The anti-malaria drug artesunate inhibits cigarette smoke and ovalbumin concurrent exposure-induced airway inflammation and might reverse glucocorticoid insensitivity

•Artesunate ameliorates cigarette smoke and OVA co-induced airway inflammation.•Artesunate inhibitts the PI3Kδ/Akt pathway.•Artesunate restores HDAC2 activity in vivo and in vitro.•Artesunate reverses glucocorticoid insensitivity in BEAS-2B cells.

BackgroundThe 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 determine the effects of artesunate on cigarette smoke and ovalbumin (OVA) concurrent exposure-induced airway inflammation, the related mechanism, and glucocorticoid insensitivity.Methods and resultsIn vivo: Female BALB/c mice concurrently exposed to cigarette smoke and OVA developed mixed eosinophilic and neutrophilic airway inflammation. Airway hyper-responsiveness, total and differential cell counts, and pro-inflammatory cytokine levels (interleukin (IL)-4, IL-8, IL-13 and tumor necrosis factor (TNF)-α) in bronchoalveolar lavage fluid (BALF) were measured. Lung tissue sections were stained for histological analysis, and proteins were extracted for Western blotting. 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: BEAS-2B cells were exposed to cigarette smoke extract (CSE) for 6 h and then stimulated with TNF-α overnight. Glucocorticoid sensitivity was evaluated by the inhibition of TNF-α-induced IL-8 production by dexamethasone. CSE reduced the effects of dexamethasone on TNF-α-induced IL-8 production in BEAS-2B cells, while artesunate reversed CSE-induced glucocorticoid insensitivity and restored HDAC2 deactivation induced by CSE.ConclusionArtesunate 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.

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