全反式视黄酸预防性给药可减轻类风湿关节炎模型大鼠的炎症

摘要

目的 探索全反式视黄酸(ATRA)对Ⅱ型胶原(CⅡ)诱导的类风湿关节炎模型(CIA)大鼠关节炎形成期关节组织结构、血清中相关炎性细胞因子表达水平,以及软骨损伤相关蛋白表达水平的影响.方法 将6～8周龄雌性Wistar大鼠随机分为空白对照组、溶剂对照组、ATRA各剂量组,给予溶剂对照组和ATRA各剂量组大鼠尾部皮内注射CⅡ和不完全弗氏佐剂诱导类风湿关节炎,空白对照组大鼠以相同方式给予等量生理盐水.自初次免疫第2天起,ATRA各剂量组大鼠腹腔注射不同剂量(0.05、0.5、5 mg/kg)的ATRA油剂,溶剂对照组腹腔注射等体积玉米油,空白对照组腹腔注射等体积生理盐水,每周3次,连续3周.观察ATRA对大鼠关节炎指数(AI)评分、膝踝关节组织病理形态学、血清中相关炎性细胞因子的表达水平及软骨损伤相关蛋白表达水平的影响.结果 自初次免疫第15天起,ATRA各剂量组和溶剂对照组AI值均显著高于空白对照组(P＜0.05),溶剂对照组AI值趋于平稳,ATRA各剂量组AI值呈上升趋势,且低于溶剂对照组(P＜0.05);膝踝关节病理切片可见,ATRA各剂量组和溶剂对照组踝关节结构出现严重紊乱,但组间关节损伤的半定量评分差异无统计学意义(P＞0.05);此外,与溶剂对照组相比,ATRA各剂量组白介素-17A(IL-17A)和肿瘤坏死因子-α(TNF-α)分泌减少(P＜0.05),白介素-10(IL-10)分泌增多(P＜0.05);膝关节中解整链蛋白金属蛋白酶(ADAMTS-4)和基质金属蛋白酶(MMP-3)表达下调(P＜0.05),其余软骨损伤相关蛋白的表达差异无统计学意义(P＞0.05).结论 在胶原诱导关节炎形成期,ATRA可抑制TNF-α、IL-17A等促炎因子的分泌,促进IL-10的分泌,从而减轻CIA大鼠关节炎形成期的炎症反应.说明ATRA在关节炎形成期可延缓疾病的进展,其作用机制可能与纠正Th1/Th2及Th17/Treg失衡有关.%Objective To investigate the effects of prophylactic administration of all-trans retinoic acid (ATRA) in relieving inflammation in a rat model of collagen-induced arthritis (CIA).Methods Female Wistar rats (6 to 8 weeks old) were randomly divided into normal control group,solvent control group,and prophylactic ATRA treatment (0.05,0.5,and 5 mg/kg) groups.All the rats except for those in normal control group were subjected to subcutaneous injection of type Ⅱ collagen and incomplete Freund adjuvant in the tails to induce CIA,followed by injection on the following day with saline,corn off or different doses of ATRA 3 times a week.The arthritis index (AI) scores,histological scores,serum levels of TNF-α,IL-17A,and IL-10,and expressions of proteases related with cartilage damage were evaluated.Results On the 15th day after the primary immumza tion,the AI scores increased significantly in all but the normal control groups;the scores increased progressively in all the 3 ATRA groups but remained lower than that in the solvent control group,which was stable over time.The rats in the 3 ATRA groups showed obvious pathologies in the knee and ankle joints,but the semi-quantitative scores of pathology damage showed no significance among them.Compared with those in solvent control group,the serum IL-17A and TNF-α levels decreased,serum IL-10 level increased,and the expressions of ADAMT-4 and MMP-3 proteins decreased significantly in the knees in the 3 ATRA groups.Conclusion ATRA can reduce the production of TNF-α and IL-17A and increase the production of IL-10 to alleviate the inflammation in rats with CIA.ATRA may delay the progression of RA by correcting the imbalance of Th1/Th2 and Th17/Treg.