Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway

• Published in: PloS one Vol. 6; no. 6; p. e20932
• Main Authors: Cheng, Chang, Ho, W Eugene, Goh, Fera Y, Guan, Shou Ping, Kong, Li Ren, Lai, Wen-Qi, Leung, Bernard P, Wong, W S Fred
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09-06-2011; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Albumin; Allergies; Alveoli; Analysis; Animal tissues; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antimalarials - pharmacology; Antimalarials - therapeutic use; Artemisinin; Artemisinins - pharmacology; Artemisinins - therapeutic use; Artesunate; Asthma; Asthma - drug therapy; Asthma - immunology; Asthma - metabolism; Asthma - pathology; Attenuation; B cells; Biomarkers; Bronchi - cytology; Bronchoalveolar Lavage Fluid - immunology; Bronchus; Chemokines; Cytokines; Cytokines - metabolism; Disease Models, Animal; Drug dosages; E-selectin; Enzyme Activation - drug effects; Eosinophilia; Eotaxin; Epidermal growth factor; Epidermal Growth Factor - pharmacology; Epidermal growth factors; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Female; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; Herbal medicine; House dust; Humans; Hypersensitivity - complications; Hypersensitivity - immunology; Immunology; Infiltration; Inflammation; Inhibition; Interleukin 13; Interleukin 17; Interleukin 4; Interleukin 5; Kinases; Life sciences; Lungs; Lymphocytes; Malaria; Medicinal plants; Medicine; Methacholine; Mice; Mice, Inbred BALB C; Mucins; Mucus; Mucus - metabolism; Neutrophils; Nitric oxide; Ovalbumin; Ovalbumin - immunology; Pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Physiology; Protein binding; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyroglyphidae - immunology; Respiratory system; Respiratory tract; Respiratory tract diseases; RNA; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Smooth muscle; Substrates; Th2 Cells - drug effects; Th2 Cells - immunology; Th2 Cells - metabolism; Th2 Cells - pathology; Singapore
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020932

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.
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.
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.