胱天蛋白酶-1阻断剂对胶原诱导性关节炎小鼠发病的影响

Effects of caspase-1 inhibitor treatment on collagen-induced arthritis in mice

目的探讨胱天蛋白酶-1（caspase-1）阻断剂VX-765对胶原诱导性关节炎（CIA）小鼠发病的影响。方法建立CIA小鼠模型。分为3组：VX-765预防治疗组（VX-765组），模型对照组（CIA组），正常对照组，每组8只小鼠。VX-765组接受VX-765腹腔注射（100mg／kg，每日2次）4周。实验结束时，小鼠关节进行大体病理学、影像（Micro—CT）、组织学评估。血清细胞因子IL-1β、IL-18、IL-33通过ELISA测定。血清细胞因子比较采用方差分析；临床积分、影像学积分、病理积分比较采用Mann—Whimev U检验。结果VX-765组与CIA组小鼠比较，关节炎临床评分（1，6．5；Q=4．5，P=0．010）、影像学积分（1，3．5；Q=2．75，P=0．038）均显著降低。VX-765组与CIA组比较，关节病理积分（1，5．5；Q=4．75，P=0．000）及细胞因子[IL-1β（2．0±1．0）与（6．9±2．4）pg／ml、IL-18（75±42）与（129±48）pg／ml、IL-33（145．46与287．22pg／ml]水平均显著降低（F=27．98，F=17．27，Q=89．72，P均〈0．01）。结论VX-765预防性治疗抑制CIA小鼠发病程度，提示caspase-1是关节炎潜在的治疗靶点。

Objective We investigated the effect of VX-765 on collagen induced arthritis （CIA）. Methods Twenty-four mice were divided into three groups： the VX-765 prophylaxis group （VX-765）, the CIA model group （CIA） and the wild-type control group （Normal）. Each group has 8 mice. Mice with CIA were in-tra-peritoneally injected with VX-765 （100 mg/kg, twice a day）, mice with CIA and controls were treated with 0.9% saline. At the end of the study, clinical scores, radiographic scores and histological scores of joints were calculated. Serum cytokine levels including interleukin （IL）-Iβ, IL-18, IL-33 were assessed by enzyme linked immunosorbent assay （ELISA）. The serum eytokines levels between the CIA group and the VX-765 groups were compared using F test. The clinical scores, radiographic scores and pathological scores between the CIA group and the VX-765 group were compared using the Mann-Whitney test. Results The clinical scores of arthritis and the radiographic scores were significantly lower in the VX-765 group （1, 1） than the CIA group （6.5, 3.5; Q=4.5, 2.75, P〈0.05）. Compared with the CIA group, the histological analysis （1, 5.5; Q= 4.75, P=0.000）,serum cytokine levels [IL-1β （2.0±1.0） vs （6.9±2.4） pg/ml, IL-18 （75±42） vs （129±48） pg/ml, IL-33 （145.46 vs 287.22） pg/ml] were significantly lower in the VX-765 group （F=27.98, F=17.27, Q=89.72, P〈0.01 ）. Conclusion These findings suggest that caspase-1 is a potential therapeutic target for rheumatoid arthritis.