BRD4抑制剂JQ1对慢性阻塞性肺疾病模型小鼠肺功能的影响

Effect of BRIM inhibitor JQ1 on lung function in mice with chronic obstructive pulmonary disease

目的探讨溴结构域蛋白4抑制剂(JQ1)对慢性阻塞性肺疾病(COPD)小鼠肺功能的影响及其机制.方法15只小鼠随机分成对照组、COPD模型组、JQ1治疗组,每组5只.采用24周慢性烟雾暴露联合脂多糖制备COPD小鼠模型,JQ1治疗组小鼠经5周腹腔注射JQ1溶液.治疗结束后检测各组小鼠第0.1秒用力呼气量与用力肺活量之比(FEV_(0.1)/FVC)、最大呼气中期流速(MMF)、呼气峰流速(PEF)、呼气气道阻力(Re)、肺动态顺应性(Cdyn).后留取小鼠眼球血及肺组织,对比各组小鼠炎症因子(IL-6、IL-8、TNF-α)及肺组织平均内衬间隔(MLI)、平均肺泡密度(MAN)、气道周围胶原面积占比和波形蛋白(vimentin VIM)等气道重塑指标情况.结果与对照组比较,COPD模型组的FEV_(0.1)/FVC、PEF、MMF和Cdyn均显著降低,Re升高;与COPD模型组比较,JQ1治疗组的FEV_(0.1)/FVC、PEF、MMF和Cdyn升高,Re降低.JQ1治疗组较COPD模型组小鼠血清及肺组织中的IL-6、IL-8、TNF-α降低;肺组织MLI减少、MAN增加,气道周围胶原蛋白沉积减少,VIM mRNA及蛋白表达水平降低.差异均有统计学意义(P<0.05).结论BRD4抑制剂JQ1可能通过改善气道炎症及气道重塑来提高COPD模型组小鼠的肺功能.

Objective To explore the effect of bromodomain protein 4(BRD4)inhibitor JQ1 on lung function in mice with chronic obstructive pulmonary disease(COPD)and its mechanism.Methods A total of 15 mice were randomly divided into control group,COPD group,and JQ1 intervention group,with 5 mice in each group.After 24 weeks of chronic CS/LPS exposure and 5 weeks of JQ1 treatment,the mice were anesthetized,and the lung function were determined including the changes of FEV_(0.1)/FVC,maximal midexpiratory flow(MMF),peek expiration flow(PEF),resistance of expiration(Re),and respiratory dynamic compliance(Cdyn).Then eyeball blood and lung tissue samples were collected to determine the levels of IL-6,IL-8,and TNF-α,and the airway remodeling indexes,such as the mean alveolar number(MAN),mean linear intercept(MLI).the ratio of collagen area around airways,and the mRNA and protein expression of vimentin(VIM).Results In the COPD group,the FEV_(0.1)/FVC,PEF,MMF,and Cdyn were significantly lower than those in the control group,while the Re was higher(P<0.05).Compared with the COPD group,JQ1 treatment could significantly alleviate the FEV_(0.1)/FVC,PEF,MMF,and Cdyn.meanwhile decrease the Re(P<0.05).Contrast to the COPD group,the levels of IL-6,IL-8,and TNF-α in serum and lung tissue were significantly decreased in the JQ1 intervention group,as well as the levels of the mRNA and protein expression of VIM(P<0.05).The MLI and the ratio of collagen area around airways were significantly lower(P<0.05).but the MAN was significantly higher(P<0.05)in the JQ1 intervention group.Conclusion The BRDl inhibitor JQ1 may protect lung function of the mice with COPD via abrogating chronic CS/LPS-induced airway inflammation and remodeling.