辛伐他汀经由雾化吸入途径给药抑制过敏性小鼠气道高反应性和气道重塑  

Simvastatin delivery via inhalation attenuates airway hyperresponsiveness and airway remodeling in a mouse model of asthma

作　　者：徐蓝 朱磊[1] 孙云[2] XU Lan;ZHU Lei;SUN Yun(Department of Pharmacy,Suzhou Ninth Hospital Affiliated to Soochow University,Suzhou 215200,China;Yangzhou University Medical Academy,Yangzhou 225001,China)

机构地区：[1]苏州大学附属苏州九院,苏州市第九人民医院药剂科,江苏苏州215200 [2]扬州大学医学院,江苏扬州225001

出　　处：《中国病理生理杂志》2023年第3期479-486,共8页Chinese Journal of Pathophysiology

基　　金：苏州市科技局民生科技-医疗卫生应用基础研究(No.SYSD2017166)。

摘　　要：目的探讨雾化吸入途径给予辛伐他汀(simvastatin,Sim)对哮喘模型小鼠气道高反应性和气道重塑的影响。方法选取BALB/c小鼠,采用卵白蛋白(ovalbumin,OVA)诱导建立哮喘小鼠模型。随机分为对照(control)组、模型(vehicle-OVA)组、Sim(5、20 g/L,i.h)-OVA组、Rho激酶抑制剂Y-27632(10 mg/kg,i.n)-OVA组和地塞米松(dexamethasone,DXM;1 mg/kg,i.p)-OVA组,每组10只。OVA末次攻击24 h后以不同浓度乙酰甲胆碱(methacholine,MCh)诱导小鼠产生气道高反应性。应用生物信号记录系统测定气道阻力(airway resistance,R_(L))和动态肺顺应性(dynamic lung compliance,C_(dyn))以评价Sim的作用强度;对各组小鼠支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)炎症细胞分类并计数;肺组织行HE和Masson染色评估炎症细胞浸润程度和黏膜下胶原沉积;Western blot法测定各组小鼠肺组织中RhoA蛋白含量。结果与vehicle-OVA组比较,预先雾化吸入Sim 5 g/L-OVA组和Sim 20 g/L-OVA组均下调MCh诱导的哮喘模型小鼠RL值(P<0.05,P<0.01),升高C_(dyn)值(P<0.05,P<0.01),降低过敏性小鼠气道高反应性;降低BALF中炎症细胞总数、嗜酸性粒细胞数、巨噬细胞数和中性粒细胞数(P<0.01);Sim 20 g/L-OVA组小鼠肺组织炎症浸润和气管周围胶原沉积面积减少,胶原容积分数减小(P<0.01),肺组织中RhoA蛋白水平降低(P<0.05)。结论雾化吸入Sim可通过下调RhoA蛋白表达减轻哮喘小鼠气道高反应性和气道重塑。AIM To study the impact of simvastatin(Sim)for delivery via inhalation on airway hyperresponsiveness and airway remodeling in a murine model of asthma.METHODS Balb/c mice(n=60)were randomly divided into control group,vehicle-ovalbumin(OVA)group,Sim(5,20 g/L,i.h)group,dexamethasone(DXM;1 mg/kg,i.p)group and Y-27632(10 mg/kg,i.n)group.Mouse model of asthma was established by OVA,and Sim was given via inhalation.Airway hyperresponsiveness was detected by airway hyperresponsiveness instrument.The morphological abnormality and tissue inflammation were detected through HE and Masson staining,and inflammatory cells of BALF were counted by Giemsa staining.The protein levels of RhoA in lung tissues were determined by Western blot.RESULTS Compared with the vehicle-OVA group,Sim at the dose of 5 and 20 g/L improved airway hyperresponsiveness(P<0.05)and the accumulation of inflammatory cells in BALF(P<0.01).Sim at a dose of 20 g/L group had a significant reduction in the inflammatory cells,collagen deposition area,the collagen volume fraction(P<0.01)and the protein levels of RhoA in the lung tissue(P<0.05).CONCLUSION Simvastatin via inhalation attenuated airway hyperresponsiveness and remodeling in asthmatic mice by down-regulation of RhoA protein expression.

关 键 词：气道高反应性 气道重塑 辛伐他汀 吸入 哮喘 

分 类 号：R562.25[医药卫生—呼吸系统] R363.2[医药卫生—内科学]