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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 AHR.Airway responsiveness of mechanically ventilated mice in response to aerosolized methacholine was measured 24 hours after the last saline aerosol or OVA aerosol with pretreatment of either DMSO or 30 mg/kg artesunate. AHR is expressed as percentage change from the baseline level of (A) lung resistance (Rl, n = 6 mice) and (B) dynamic compliance (Cdyn, n = 6 mice). Rl is defined as the pressure driving respiration divided by flow. Cdyn refers to the distensibility of the lung and is defined as the change in volume of the lung produced by a change in pressure across the lung. *Significant difference from DMSO control, p<0.05.
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pone-0020932-g004: Effects of artesunate on OVA-induced AHR.Airway responsiveness of mechanically ventilated mice in response to aerosolized methacholine was measured 24 hours after the last saline aerosol or OVA aerosol with pretreatment of either DMSO or 30 mg/kg artesunate. AHR is expressed as percentage change from the baseline level of (A) lung resistance (Rl, n = 6 mice) and (B) dynamic compliance (Cdyn, n = 6 mice). Rl is defined as the pressure driving respiration divided by flow. Cdyn refers to the distensibility of the lung and is defined as the change in volume of the lung produced by a change in pressure across the lung. *Significant difference from DMSO control, p<0.05.

Mentions: To investigate the effect of artesunate on airway hyperresponsiveness (AHR) in response to increasing concentrations of methacholine, we measured both RI and Cdyn in mechanically ventilated mice. Rl is defined as the pressure driving respiration divided by flow. Cdyn refers to the distensibility of the lung and is defined as the change in volume of the lung produced by a change in pressure across the lung. OVA-challenged mice developed AHR which is typically reflected by high RI and low Cdyn (Figure 4). Artesunate (30 mg/kg) dramatically reduced RI and restored Cdyn in OVA-challenged mice in response to methacholine aerosol, suggesting that immune-mediated airway pathology in vivo was modified.


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 AHR.Airway responsiveness of mechanically ventilated mice in response to aerosolized methacholine was measured 24 hours after the last saline aerosol or OVA aerosol with pretreatment of either DMSO or 30 mg/kg artesunate. AHR is expressed as percentage change from the baseline level of (A) lung resistance (Rl, n = 6 mice) and (B) dynamic compliance (Cdyn, n = 6 mice). Rl is defined as the pressure driving respiration divided by flow. Cdyn refers to the distensibility of the lung and is defined as the change in volume of the lung produced by a change in pressure across the lung. *Significant difference from DMSO control, p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111464&req=5

pone-0020932-g004: Effects of artesunate on OVA-induced AHR.Airway responsiveness of mechanically ventilated mice in response to aerosolized methacholine was measured 24 hours after the last saline aerosol or OVA aerosol with pretreatment of either DMSO or 30 mg/kg artesunate. AHR is expressed as percentage change from the baseline level of (A) lung resistance (Rl, n = 6 mice) and (B) dynamic compliance (Cdyn, n = 6 mice). Rl is defined as the pressure driving respiration divided by flow. Cdyn refers to the distensibility of the lung and is defined as the change in volume of the lung produced by a change in pressure across the lung. *Significant difference from DMSO control, p<0.05.
Mentions: To investigate the effect of artesunate on airway hyperresponsiveness (AHR) in response to increasing concentrations of methacholine, we measured both RI and Cdyn in mechanically ventilated mice. Rl is defined as the pressure driving respiration divided by flow. Cdyn refers to the distensibility of the lung and is defined as the change in volume of the lung produced by a change in pressure across the lung. OVA-challenged mice developed AHR which is typically reflected by high RI and low Cdyn (Figure 4). Artesunate (30 mg/kg) dramatically reduced RI and restored Cdyn in OVA-challenged mice in response to methacholine aerosol, suggesting that immune-mediated airway pathology in vivo was modified.

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