目的 观察Bortezomib能否通过抑制核因子-κB(nuclear factor-κB, NF-κB)活性起到治疗炎症性肠病(inflammatory bowel disease,IBD)的作用.方法 160只Balb/c小鼠随机分成Bortezomib高、中、低剂量治疗组,正常对照组和模型对照组,每组32只. DSS法构建IBD模型后,高、中、低治疗组分别予以Bortezomib溶液1.0 mg/kg、0.6 mg/kg、0.2 mg/kg腹腔注射,对照组予以PBS腹腔注射.分别于用药开始前、用药后1 d、3 d、7 d观察疾病活动指数(disease activity index,DAI)、组织学评分,ELISA法测定肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的血清水平;EMSA法评估核NF-κB p65与DNA结合的活性.结果 造模后,小鼠DAI、组织学评分、TNF-α水平和NF-κB p65活性均较正常对照组显著降低,而应用Bortezomib治疗后,NF-κB p65活性显著受到抑制, TNF-α水平均逐渐降低,且DAI、组织学评分也均显著降低,具有明显的时间和剂量依赖性.结论 Bortezomib对小鼠结肠炎动物模型具有保护作用,可能通过抑制NF-κB的活性,下调TNF-α的表达发挥作用.随着Bortezomib治疗剂量和治疗天数的增加,对NF-κB的活性抑制作用越来越明显,对IBD的治疗作用也越来越来明显.%Objective To observe whether or not Bortezomib by inhibiting the activity of nuclear factor-κB(NF-κB) can play a role in the treatment of inflammatory bowel disease (IBD). Methods Mice were challenged with drinking water containing 30 g/L dextran sulfate sodium (DSS) for 7 consecutive days and then intraperitoneally treated with three doses of Bortezomib (0.2,0.6,or 1 mg/kg) for 1-,3-or 7-day,respectively. Mice in normal control and DSS groups were given the equivalent volume of PBS. DAI score, histological score and serum levels of TNF-α were ob-served. The expression levels of NF-κB p65 were evaluated by EMSA. Results DAI score,histological score,TNF-α and NF-κB p65 activity in mice with IBD were significantly lower than those in normal control group. After treatment with Bortezomib,the NF-κB p65 activity was significantly suppressed, the level of TNF-α was gradually reduced, the DAI,histological score were all down-regulated,and had obvious time and dose dependent. Conclusion These find-ings demonstrate that Bortezomib exerts a protective effect on DSS-induced colitis in experimental mousemodels, proba-bly by inhibiting DNA binding activity of NF-κB,down-regulating the expression levels of TNF-α. With the increase of Bortezomib dose and treatment days,the inhibitory effect on NF-κB activity is more and more obvious,and the therapeu-tic effect on IBD is also more and more obvious.
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