抑制G蛋白偶联受体40通过RhoA/ROCK1信号通路缓解小鼠过敏性哮喘

Inhibition of GPR40 alleviates allergic asthma in mice through RhoA/ROCK1 signaling pathway

目的:探究抑制G蛋白偶联受体40(GPR40)减轻过敏性哮喘小鼠症状的作用及机制。方法:将28只雄性C57BL/6小鼠随机分为正常对照组、哮喘模型组(用卵清蛋白建立过敏性哮喘模型)、低剂量GPR40抑制剂DC260126干预组(3 mg/kg DC260126组)和高剂量DC260126干预组(10 mg/kg DC260126组),每组7只。通过小鼠肺功能仪检测各组小鼠气道高反应性;对各组小鼠支气管肺泡灌洗液(BALF)炎症细胞分类并予以计数;肺组织切片进行HE染色评估炎症细胞浸润程度和炎症评分;Western blot检测肺组织中GPR40、GTP-RhoA和Rho相关激酶1(ROCK1)蛋白表达水平。结果:与哮喘模型组相比,10 mg/kg DC260126组小鼠气道阻力显著降低(P<0.05),BALF中的炎症细胞显著减少(P<0.05),肺组织嗜酸性粒细胞和淋巴细胞浸润显著减少(P<0.01),肺组织中GTPRhoA和ROCK1蛋白水平显著降低(P<0.01)。结论:抑制GPR40可能通过Rho/ROCK1信号通路减轻小鼠过敏性哮喘气道炎症和气道高反应性。

AIM:To investigate the effect of inhibition of G-protein-coupled receptor 40(GPR40)on the symptoms of asthmatic mice,and to explore the mechanism.METHODS:Healthy male C57 BL/6 mice(n=28)were randomly divided into normal control group,model group,low-dose GPR40 inhibitor DC260126 group(3 mg/kg DC260126 group)and high-dose DC260126 group(10 mg/kg DC260126 group). The allergic asthma mouse model was induced by ovalbumin. The airway hyperresponsiveness was detected by the mouse lung function instrument. The pathological changes of the lung tissues were observed by HE staining. The protein levels of GPR40,GTP-RhoA and Rho-associated kinase 1(ROCK1)in lung tissues were determined by Western blot.RESULTS:Compared with model group,DC260126 at the dose of 10 mg/kg significantly reduced the airway resistance and the accumulation of inflammatory cells. The inhibition of GPR40 decreased the infiltration of eosinophils and lymphocytes in lung tissues. In addition,both GTP-RhoA and ROCK1 were significantly decreased after the treatment with 10 mg/kg DC260126.CONCLUSION:Inhibition of GPR40 attenuates the airway inflammation and airway hyperresponsiveness of allergic asthma mice through the Rho/ROCK1 signaling pathway.