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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 house dust mite extracts-induced pulmonary inflammatory cell recruitment.Inflammatory cell counts in BAL fluid obtained from mice 72 hours after the last house dust mitechallenge (n = 6 mice) markedly increased as compared to saline control (n = 4 mice). Artesunate (30 mg/kg, n = 6 mice) significantly suppressed house dust mite-induced increases in BAL fluid total cell and eosinophil counts as compared with vehicle control (DMSO, n = 5). Differential cell counts were performed on a minimum of 500 cells to identify (Eos), macrophage (Mac), neutrophil (NEU), and lymphocyte (Lym). *Significant difference from DMSO control, p<0.05.
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pone-0020932-g007: Effects of artesunate on house dust mite extracts-induced pulmonary inflammatory cell recruitment.Inflammatory cell counts in BAL fluid obtained from mice 72 hours after the last house dust mitechallenge (n = 6 mice) markedly increased as compared to saline control (n = 4 mice). Artesunate (30 mg/kg, n = 6 mice) significantly suppressed house dust mite-induced increases in BAL fluid total cell and eosinophil counts as compared with vehicle control (DMSO, n = 5). Differential cell counts were performed on a minimum of 500 cells to identify (Eos), macrophage (Mac), neutrophil (NEU), and lymphocyte (Lym). *Significant difference from DMSO control, p<0.05.

Mentions: To validate the anti-inflammatory effects of artesunate in airway inflammation more comparable to human situation, we have developed a house dust mite mouse asthma model as described previously [38], [39]. Intratracheal administration of house dust mite extract (100 µg per mouse) on day 0, day 7 and day 14 resulted a notable increase in BAL fluid total cell and eosinophil counts, as compare with saline control. Pre-treatment with artesunate (30 mg/kg) significantly (p<0.05) suppressed the total and eosinophil counts in BAL fluid as compared with the DMSO vehicle control (Figure 7).


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 house dust mite extracts-induced pulmonary inflammatory cell recruitment.Inflammatory cell counts in BAL fluid obtained from mice 72 hours after the last house dust mitechallenge (n = 6 mice) markedly increased as compared to saline control (n = 4 mice). Artesunate (30 mg/kg, n = 6 mice) significantly suppressed house dust mite-induced increases in BAL fluid total cell and eosinophil counts as compared with vehicle control (DMSO, n = 5). Differential cell counts were performed on a minimum of 500 cells to identify (Eos), macrophage (Mac), neutrophil (NEU), and lymphocyte (Lym). *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-g007: Effects of artesunate on house dust mite extracts-induced pulmonary inflammatory cell recruitment.Inflammatory cell counts in BAL fluid obtained from mice 72 hours after the last house dust mitechallenge (n = 6 mice) markedly increased as compared to saline control (n = 4 mice). Artesunate (30 mg/kg, n = 6 mice) significantly suppressed house dust mite-induced increases in BAL fluid total cell and eosinophil counts as compared with vehicle control (DMSO, n = 5). Differential cell counts were performed on a minimum of 500 cells to identify (Eos), macrophage (Mac), neutrophil (NEU), and lymphocyte (Lym). *Significant difference from DMSO control, p<0.05.
Mentions: To validate the anti-inflammatory effects of artesunate in airway inflammation more comparable to human situation, we have developed a house dust mite mouse asthma model as described previously [38], [39]. Intratracheal administration of house dust mite extract (100 µg per mouse) on day 0, day 7 and day 14 resulted a notable increase in BAL fluid total cell and eosinophil counts, as compare with saline control. Pre-treatment with artesunate (30 mg/kg) significantly (p<0.05) suppressed the total and eosinophil counts in BAL fluid as compared with the DMSO vehicle control (Figure 7).

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