目的 The anti-malaria drug artesunate has been shown to attenuate experimental allergic asthma via inhibition of the phosphatidylinositol 3-kinase(PI3K)/Akt pathway.This study was to further determined the effects of artesunate on cigarette smoke and ovalbumin(OVA)concurrent exposure-induced airway inflammation,the related mechanism,and glucocorticoid insensitivity.方法 In vivo：A total of 75 female specific pathogen free BALB/c mice were divided randomly into five groups：normal group,cigarette smoke-exposed asthmatic group,vehicle group,artesunate group and dexamethasone group.The latter four groups were exposed on cigarette smoke for 40 days,normal group mice were exposed to ambient air as control.The latter four groups were sensitized by i.p.injections of 20 μg OVA and 4 mg Al(OH)3 suspended in 0.1 ml saline on days 10,17 and 24.Seven days after the last sensitization,mice were challenged with 1％OVA aerosol for 30 min per day in the afternoon until day 40.Two hours before each aerosol challenge,vehicle(5％NaHCO3 containing 5％DMSO),artesunate(30mg/kg,dissolved in 5％DMSO and diluted with 5％NaHCO3),and dexamethasone(1mg/kg,dissolved in saline)was given by i.p.injection to mice in the Vehicle,artesunate,and dexamethasone groups,respectively.Normal group and cigarette smoke-exposed asthmatic group mice were saline sensitized and challenged as negative controls.Six mice in each group were measured airway hyper-responsiveness,and inspiratory and expiratory resistance and dynamic compliance were analyzed.Cells in bronchoalveolar lavage fluid(BALF)of the remaining nine mice were collected and analyzed by absolute different cell counts.IL-4,IL-8,IL-13 and TNF-α levels in BALF were tested by ELISA.The pathological changes of lung tissues were observed by HE staining.Histone deacetylase 2(HDAC2)activity in lung tissue were tested by HDAC2 activity kit.And the expression levels of PI3Kδ、PI3Kγ、p-Akt1、Akt1、p-HDAC2、HDAC2 were measured by Western-blotting.In vitro：BEAS-2B cells were cultured and were divided randomly into five groups：control group,CSE incubated group,dexamethasone group,common group and artesunate group.The latter four groups were incubated with CSE for 6 hours,then were stimulated with TNF-α overnight after culture medium were changed.The latter three groups were treated with dexamethasone(10-11 to 10-6 M),both dexamethasone and artesunate befor TNF-α stimulated and artesunate(10μM),respectively,for 1 h.IL-8 levels were tested by ELISA.The 50％inhibitory concentration(IC50)values of dexamethasone for IL-8 production were calculated using GraphPad Prism version 5.0 software.And HDAC2 activity in cells were tested by HDAC2 activity kit.结果 In vivo：Artesunate reduced methacholine-induced airway hyper-responsiveness,suppressed pulmonary inflammation cell recruitment and IL-4,IL-8,IL-13 and TNF-α levels,selectively inhibited PI3Kδ/Akt pathway,and restored HDAC2 activity.In vitro：CSE reduced the effects of dexamethasone on TNF-α-induced IL-8 production in BEAS-2B cells,while artesunate reversed CSEinduced glucocorticoid insensitivity and restored HDAC2 deactivation induced by CSE.结论 Artesunate ameliorated cigarette smoke and OVA concurrent exposure-induced airway inflammation,inhibited the PI3Kδ/Akt pathway,restored HDAC2 activity,and reversed CSE-induced glucocorticoid insensitivity in BEAS-2B cells.These findings indicate that artesunate might play a protective role in asthma induced by cigarette smoke and glucocorticoid insensitivity.