二甲双胍和孟鲁司特在急性和慢性过敏性哮喘小鼠模型中的作用

Effects of Metformin and Montelukast in Acute and Chronic Allergic Asthma Mouse Models

【目的】对比分析屋尘螨(HDM)诱导的过敏性哮喘小鼠模型26 d的急性模型和59 d的慢性模型,评价二甲双胍和孟鲁司特对气道炎症和气道重塑病理效应的改善作用。【方法】HDM致敏和激发构建急性和慢性过敏性哮喘小鼠模型,设置药物干预组包括阳性药物对照组(HDM+布地奈德)、二甲双胍组(HDM+二甲双胍)和孟鲁司特钠组(HDM+孟鲁司特钠),干预药物于每次HDM激发前1 h或30 min,经滴鼻(布地奈德1mg/kg)或腹腔注射(二甲双胍200 mg/kg、孟鲁司特钠10 mg/kg)给药。各实验组小鼠处死后苏木素-伊红染色和马松染色分析小鼠的肺部病理特征;采用Image J软件进行气道炎症细胞浸润评分和胶原沉积评分,以及分析支气管形态参数,包括支气管壁厚度和支气管平滑肌厚度;采用ELISA方法检测小鼠血清总IgE水平,qRT-PCR检测炎症因子IL-4、IL-5、IL-13 mRNA转录水平。【结果】慢性模型小鼠的血清总IgE水平、气道周围胶原沉积程度、气道平滑肌厚度显著高于急性模型小鼠(P<0.05)。布地奈德干预可以显著改善急性组小鼠的气道炎症(P<0.05);和HDM造模组相比,二甲双胍干预对HDM诱导急性哮喘小鼠有明显的气道炎症改善(P<0.05)作用,对气道重塑无显著作用(P>0.05),对慢性模型小鼠的气道炎症和气道重塑均无显著作用(P>0.05);在慢性组的孟鲁司特钠干预组中,小鼠的气道炎症和气道重塑均无明显的改善(P>0.05)。【结论】相比26 d的急性模型,59 d的慢性哮喘模型有更高水平的炎症反应和气道重塑效应,二甲双胍能有效改善HDM诱导急性哮喘小鼠中的气道炎症,孟鲁司特钠对慢性哮喘小鼠气道炎症和气道重塑均无显著作用。

【Objective】To compare the effects of metformin and montelukast on airway inflammation and remodeling in the acute and chronic house dust mite(HDM)-induced asthma mouse models.【Methods】HDM-induced acute and chronic asthma mouse models were established and treated with 1mg/kg of budesonide,200 mg/kg of metformin,or 10 mg/kg of montelukast,respectively.The drugs were administrated via intranasal instillation or intraperitoneal injection 1 h or 30 min prior to each HDM challenge.Hematoxylin-Eosin and Masson’s trichrome staining were used to analyze the lung-pathological characteristics of mice.The score analysis of airway inflammatory cell infiltration and collagen deposition and the measurement of bronchial morphological parameters including bronchial wall thickness and bronchial smooth muscle thickness were determined by Image J software.Total serum IgE level,mRNA transcription level of inflammatory factors IL-4,IL-5,and IL-13 were detected by ELISA and qRT-PCR.【Results】HDM-induced chronic model had significantly increased total serum IgE level,airway collagen deposition and thickness of airway smooth muscle than the acute model(P<0.05).Budesonide significantly attenuated airway inflammation in the HDM-induced acute model(P<0.05).Metformin significantly improved airway inflammation(P<0.05)and had no significant effect on airway remodeling(P>0.05)in the HDM-induced acute model.Both metformin and montelukast had no significant effect on airway inflammation and remodel-ing(P>0.05)in the chronic model.【Conclusion】Compared with the 26-day acute model,the 59-day chronic asthma mouse model has a higher level of serum IgE,pulmonary Th2 cytokine transcripts and airway collagen deposition.Metfor-min can effectively ameliorate airway inflammation in the HDM-induced acute mouse model,and montelukast has no sig-nificant effect on airway inflammation and remodeling in the HDM-induced chronic mouse model.