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目的探讨磷酸川芎嗪片联合甲氨蝶呤干预对胶原诱导关节炎大鼠(collagen induced arthritis,CIA)炎症反应及血液流变的影响。方法将55只雄性SD大鼠按体重分层,随机选取9只作为正常对照组,其余46只采用牛Ⅱ型胶原诱导法制备大鼠关节炎模型。对成模大鼠(40只),按足趾肿胀程度分层随机方法分为模型(CIA)组、甲氨蝶呤(MTX)组、磷酸川芎嗪(TMP)组及联用(MTX+TMP)组,每组10只。各药物干预组分别给予以下药物灌胃:MTX组给予MTX 1.2 mg/kg,每周1次,连续4周;TMP组予TMP 40 mg/kg,每日1次,先连续给药10天,停药7天,再继续给药10天;MTX+TMP组分别给予等剂量两种药物,即在两药都给予时,给予两药的等剂量混合药物;在MTX停药时只给予TMP,则按照TMP组方法给药;正常对照组及CIA组给予等量生理盐水。分别于给药第0、4、1 1、18、26天检测大鼠脚掌厚度和踝关节直径。4周后杀鼠取材,观察各组大鼠关节病理变化;采用E LISA方法检测各组大鼠血清细胞因子IL-1β、IL-6及IL-17A变化,检测血浆血流变学指标纤维蛋白原(FIB)含量及血小板聚集率(PAg)变化。结果与正常对照组比较,CIA组大鼠脚掌厚度与踝关节直径明显增加(P<0.01),FIB含量及PAg均升高(P<0.05,P<0.01);血清IL-1β、IL-6及IL-17A水平亦明显升高(P<0.01);关节滑膜出现明显的细胞增生、炎细胞浸润、组织充血水肿,血管翳形成浸入软骨,出现明显的坏死。与CIA组比较,各药物干预组大鼠脚掌厚度与踝关节直径均减小(P<0.05,P<0.01),其中MTX组效果优于TMP组及MTX+TMP组(P<0.05,P<0.01);MTX组FIB含量降低(P<0.05),血清IL-1β、IL-6水平亦降低(P<0.05);TMP组和MTX+TMP组FIB含量、血清IL-1β、IL-6水平降低,且MTX+TMP组FIB和IL-6水平明显低于MTX组及TMP组,差异有统计学意义(P<0.01);在降低PAg和血清IL-17A水平方面,TMP组优于MTX组及MTX+TMP组;各药物均可显著改善关节病理,联用效果最佳。结论 TMP联合MTX可以显著改善胶原诱导关节炎大鼠的炎症反应及全血FIB含量。
Objective To investigate the effects of ligustrazine triphosphate combined with methotrexate on inflammation and blood rheology in collagen induced arthritis (CIA) rats. Methods Fifty-five male SD rats were stratified by body weight. Nine rats were randomly selected as the normal control group and the remaining 46 rats were induced by collagen type Ⅱ collagen. Forty rats were randomly divided into model group (CIA), methotrexate (MTX) group, ligustrazine phosphate (TMP) group and MTX + TMP group ) Group, 10 in each group. Each drug intervention group were given the following drug gavage: MTX group was given MTX 1.2 mg / kg once a week for 4 weeks; TMP group TMP 40 mg / kg, once daily for 10 days, The drug was discontinued for 7 days and then continued to be administered for 10 days. MTX + TMP group were given equal doses of two drugs, that is, when the two drugs are given, the two drugs were given the same dose of mixed drugs; Then according to TMP group method; normal control group and CIA group given the same amount of saline. The rats’ paw thickness and ankle diameter were measured on the 0th, 4th, 11th, 18th, and 26th days respectively. Four weeks later, the mice were sacrificed and the pathological changes of the joints were observed. The changes of the serum cytokines IL-1β, IL-6 and IL-17A in each group were detected by E-ELISA. The changes of plasma hemorheology, fibrin (FIB) content and platelet aggregation rate (PAg) changes. Results Compared with the normal control group, the thickness and the ankle diameter of the foot in rats in CIA group were significantly increased (P <0.01), and the levels of FIB and PAg were significantly increased (P <0.05, P <0.01). The levels of IL-1β and IL- (P <0.01). Significant cell proliferation, infiltration of inflammatory cells, congestion and edema occurred in the synovium of joints and infiltration of cartilage into the cartilage with obvious necrosis. Compared with CIA group, the thickness and the diameter of ankle in both groups decreased (P <0.05, P <0.01), and the MTX group was better than TMP group and MTX + TMP group (P <0.05, P < 0.01). The levels of FIB and the level of IL-1β and IL-6 in the TMP group and the MTX + TMP group were lower than those in the MTX group (P <0.05) , And the levels of FIB and IL-6 in MTX + TMP group were significantly lower than those in MTX group and TMP group (P <0.01). TMP group was better than MTX group in reducing PAg and serum IL-17A level And MTX + TMP group; each drug can significantly improve joint pathology, combined with the best. Conclusion TMP combined with MTX can significantly improve collagen-induced arthritis in rats inflammatory response and FIB content.