title: The anti-malaria drug artesunate inhibits cigarette smoke and ovalbumin concurrent exposure-induced airway inflammation and might reverse glucocorticoid insensitivity.
abstract: BACKGROUND
  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 determine the effects of artesunate on cigarette smoke and ovalbumin (OVA) concurrent exposure-induced airway inflammation, the related mechanism, and glucocorticoid insensitivity.
  
  
  RESULTS
  In 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 6h 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Qiongzhen
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Department of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. Electronic address: jiangtao_l@263.net.
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Lin
authors.affiliation: Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Medical Science, China-Japan Friendship Hospital, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Clinical Medical Science, China-Japan Friendship Hospital, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D000077332:Artesunate; D001249:Asthma / Q000139:chemically induced / Q000517:prevention & control; D016535:Bronchial Hyperreactivity / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced* / Q000517:prevention & control*; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D012140:Respiratory Tract Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D016207:Cytokines; D005938:Glucocorticoids; D012906:Smoke; D000077332:Artesunate; D003907:Dexamethasone; D010047:Ovalbumin
keywords: Airway inflammation; Artesunate; Glucocorticoid; HDAC2; PI3Kδ; Severe asthma