依鲁替尼长期给药对姥鲛烷诱导的系统性红斑狼疮模型小鼠的治疗作用和副作用

发布时间：2018-08-21 09:31

【摘要】：目的评估依鲁替尼长期给药对姥鲛烷诱导的系统性红斑狼疮(SLE)模型小鼠的治疗作用及副作用。方法 6周龄雌性BALB/c小鼠ip给予姥鲛烷0.5mL制备SLE小鼠模型。4周后,根据抗双链DNA(DS-DNA)抗体滴度和体质量均匀分为模型组、依鲁替尼30 mg·kg~(-1)治疗组和泼尼松10 mg·kg~(-1)治疗组,每天ig给药1次,连续28周。每4周测定1次体质量,ELISA法测定血清中抗DS-DNA抗体、抗单链DNA(SS-DNA)抗体和抗组蛋白抗体水平,评估关节炎红肿等症状的评分及发病率;生物化学法检测血清肌酐、尿素氮和尿液尿蛋白水平评估肾功能。给药28周后处死小鼠,ELISA检测白细胞介素6(IL-6)、干扰素γ(IFN-γ)和肿瘤坏死因子α(TNF-α)水平;采集心、肝、脾、肺和肾,称重并计算脏器系数;生物化学法检测血清谷丙转氨酶、谷草转氨酶和碱性磷酸酶活性评估肝功能;HE染色观察后足和肾组织病理变化,并用免疫组化法检测肾组织免疫复合物IgG沉积。结果与正常对照组比较,模型组抗DS-DNA,SS-DNA和组蛋白抗体及IL-6,IFN-γ和TNF-α水平均明显升高(P0.01),血清肌酐、尿素氮和尿蛋白升高,关节炎症状严重(P0.01),后足组织炎症细胞浸润严重(P0.01),肾和脾显著增大(P0.01)与模型组相比,依鲁替尼治疗28周可减缓SLE模型小鼠体质量下降,降低抗DS-DNA,SS-DNA和组蛋白抗体水平(P0.01),减轻小鼠关节红肿等症状(P0.01),并降低关节炎发病率,降低血清细胞因子IL-6,IFN-γ和TNF-α水平(P0.01);后足关节病理观察显示,炎症细胞浸润、血管翳形成、软骨破坏和骨吸收减轻(P0.01);肾组织病理观察显示,炎症细胞浸润和IgG免疫复合物沉积减少,血清肌酐、尿素氮和尿蛋白水平降低(P0.01),血清GPT和ALP活性亦降低(P0.01)。结论依鲁替尼给药28周对SLE模型小鼠有一定的治疗作用,未见明显副作用。
[Abstract]:Objective To evaluate the therapeutic effect and side effects of long-term administration of ilutinil in mice with systemic lupus erythematosus (SLE) induced by mammoth alkane.Methods Six-week-old female BALB/c mice were given IP of mammoth alkane 0.5mL to prepare SLE mice model.Four weeks later, the mice were divided into model group according to the titer of anti-double-stranded DNA (DS-DNA) antibody and body mass uniformity. G ~ (- 1) treatment group and prednisone 10 mg ~ (- 1) treatment group were given Ig once a day for 28 weeks. The body mass was measured once every four weeks. The levels of anti-DS-DNA antibody, anti-single stranded DNA (SS-DNA) antibody and anti-histone antibody in serum were determined by ELISA. The symptoms such as arthritis and swelling were evaluated. The mice were sacrificed 28 weeks after administration, and the levels of interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were detected by ELISA; the heart, liver, spleen, lung and kidney were collected, weighed and organ coefficients were calculated; the activities of serum alanine aminotransferase, glutamic oxalate aminotransferase and alkaline phosphatase were measured by biochemical method. Results Compared with the normal control group, the levels of anti-DS-DNA, SS-DNA and histone antibodies, IL-6, IFN-gamma and TNF-alpha in the model group were significantly increased (P 0.01), serum creatinine, urea nitrogen and urine protein were increased, and arthritis was observed. Compared with the model group, the body weight of SLE model mice decreased, the levels of anti-DS-DNA, SS-DNA and histone antibodies decreased (P 0.01), and the symptoms of arthritis decreased (P 0.01). Low serum levels of cytokines IL-6, IFN-gamma and TNF-alpha (P 0.01); Inflammatory cell infiltration, pannus formation, cartilage destruction and bone resorption decreased (P 0.01); Renal histopathological observation showed that inflammatory cell infiltration and IgG immune complex deposition decreased, serum creatinine, urea nitrogen and urine protein levels decreased (P 0.01), serum creatinine, urea nitrogen and urine protein levels decreased (P 0.01). GPT and ALP activities also decreased (P 0.01). Conclusion Irutinil Administration for 28 weeks has a certain therapeutic effect on SLE mice without obvious side effects.
【作者单位】：上海润诺生物科技有限公司;复旦大学生命科学学院;
【基金】：国家国际科技合作专项基金(2013DFA30870)~~
【分类号】：R-332;R593.241

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