Decrease of CD68 Synovial Macrophages in Celastrol Treated Arthritic Rats.
Decrease of CD68 Synovial Macrophages in Celastrol Treated Arthritic Rats.
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DOI：
10.1371/journal.pone.0142448
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Fonseca JE
中科院分区：
文献类型：
--
作者：
Cascão R;Vidal B;Lopes IP;Paisana E;Rino J;Moita LF;Fonseca JE
类风湿性关节炎（RA）是一种慢性免疫介导的炎症性疾病，其特征是关节内细胞浸润、滑膜细胞过度增殖和骨损伤。现有的RA治疗仅在约30%的患者中诱导缓解，具有重要的不良反应，并且其使用受到其高成本的限制。因此，具有可接受的安全性和低生产成本的可控制关节炎的化合物仍然是未满足的需求。我们已经证明，在体外，雷公藤红素抑制在RA中起重要作用的IL-1β和TNF，并且在体内，雷公藤红素具有显著的抗炎特性。我们在这项工作中的主要目标是测试雷公藤红素在佐剂诱导的大鼠关节炎模型（AIA）中对亚衬CD 68巨噬细胞（新型RA治疗的治疗反应的生物标志物）的数量以及对整体滑膜组织细胞结构和关节结构的影响。在关节炎发展的早期（疾病诱导后4天）和晚期（疾病诱导后11天）阶段向AIA大鼠施用雷公藤红素。治疗期间对两组患者进行炎症评分、踝关节周长及体重评价。在疾病进展22天后处死大鼠，收集血液、内脏和爪样品，分别用于毒理学血液参数和血清促炎细胞因子定量，以及组织病理学和免疫组织化学评价。在这里，我们报告雷公藤红素显着减少亚衬CD 68巨噬细胞和整体滑膜炎性细胞的数量，并停止关节破坏，没有副作用。我们的研究结果验证雷公藤红素作为一个有前途的化合物治疗关节炎。
Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by cellular infiltration into the joints, hyperproliferation of synovial cells and bone damage. Available treatments for RA only induce remission in around 30% of the patients, have important adverse effects and its use is limited by their high cost. Therefore, compounds that can control arthritis, with an acceptable safety profile and low production costs are still an unmet need. We have shown, in vitro, that celastrol inhibits both IL-1β and TNF, which play an important role in RA, and, in vivo, that celastrol has significant anti-inflammatory properties. Our main goal in this work was to test the effect of celastrol in the number of sublining CD68 macrophages (a biomarker of therapeutic response for novel RA treatments) and on the overall synovial tissue cellularity and joint structure in the adjuvant-induced rat model of arthritis (AIA). Celastrol was administered to AIA rats both in the early (4 days after disease induction) and late (11 days after disease induction) phases of arthritis development. The inflammatory score, ankle perimeter and body weight were evaluated during treatment period. Rats were sacrificed after 22 days of disease progression and blood, internal organs and paw samples were collected for toxicological blood parameters and serum proinflammatory cytokine quantification, as well as histopathological and immunohistochemical evaluation, respectively. Here we report that celastrol significantly decreases the number of sublining CD68 macrophages and the overall synovial inflammatory cellularity, and halted joint destruction without side effects. Our results validate celastrol as a promising compound for the treatment of arthritis.