全反式视黄酸对CIA大鼠血清炎性细胞因子及软骨损伤相关蛋白表达的影响

The Effects of All-trans Retinoic Acid on the Expression of Inflammatory Cytokines and Cartilage Damage Related Protease in Rats with Collagen Induced Arthritis

目的探讨全反式视黄酸(ATRA)对胶原诱导的类风湿关节炎模型大鼠(CIA大鼠)关节炎症反应、炎性相关细胞因子及软骨损伤相关蛋白表达的影响。方法将雌性Wistar大鼠随机分为空白对照组和造模组,造模组采用牛CⅡ型胶原和不完全弗氏佐剂诱导关节炎。造模成功后,将模型鼠随机分为CIA模型组和ATRA治疗组。ATRA治疗组给予不同剂量(0.50mg/kg、1.00mg/kg)的ATRA腹腔注射,3次/周,连续治疗6周。空白对照组给予等体积的生理盐水,CIA模型组给予等体积玉米油。观察CIA大鼠关节炎指数(AI)评分、血清炎性相关细胞因子的水平、膝和踝关节组织病理形态学改变及软骨损伤相关蛋白的表达。结果 ATRA干预6周后,不同剂量ATRA治疗组AI评分与CIA模型组相比,差异均无统计学意义(P>0.05);HE染色示,CIA模型组和ATRA 1.00mg/kg剂量组膝、踝关节结构紊乱,ATRA 0.50mg/kg剂量组膝关节结构有所改善。此外,与CIA模型组相比,ATRA可抑制促炎细胞因子干扰素-γ、肿瘤坏死因子-α、白介素-17A的分泌(P<0.05),促进白介素-4的分泌(P<0.05);下调解整链蛋白金属蛋白酶(ADAMTS)-4、基质金属蛋白酶(MMP)3、MMP1的表达(P<0.05)。结论 ATRA可在一定程度上抑制促炎因子分泌,纠正Th1/Th2及Th17/Treg失衡,并抑制软骨损伤相关酶类的蛋白表达,对类风湿关节炎有潜在的有利影响。

Objective To investigate the effects of all-trans retinoic acid（ATRA）on arthritis and the expressions of inflammatory cytokines and cartilage damage related proteases of the collagen-induced arthritis model（CIA）rats in vivo.Methods The CIA model of rheumatoid arthritis was induced with CⅡ and incomplete Freund＇s adjuvant.The rats were randomly divided into control group,CIA model group and two ATRA dose groups（ATRA 0.50mg/kg group and ATRA 1.00mg/kg group）.ATRA were given three times per week for six weeks in ATRA groups.Morphological changes,arthritis index（AI）scores,the semi-quantitative scores of pathology damage,the protein expressions of cartilage damage related proteases and the serum levels of TNF-α,IL-17 A,IFN-γ,IL-4,IL-10 were observed.Results The AI scores of ATRA groups were similar to CIA model group（P〈0.05）.Apparent morphological disorders in knee and ankle joints were observed in the CIA model group and ATRA 1.00mg/kg group.The structure of knee joint was improved slightly in ATRA 0.50mg/kg group.The serum levels of TNF-α,IFN-γand IL-17 A were decreased in both ATRA groups;ATRA also can increase the serum level of IL-4.Compared to CIA model group,the protein expressions of ADAMTS-4,MMP3,MMP1 were decreased in both ATRA groups（P〈0.05）.Conclusion ATRA,which was able to inhibit pro-inflammatory cytokines secretion,could correct the imbalance of Th1/Th2 and Th17/Treg. ATRA also can reduce the expressions of cartilage damage related proteases,which proved that ATRA may have a beneficial effect on rheumatoid arthritis.