柚皮苷对哮喘模型小鼠气道炎症细胞凋亡的促进作用及其机制

Promoting Effect of Naringin on Airway Inflammatory Cell Apoptosis in Asthmatic Mice and Its Mechanism

目的探讨柚皮苷对哮喘模型小鼠气道炎症细胞凋亡的调节作用及其与苦味受体(Tas2rs)的关系。方法36只BALB/c小鼠随机分为6组(n=6):空白对照组、卵清蛋白模型组(OVA)、地塞米松组(10 mg·kg^(-1),阳性对照药物)、柚皮苷低、中、高剂量组(10、20、40 mg·kg^(-1))。除空白对照组外,各组小鼠均采用OVA诱导气道哮喘。溶媒、地塞米松或柚皮苷连续灌胃6天,测定小鼠呼吸功能及肺泡灌洗液细胞数量,观察小鼠肺及气道形态,测定呼吸系统阻力(Rrs)、肺的弹性阻力(Ers)和呼吸顺应性(Crs),测定肺组织相关促凋亡因子mRNA表达水平,测定Tas2rs及其下游基因mRNA表达水平。结果与OVA模型组比较,柚皮苷可以剂量依赖性降低Rrs和Ers,增加Crs,降低白细胞、嗜酸性粒细胞、淋巴细胞和中性粒细胞数量;与OVA模型组比较,柚皮苷高剂量组小鼠肺组织炎性细胞浸润显著减少,肺、气道组织的Tas2r108、Tas2r135和Tas2r143及其下游靶基因α-gust和Trpm5的mRNA表达水平显著降低,促凋亡因子P53、Bax和Casp3的mRNA表达水平均增加,而凋亡抑制因子Bcl2的mRNA表达水平降低。结论柚皮苷预防性给药可促进哮喘小鼠气道Tas2rs信号活化,降低气道炎性细胞数量,减轻气道损伤。柚皮苷作为Tas2rs激动剂可作为潜在的抗哮喘药物进行开发。

Objective To investigate the regulation of naringin on apoptosis of airway inflammatory cells in asthmatic mice and its relationship with Tas2rs.Methods 36 BALB/c mice were randomly divided into 6 groups(n=6):blank control group,ovalbumin model group(OVA),dexamethasone group(10 mg·kg^(-1),positive control drug),naringin low,medium and high dose groups(10,20,40 mg·kg^(-1)).Airway asthma was induced by OVA in all groups except the blank control group.After continuous administration of solvent,dexamethasone or naringin for 6 days,the respiratory function and the number of cells in alveolar lavage fluid of mice were measured,the lung and airway morphology of mice were observed,respiratory resistance(Rrs),lung elastic resistance(Ers)and respiratory compliance(Crs)were measured,and mRNA expression levels of lung tissue-related pro-apoptotic factors were measured.The mRNA expression levels of Tas2rs and its downstream genes were determined.Results Compared with OVA model group,naringin could dosedependent decrease Rrs and Ers,increase Crs,and decrease the number of leukocytes,eosinophils,lymphocytes and neutrophils.Compared with OVA model group,the infiltration of inflammatory cells in lung tissue was significantly reduced in high-dose naringin group,and the mRNA expression levels of Tas2r108,Tas2r135,Tas2r143 and their downstream target genesα-gust and Trpm5 in lung and airway tissue were significantly decreased.The mRNA expression levels of proapoptotic factors P53,Bax and Casp3 were increased,while the mRNA expression levels of apoptosis inhibitor Bcl2 were decreased.Conclusion Naringin prophylactic administration can promote the activation of airway Tas2rs signal,decrease the number of airway inflammatory cells and alleviate airway injury in asthmatic mice.Naringin as a Tas2rs agonist can be developed as a potential anti-asthmatic agent.