title: Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway.
abstract: BACKGROUND
  Phosphoinositide 3-kinase (PI3K)/Akt pathway is linked to the development of asthma. Anti-malarial drug artesunate is a semi-synthetic derivative of artemisinin, the principal active component of a medicinal plant Artemisia annua, and has been shown to inhibit PI3K/Akt activity. We hypothesized that artesunate may attenuate allergic asthma via inhibition of the PI3K/Akt signaling pathway.
  
  
  RESULTS
  Female BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Artesunate dose-dependently inhibited OVA-induced increases in total and eosinophil counts, IL-4, IL-5, IL-13 and eotaxin levels in bronchoalveolar lavage fluid. It attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, IL-17, IL-33 and Muc5ac in lung tissues, and airway hyperresponsiveness to methacholine. In normal human bronchial epithelial cells, artesunate blocked epidermal growth factor-induced phosphorylation of Akt and its downstream substrates tuberin, p70S6 kinase and 4E-binding protein 1, and transactivation of NF-κB. Similarly, artesunate blocked the phosphorylation of Akt and its downstream substrates in lung tissues from OVA-challenged mice. Anti-inflammatory effect of artesunate was further confirmed in a house dust mite mouse asthma model.
  
  
  CONCLUSIONS
  Artesunate ameliorates experimental allergic airway inflammation probably via negative regulation of PI3K/Akt pathway and the downstream NF-κB activity. These findings provide a novel therapeutic value for artesunate in the treatment of allergic asthma.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.
authors.forename: Chang
authors.initials: C
authors.lastname: Cheng
authors.forename: W Eugene
authors.initials: WE
authors.lastname: Ho
authors.forename: Fera Y
authors.initials: FY
authors.lastname: Goh
authors.forename: Shou Ping
authors.initials: SP
authors.lastname: Guan
authors.forename: Li Ren
authors.initials: LR
authors.lastname: Kong
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Lai
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
authors.forename: W S Fred
authors.initials: WS
authors.lastname: Wong
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001980:Bronchi / Q000166:cytology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000150:complications* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D039981:Pyroglyphidae / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D000962:Antimalarials; D037621:Artemisinins; D016207:Cytokines; D000077332:Artesunate; D004815:Epidermal Growth Factor; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt