Interleukin 13 Increases Contractility of Murine Tracheal Smooth Muscle by a Phosphoinositide 3-kinase p110δ-Dependent Mechanism

Farghaly, Hanan S.M.; Blagbrough, Ian S.; Medina-Tato, David A.; Watson, Malcolm L.

doi:10.1124/mol.108.045419

Cited by 36 publications

(29 citation statements)

References 41 publications

(53 reference statements)

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“…More recently, p110δ PI3K has been shown to mediate IL-13-induced mouse tracheal smooth muscle hyperreactivity to methacholine [57]. We report here that artesunate significantly inhibited OVA-induced AHR to increasing concentrations of methacholine.…”

Section: Discussionsupporting

confidence: 48%

Anti-Malarial Drug Artesunate Attenuates Experimental Allergic Asthma via Inhibition of the Phosphoinositide 3-Kinase/Akt Pathway

Chang

Goh

et al. 2011

PLoS ONE

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BackgroundPhosphoinositide 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 FindingsFemale 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/SignificanceArtesunate 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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Section: Discussionsupporting

confidence: 48%

Anti-Malarial Drug Artesunate Attenuates Experimental Allergic Asthma via Inhibition of the Phosphoinositide 3-Kinase/Akt Pathway

Chang

Goh

et al. 2011

PLoS ONE

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“…We lastly investigated the role of phosphoinositide 3-kinases (PI3Ks), which were previously shown to regulate calcium flux in airway smooth muscle cells [30] and to be involved in the IL-13-induced increase in tracheal contractility in mouse [31]. Wortmanin (0.5 μM) and PI-828 (2 μM overnight) potentiated the relaxation to chloroquine and phenanthroline (Figure 8), which translated into a significant increase in pD 2 for relaxation to chloroquine in bronchi treated with PI-828 only (4.5 ± 0.2 in the absence of PI-828 vs .…”

Section: Resultsmentioning

confidence: 99%

The expression and relaxant effect of bitter taste receptors in human bronchi

et al. 2013

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BackgroundBitter-taste receptors (TAS2Rs) have recently been involved in the relaxation of mouse and guinea pig airways, and increased expression of TAS2Rs was shown in blood leucocytes from asthmatic children. We sought to identify and characterize the TAS2Rs expressed in isolated human bronchi and the subtypes involved in relaxation.MethodsHuman bronchi were isolated from resected lungs and TAS2R transcripts were assessed with RT-qPCR. Relaxation to TAS2R agonists was tested in organ bath in the presence or absence of pharmacological modulators of the signalling pathways involved in bronchial relaxation.ResultsWe detected the expression of TAS2R transcripts in human bronchi. The non-selective agonists chloroquine, quinine, caffeine, strychnine and diphenidol produced a bronchial relaxation as effective and potent as theophylline but much less potent than formoterol and isoproterenol. Denatonium, saccharin and colchicine did not produce relaxation. Receptor expression analysis together with the use of selective agonists suggest a predominant role for TAS2R5, 10 and 14 in bitter taste agonist-induced relaxation. The mechanism of relaxation was independent of the signalling pathways modulated by conventional bronchodilators and may be partly explained by the inhibition of phosphatidylinositol-3-kinases.ConclusionsThe TAS2Rs may constitute a new therapeutic target in chronic obstructive lung diseases such as asthma.

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“…Moreover, we showed that LY294002 also prevents the release of IL-6 in response to TGF-β, demonstrating for the first time the involvement of PI3Ks in TGF-β-induced IL-6 release. LY294002 was effective at 5 and 10 μM, concentrations shown to potently inhibit PI3K activity in human ASMCs (17). It is possible that Smad3 and PI3K may act synergistically to induce Nox4 expression and IL-6 release.…”

Section: Discussionmentioning

confidence: 99%

TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells

Michaeloudes

Sukkar

Khorasani

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

170

117

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Reactive oxygen species (ROS) are generated as a result of normal cellular metabolism, mainly through the mitochondria and peroxisomes, but their release is enhanced by the activation of oxidant enzymes such as NADPH oxidases or downregulation of endogenous antioxidant enzymes such as manganese-superoxide dismutase (MnSOD) and catalase. Transforming growth factor-β (TGF-β), found to be overexpressed in airway smooth muscle (ASM) from asthmatic and chronic obstructive pulmonary disease patients, may be a pivotal regulator of abnormal ASM cell (ASMC) function in these diseases. An important effect of TGF-β on ASMC inflammatory responses is the induction of IL-6 release. TGF-β also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-β on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redox-dependent pathways in the mediation of the proinflammatory effects of TGF-β in ASMCs is unclear. In this study, we show that TGF-β induced the expression of Nox4 while at the same time inhibiting the expression of MnSOD and catalase. This change in oxidant/antioxidant enzymes was accompanied by elevated ROS levels and IL-6 release. Further studies revealed a role for Smad3 and phosphatidyl-inositol kinase-mediated pathways in the induction of oxidant/antioxidant imbalance and IL-6 release. The changes in oxidant/antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetyl-cysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox-dependent activation of Smad3 by TGF-β. Moreover, these findings suggest a potential role for NAC in preventing TGF-β-mediated pro-oxidant and proinflammatory responses in ASMCs. Knockdown of Nox4 using small interfering RNA partially prevented the inhibition of MnSOD but had no effect on catalase and IL-6 expression. These findings provide novel insights into redox regulation of ASM function by TGF-β.

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Interleukin 13 Increases Contractility of Murine Tracheal Smooth Muscle by a Phosphoinositide 3-kinase p110δ-Dependent Mechanism

Cited by 36 publications

References 41 publications

Anti-Malarial Drug Artesunate Attenuates Experimental Allergic Asthma via Inhibition of the Phosphoinositide 3-Kinase/Akt Pathway

Anti-Malarial Drug Artesunate Attenuates Experimental Allergic Asthma via Inhibition of the Phosphoinositide 3-Kinase/Akt Pathway

The expression and relaxant effect of bitter taste receptors in human bronchi

TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells

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