【摘要】：目的評估依魯替尼長期給藥對姥鮫烷誘導(dǎo)的系統(tǒng)性紅斑狼瘡(SLE)模型小鼠的治療作用及副作用。方法 6周齡雌性BALB/c小鼠ip給予姥鮫烷0.5mL制備SLE小鼠模型。4周后,根據(jù)抗雙鏈DNA(DS-DNA)抗體滴度和體質(zhì)量均勻分為模型組、依魯替尼30 mg·kg~(-1)治療組和潑尼松10 mg·kg~(-1)治療組,每天ig給藥1次,連續(xù)28周。每4周測定1次體質(zhì)量,ELISA法測定血清中抗DS-DNA抗體、抗單鏈DNA(SS-DNA)抗體和抗組蛋白抗體水平,評估關(guān)節(jié)炎紅腫等癥狀的評分及發(fā)病率;生物化學(xué)法檢測血清肌酐、尿素氮和尿液尿蛋白水平評估腎功能。給藥28周后處死小鼠,ELISA檢測白細胞介素6(IL-6)、干擾素γ(IFN-γ)和腫瘤壞死因子α(TNF-α)水平;采集心、肝、脾、肺和腎,稱重并計算臟器系數(shù);生物化學(xué)法檢測血清谷丙轉(zhuǎn)氨酶、谷草轉(zhuǎn)氨酶和堿性磷酸酶活性評估肝功能;HE染色觀察后足和腎組織病理變化,并用免疫組化法檢測腎組織免疫復(fù)合物IgG沉積。結(jié)果與正常對照組比較,模型組抗DS-DNA,SS-DNA和組蛋白抗體及IL-6,IFN-γ和TNF-α水平均明顯升高(P0.01),血清肌酐、尿素氮和尿蛋白升高,關(guān)節(jié)炎癥狀嚴重(P0.01),后足組織炎癥細胞浸潤嚴重(P0.01),腎和脾顯著增大(P0.01)與模型組相比,依魯替尼治療28周可減緩SLE模型小鼠體質(zhì)量下降,降低抗DS-DNA,SS-DNA和組蛋白抗體水平(P0.01),減輕小鼠關(guān)節(jié)紅腫等癥狀(P0.01),并降低關(guān)節(jié)炎發(fā)病率,降低血清細胞因子IL-6,IFN-γ和TNF-α水平(P0.01);后足關(guān)節(jié)病理觀察顯示,炎癥細胞浸潤、血管翳形成、軟骨破壞和骨吸收減輕(P0.01);腎組織病理觀察顯示,炎癥細胞浸潤和IgG免疫復(fù)合物沉積減少,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)。結(jié)論依魯替尼給藥28周對SLE模型小鼠有一定的治療作用,未見明顯副作用。
[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.
【作者單位】： 上海潤諾生物科技有限公司;復(fù)旦大學(xué)生命科學(xué)學(xué)院;
【基金】：國家國際科技合作專項基金(2013DFA30870)~~
【分類號】：R-332;R593.241

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