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

Cheng C, Ho WE, Goh FY, Guan SP, Kong LR, Lai WQ, Leung BP, Wong WS - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.

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.

Methodology/principal findings: 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.

Conclusion/significance: 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.

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Related in: MedlinePlus

Effects of artesunate on OVA-induced BAL fluid cytokine and chemokine levels.BAL fluids were collected 24 hours after the last OVA aerosol challenge. Levels of IL-4, IL-5, IL-12, IL-13, eotaxin and IFN-γ were analyzed using ELISA (n = 6–9 mice). Lower limits of detection were as follows: IL-4 and IL-5 at 4 pg/ml; IL-12, IL-13 and IFN-γ at 15.6 pg/ml; and eotaxin at 2 pg/ml. Values shown are the mean ± SEM. *Significant difference from DMSO control, p<0.05.
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pone-0020932-g002: Effects of artesunate on OVA-induced BAL fluid cytokine and chemokine levels.BAL fluids were collected 24 hours after the last OVA aerosol challenge. Levels of IL-4, IL-5, IL-12, IL-13, eotaxin and IFN-γ were analyzed using ELISA (n = 6–9 mice). Lower limits of detection were as follows: IL-4 and IL-5 at 4 pg/ml; IL-12, IL-13 and IFN-γ at 15.6 pg/ml; and eotaxin at 2 pg/ml. Values shown are the mean ± SEM. *Significant difference from DMSO control, p<0.05.

Mentions: OVA inhalation in sensitized mice caused a notable increase in IL-4, IL-5, IL-13 and eotaxin levels in BAL fluid as compared with saline aerosol control (Figure 2). In contrast, BAL fluid level of IFN-γ and IL-12, two Th1 cytokines, dropped slightly in OVA-challenged mice. Artesunate drastically reduced IL-13 and eoxtain, and to a lesser extent, IL-4 and IL-5 levels in BAL fluid in a dose-dependent manner as compared with DMSO control (Figure 2). Noticeably, artesunate at 10 and 30 mg/kg could up-regulated IFN-γ and IL-12 levels in BAL fluid levels similar to those in saline control mice. This finding implies that artesunate is able to modify the Th2-predominant immune activity in our OVA-induced mouse asthma model. Alternatively, the increase in IL-12 BAL fluid level in artesunate-treated mice may be due to enhanced IL-12 production by dendritic cells upon inhibition of PI3K [24]. The exact mechanism that mediates up-regulation of IFN-γ and IL-12 BAL fluid levels remains to be determined.


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

Cheng C, Ho WE, Goh FY, Guan SP, Kong LR, Lai WQ, Leung BP, Wong WS - PLoS ONE (2011)

Effects of artesunate on OVA-induced BAL fluid cytokine and chemokine levels.BAL fluids were collected 24 hours after the last OVA aerosol challenge. Levels of IL-4, IL-5, IL-12, IL-13, eotaxin and IFN-γ were analyzed using ELISA (n = 6–9 mice). Lower limits of detection were as follows: IL-4 and IL-5 at 4 pg/ml; IL-12, IL-13 and IFN-γ at 15.6 pg/ml; and eotaxin at 2 pg/ml. Values shown are the mean ± SEM. *Significant difference from DMSO control, p<0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3111464&req=5

pone-0020932-g002: Effects of artesunate on OVA-induced BAL fluid cytokine and chemokine levels.BAL fluids were collected 24 hours after the last OVA aerosol challenge. Levels of IL-4, IL-5, IL-12, IL-13, eotaxin and IFN-γ were analyzed using ELISA (n = 6–9 mice). Lower limits of detection were as follows: IL-4 and IL-5 at 4 pg/ml; IL-12, IL-13 and IFN-γ at 15.6 pg/ml; and eotaxin at 2 pg/ml. Values shown are the mean ± SEM. *Significant difference from DMSO control, p<0.05.
Mentions: OVA inhalation in sensitized mice caused a notable increase in IL-4, IL-5, IL-13 and eotaxin levels in BAL fluid as compared with saline aerosol control (Figure 2). In contrast, BAL fluid level of IFN-γ and IL-12, two Th1 cytokines, dropped slightly in OVA-challenged mice. Artesunate drastically reduced IL-13 and eoxtain, and to a lesser extent, IL-4 and IL-5 levels in BAL fluid in a dose-dependent manner as compared with DMSO control (Figure 2). Noticeably, artesunate at 10 and 30 mg/kg could up-regulated IFN-γ and IL-12 levels in BAL fluid levels similar to those in saline control mice. This finding implies that artesunate is able to modify the Th2-predominant immune activity in our OVA-induced mouse asthma model. Alternatively, the increase in IL-12 BAL fluid level in artesunate-treated mice may be due to enhanced IL-12 production by dendritic cells upon inhibition of PI3K [24]. The exact mechanism that mediates up-regulation of IFN-γ and IL-12 BAL fluid levels remains to be determined.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.

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.

Methodology/principal findings: 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.

Conclusion/significance: 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.

Show MeSH
Related in: MedlinePlus