川芎嗪调控Gαs/cAMP/PKA信号通路改善哮喘模型大鼠气道炎症的作用研究

Effect of ligustrazine on Gαs/cAMP/PKA signal activity and airway inflammation in asthmatic rats

目的探讨川芎嗪对卵蛋白(ovalbumin,OVA)致敏并攻击的幼龄哮喘大鼠Gαs/cAMP/PKA信号活性的影响。方法通过OVA致敏、攻击复制哮喘大鼠模型,观察川芎嗪干预后哮喘大鼠的气道高反应(airway hyperresponsiveness,AHR)、肺组织病理学变化,检测血清中IL-4、IL-5、IL-13、TNF-α的水平、血浆及肺组织中cAMP水平、肺组织PKA表达、肺组织Gαs、GRK2、CREB基因和蛋白表达。结果与对照组相比,哮喘大鼠肺阻力增加、肺顺应性降低(P<0.05),肺组织病理改变明显,外周血IL-4、IL-5、IL-13、TNF-α水平明显升高(P<0.05);血浆及肺组织cAMP含量下降,肺组织PKA和CREB表达下调(P<0.01),肺组织中Gαs表达明显下调,而GRK2表达明显上调。与哮喘模型组相比,川芎嗪能够抑制AHR发生,降低哮喘大鼠的肺阻力(P<0.05),并增加肺顺应性,抑制大鼠肺组织炎症细胞浸润以及杯状细胞、纤维增生,明显降低哮喘大鼠外周血IL-4、IL-5、IL-13、TNF-α水平(P<0.01);增加血清、肺组织cAMP含量及肺组织PKA、CREB的表达量,抑制大鼠肺组织中GRK2表达并上调Gαs表达(P<0.05)。结论川芎嗪能有效抑制哮喘大鼠AHR的发生,抑制炎症反应,这一作用可能与上调Gαs/cAMP/PKA通路活性相关。

Aim To investigate the effect of ligustrazine on G-protein coupled receptor signal activity in ovalbumin(OVA)-sensitized and challenged asthmatic rats.Methods This study replicated an OVA-induced juvenile asthmatic rat model,and investigated the effect of ligustrazine on airway hyperresponsiveness,airway inflammation,lung histopathology,IL-4,IL-5,IL-13,TNF-αlevels in serum,cAMP concentration in plasma,CREB,PKA,Gαs and GRK2 expression in lung tissues.Results It was showed that the resistance of lung(RL)in asthmatic rats increased,while the pulmonary dynamic compliance(Cdyn)significantly decreased(P<0.05)compared with the control rats,and the lung tissue injury was serious;the levels of IL-4,IL-5,IL-13,and TNF-αin serum were significantly increased(P<0.01).The cAMP level in plasma was reduced and the CREB and PKA expressions were down-regulated significantly(P<0.05).The Gαs expression in lung in asthmatic rats was down-regulated while the GRK2 expression was up-regulated(P<0.01).Ligustrazine could improve the lung injury and lung function of asthmatic rats,decrease RL and increase Cdyn(P<0.05),decrease the levels of IL-4,IL-5,IL-13,and TNF-αin serum(P<0.01),increase cAMP in plasma and up-regulate the PKA and CREB expression,down-regulate the GRK2 expression and up-regulate the Gαs expression significantly(P<0.01).Conclusions The above study shows that ligustrazine can reduce the AHR,inhibit the inflammation in asthma,and the up-regulating of Gαs/cAMP/PKA signal activity may be its mechanism.