目的 探讨痹祺胶囊和秋水仙碱联合用药治疗大鼠急性痛风性关节炎的药效作用和机制。方法 通过尿酸钠晶体诱导构建急性痛风性关节炎大鼠模型，随机分为对照组、模型组、秋水仙碱（0.45、0.9 mg/kg）组、痹祺胶囊（180、360 mg/kg）组、痹祺胶囊（180 mg/kg）＋秋水仙碱（0.45 mg/kg）组、痹祺胶囊（360 mg/kg）＋秋水仙碱（0.9 mg/kg）组。测定大鼠踝关节肿胀度。苏木素–伊红（HE）染色检测踝关节组织病理学变化。酶联免疫吸附实验（ELISA）检测炎症细胞因子肿瘤坏死因子α（TNF-α）、白细胞介素-6（IL-6）的水平。Western blotting分析大鼠踝关节滑膜组织中NOD受体蛋白3（NLRP3）、凋亡相关斑点样蛋白（ASC）、白细胞介素（IL）-1β、IL-18蛋白表达情况。结果 与模型组相比，痹祺胶囊或秋水仙碱单独给药，以及两者联合用药均能够减轻模型大鼠踝关节的肿胀度（P＜0.05、0.01、0.001）；与单用痹祺胶囊360 mg/kg组或秋水仙碱0.9 mg/kg组相比，在12、24 h时，痹祺胶囊360 mg/kg＋秋水仙碱0.9 mg/kg组大鼠关节肿胀程度显著减轻（P＜0.05、0.01）。痹祺胶囊与秋水仙碱单独给药均能在一定程度上减轻滑膜细胞增生及炎性细胞浸润情况，且痹祺胶囊与秋水仙碱联合应用比单独给药具有更强的改善作用。与模型组相比，痹祺胶囊与秋水仙碱单独给药组大鼠血清中IL-6水平明显降低（P＜0.05、0.01、0.001）；痹祺胶囊180 mg/kg＋秋水仙碱0.45 mg/kg组大鼠血清中IL-6水平较秋水仙碱0.45 mg/kg组显著降低（P＜0.001），痹祺胶囊360 mg/kg＋秋水仙碱0.9 mg/kg组则较痹祺胶囊360 mg/kg组显著降低（P＜0.05）。与模型组相比，痹祺胶囊与秋水仙碱单独给药组大鼠血清中TNF-α水平明显降低（P＜0.05、0.01、0.001）；痹祺胶囊180 mg/kg＋秋水仙碱0.45 mg/kg组大鼠血清TNF-α水平较痹祺胶囊180 mg/kg组显著降低（P＜0.01），痹祺胶囊360 mg/kg＋秋水仙碱0.9 mg/kg组血清TNF-α水平则较痹祺胶囊360 mg/kg组和秋水仙碱0.9 mg/kg组显著降低（P＜0.001）。与模型组相比，秋水仙碱0.9 mg/kg组、痹祺胶囊360 mg/kg组、痹祺胶囊＋秋水仙碱组大鼠滑膜组织中NLRP3、ASC、IL-18、IL-1β蛋白表达量均明显降低（P＜0.05、0.01、0.001），且联合用药对NLRP3炎症小体相关蛋白表达的抑制作用明显强于痹祺胶囊或秋水仙碱单独给药（P＜0.01、0.001）。结论 痹祺胶囊和秋水仙碱联用能够协同改善急性痛风性关节炎相关表型，通过抑制NLRP3介导的过度炎症反应有效减轻相关病理损伤，为两者联合应用治疗急性痛风性关节炎的临床应用提供依据和参考。

Objective To investigate the pharmacological effects and mechanism of the combination therapy of Biqi Capsules and colchicine in treatment of acute gouty arthritis. Methods Acute gouty arthritis rat model was established by the monosodium urate crystals injection. Rats were randomly divided into eight groups, control group, model group, colchicine group (0.45 and 0.9 mg/kg), Biqi Capsules group (180 and 360 mg/kg), Biqi Capsules 180 mg/kg + colchicine 0.45 mg/kg group, and Biqi Capsules 360 mg/kg + colchicine 0.9 mg/kg group. The swelling degree of rat ankle joint were recorded. HE staining was used to determine the pathological structural changes in rat ankle joint. The serum levels of TNF-α and IL-6 were determined by ELISA. Western blotting was used to determine the protein expression levels of NLRP3, ASC, IL-1β, and IL-18 in the synovial tissue of the rat ankle joint. Results Compared with the model group, the administration of Biqi Capsules or colchicine, as well as the combination of the two could all reducde the swelling degree of the ankle joint in model rats (P < 0.05, 0.01, 0.001). Compared with the 360 mg/kg of Biqi Capsules alone or 0.9 mg/kg of colchicine group, at 12 and 24 hours, the degree of joint swelling in the group of 360 mg/kg of Biqi Capsules + 0.9 mg/kg of colchicine was significantly reduced (P < 0.05, 0.01). Both Biqi Capsules and colchicine could alleviated the proliferation of synovial cells and the infiltration of inflammatory cells, and the combined application of Biqi Capsules and colchicine had a stronger improvement effect than administration alone. Compared with the model group, the levels of IL-6 in the serum of rats in the Biqi Capsules group and the colchicine group were significantly decreased (P < 0.05, 0.01, 0.001), the level of IL-6 in the serum of rats in the group of Biqi Capsules 180 mg/kg + colchicine 0.45 mg/kg was significantly lower than that in the colchicine group 0.45 mg/kg (P < 0.001). Biqi Capsules 360 mg/kg + colchicine 0.9 mg/kg group was significantly lower than that in Biqi Capsules 360 mg/kg group (P < 0.05). Compared with the model group, the levels of TNF-α in the serum of rats in the Biqi Capsules group and colchicine group were significantly decreased (P < 0.05, 0.01, 0.001). The serum TNF-α level in the Biqi Capsules 180 mg/kg + colchicine 0.45 mg/kg group was significantly lower than that in the Biqi Capsules 180 mg/kg group (P < 0.01). The serum TNF-α level in the Biqi Capsules 360 mg/kg+ colchicine 0.9 mg/kg group was significantly lower than that in the Biqi Capsule 360 mg/kg group and the colchicine 0.9 mg/kg group (P < 0.001). Compared with the model group, the protein expression levels of NLRP3, ASC, IL-18, and IL-1β in the synovial tissues of rats in the colchicine 0.9 mg/kg group, the Biqi Capsules 360 mg/kg group and the Biqi Capsules + colchicine group were significantly decreased (P < 0.05, 0.01, 0.001). Moreover, the inhibitory effect of combined medication on the expression of NLRP3 inflammasome-related protein was significantly stronger than that of Biqi Capsules or colchicine (P < 0.01, 0.001). Conclusion Combination of Biqi Capsules and colchicine can synergistically improve the acute gouty arthritis-related phenotypes and pathological damage via inhibiting the NLRP3 mediated inflammatory response, which providing a basis and reference for the combination use of Biqi Capsules and colchicine on the treatment of acute gouty arthritis in clinic.

R982

中华中医药学会青年人才托举工程项目（CACM-2021-QNRC2-B12）