CFA激发的促炎症细胞因子表达, 二者均能抑制NO合成, 可见NO是RA发病的重要媒介因素. 青蒿琥酯和雷帕霉素通过阻断NO产生的连锁效应展示了预防及治疗RA的潜在应用前景.
关键词 类风湿性关节炎 一氧化氮 缺氧 病因学 发病机理
Artemisinin and Rapamycin Compromise Nitric Oxide-driven and Hypoxia-triggered Acute Articular Synovitis in Mice
WU Pei1, BAO Fei2, ZHENG Qing3, XIAO Na1, WANG DaTing1 & ZENG QingPing1
1 Tropical Medicine Institute, Guangzhou University of Chinese Medicine, Guangzhou 510405, China;
2 Department of Radiotherapy, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China;
3 College of Pharmacology, Jinan University, Guangzhou 510632, China
To investigate the etiological cause of rheumatoid arthritis (RA) and reveal the mechanism underlying the artemisinin and rapamycin against RA, the present work has established a mouse model of the complete Freund's adjuvant (CFA)-induced acute arthritis (CIAA). The inflammation morphological and histopathological comparisons of CIAA with the classic collagen-induced arthritis (CIA) indicated that CIAA perfectly simulates CIA in articular erythema and edema, synovial hyperplasia, and inflammatory infiltration in a substantially shortened modeling time (from 28 to 3d). Intra-articular injection with CFA allows global up-regulation of pro-inflammatory cytokine genes, dramatic burst of nitric oxide (NO), overexpression of hypoxia inducible factor 1 alpha (HIF-1) and vascular epithelial growth factor (VEGF), and synovial angiogenesis and hyperplasia. Aticular injection of mice with the NO donor compound sodium nitroprusside (SNP) also causes articular erythema and edema, whereas co-administration of CFA with the NO synthetic inhibitor NG-monomethyl-L-arginine (L-NMMA) abrogates articular inflammation. SNP activates pro-inflammatory cytokines but suppresses inducible NO synthase within three days, and upregulates HIF-1 and VEGF within two weeks. Pre- and post-injection of modeling CIAA mice with artesunate and/or rapamycin reverses hypoxia-induced expression of HIF-1 and VEGF, synovial angiogenesis, tumor-like hyperplasia, and lymphocytic inflammatory infiltration. While artesunate fails to completely repress CFA-induced immune activation, rapamycin down-regulates CFA-triggered expression of pro-inflammatory cytokines. Nevertheless, both artesunate and rapamycin are able to inhibit NO production. Conclusively, NO serves as a pivotal mediator of RA pathogenesis, and artemisinin and rapamycin, by blocking NO generation, hold potential promise in prophylactic and therapeutic interventions of RA patients.
rheumatoid arthritis, nitric oxide, hypoxia, etiology, pathogenesis
https://blog.sciencenet.cn/blog-281238-616752.html
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