Limits...
Wnt/β-catenin signaling modulates human airway sensitization induced by β2-adrenoceptor stimulation.

Faisy C, Grassin-Delyle S, Blouquit-Laye S, Brollo M, Naline E, Chapelier A, Devillier P - PLoS ONE (2014)

Bottom Line: Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535).Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization.Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation.

View Article: PubMed Central - PubMed

Affiliation: Unité Propre de Recherche de l'Enseignement Supérieur, Equipe d'Accueil 220, Université Versailles Saint-Quentin, Hôpital Foch, Suresnes, France; Medical Intensive Care Unit, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.

ABSTRACT

Background: Regular use of β2-agonists may enhance non-specific airway responsiveness. The wingless/integrated (Wnt) signaling pathways are responsible for several cellular processes, including airway inflammation and remodeling while cAMP-PKA cascade can activate the Wnt signaling. We aimed to investigate whether the Wnt signaling pathways are involved in the bronchial hyperresponsiveness induced by prolonged exposure to β2-adrenoceptor agonists in human isolated airways.

Methods: Bronchi were surgically removed from 44 thoracic surgery patients. After preparation, bronchial rings and primary cultures of bronchial epithelial cells were incubated with fenoterol (0.1 µM, 15 hours, 37 °C), a β2-agonist with high intrinsic efficacy. The effects of inhibitors/blockers of Wnt signaling on the fenoterol-induced airway sensitization were examined and the impact of fenoterol exposure on the mRNA expression of genes interacting with Wnt signaling or cAMP-PKA cascade was assessed in complete bronchi and in cultured epithelial cells.

Results: Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535). Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization. Fenoterol exposure did not change the mRNA expression of genes regulating Wnt signaling or cAMP-PKA cascade.

Conclusions: Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation. Future experiments based on the results of the present study will be needed to determine the impact of prolonged fenoterol exposure on the extra- and intracellular Wnt signaling pathways at the protein expression level.

Show MeSH

Related in: MedlinePlus

Concentration–response curves for endothelin-1 (ET-1)–induced contraction in human bronchi after 15 hours of incubation with 0.1 µM fenoterol or Krebs–Henseleit solution for the paired control (open circles, control; filled circles, 0.1 µM fenoterol).ΔEmax: difference between maximal induced contractions of fenoterol-pretreated bronchi and paired-control bronchi. Values are means ± SEM (n = 44). *P<.01, **P<.001 fenoterol vs paired control.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4216012&req=5

pone-0111350-g002: Concentration–response curves for endothelin-1 (ET-1)–induced contraction in human bronchi after 15 hours of incubation with 0.1 µM fenoterol or Krebs–Henseleit solution for the paired control (open circles, control; filled circles, 0.1 µM fenoterol).ΔEmax: difference between maximal induced contractions of fenoterol-pretreated bronchi and paired-control bronchi. Values are means ± SEM (n = 44). *P<.01, **P<.001 fenoterol vs paired control.

Mentions: Mean patted-dry weight of bronchi exposed to fenoterol was comparable with that of their paired controls (28.21±2.18 vs 27.55±1.90 mg, n = 44, P = 0.76). Fenoterol (0.1 µM, 15 hours) did not change significantly the basal tone of human bronchi before contraction with ET-1 (1.16±0.08 vs 1.08±0.08 g in paired controls, n = 44, P = 0.39). Incubation of the bronchi with 0.1 µM fenoterol significantly enhanced the ET-1–induced contraction (Figure 2). Emax was 3.12±0.14 g in the presence of fenoterol vs 1.94±0.11 g for the paired–control rings (ΔEmax  =  1.18±0.12 g, n = 44, P<.0001). −log EC50 values was 8.36±0.09 log units in the presence of fenoterol vs 8.27±0.10 log units for the paired–control rings [Δ(−log EC50)  =  0.08±0.09, n = 44, P = 0.37; Fig. 2].


Wnt/β-catenin signaling modulates human airway sensitization induced by β2-adrenoceptor stimulation.

Faisy C, Grassin-Delyle S, Blouquit-Laye S, Brollo M, Naline E, Chapelier A, Devillier P - PLoS ONE (2014)

Concentration–response curves for endothelin-1 (ET-1)–induced contraction in human bronchi after 15 hours of incubation with 0.1 µM fenoterol or Krebs–Henseleit solution for the paired control (open circles, control; filled circles, 0.1 µM fenoterol).ΔEmax: difference between maximal induced contractions of fenoterol-pretreated bronchi and paired-control bronchi. Values are means ± SEM (n = 44). *P<.01, **P<.001 fenoterol vs paired control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216012&req=5

pone-0111350-g002: Concentration–response curves for endothelin-1 (ET-1)–induced contraction in human bronchi after 15 hours of incubation with 0.1 µM fenoterol or Krebs–Henseleit solution for the paired control (open circles, control; filled circles, 0.1 µM fenoterol).ΔEmax: difference between maximal induced contractions of fenoterol-pretreated bronchi and paired-control bronchi. Values are means ± SEM (n = 44). *P<.01, **P<.001 fenoterol vs paired control.
Mentions: Mean patted-dry weight of bronchi exposed to fenoterol was comparable with that of their paired controls (28.21±2.18 vs 27.55±1.90 mg, n = 44, P = 0.76). Fenoterol (0.1 µM, 15 hours) did not change significantly the basal tone of human bronchi before contraction with ET-1 (1.16±0.08 vs 1.08±0.08 g in paired controls, n = 44, P = 0.39). Incubation of the bronchi with 0.1 µM fenoterol significantly enhanced the ET-1–induced contraction (Figure 2). Emax was 3.12±0.14 g in the presence of fenoterol vs 1.94±0.11 g for the paired–control rings (ΔEmax  =  1.18±0.12 g, n = 44, P<.0001). −log EC50 values was 8.36±0.09 log units in the presence of fenoterol vs 8.27±0.10 log units for the paired–control rings [Δ(−log EC50)  =  0.08±0.09, n = 44, P = 0.37; Fig. 2].

Bottom Line: Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535).Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization.Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation.

View Article: PubMed Central - PubMed

Affiliation: Unité Propre de Recherche de l'Enseignement Supérieur, Equipe d'Accueil 220, Université Versailles Saint-Quentin, Hôpital Foch, Suresnes, France; Medical Intensive Care Unit, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.

ABSTRACT

Background: Regular use of β2-agonists may enhance non-specific airway responsiveness. The wingless/integrated (Wnt) signaling pathways are responsible for several cellular processes, including airway inflammation and remodeling while cAMP-PKA cascade can activate the Wnt signaling. We aimed to investigate whether the Wnt signaling pathways are involved in the bronchial hyperresponsiveness induced by prolonged exposure to β2-adrenoceptor agonists in human isolated airways.

Methods: Bronchi were surgically removed from 44 thoracic surgery patients. After preparation, bronchial rings and primary cultures of bronchial epithelial cells were incubated with fenoterol (0.1 µM, 15 hours, 37 °C), a β2-agonist with high intrinsic efficacy. The effects of inhibitors/blockers of Wnt signaling on the fenoterol-induced airway sensitization were examined and the impact of fenoterol exposure on the mRNA expression of genes interacting with Wnt signaling or cAMP-PKA cascade was assessed in complete bronchi and in cultured epithelial cells.

Results: Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535). Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization. Fenoterol exposure did not change the mRNA expression of genes regulating Wnt signaling or cAMP-PKA cascade.

Conclusions: Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation. Future experiments based on the results of the present study will be needed to determine the impact of prolonged fenoterol exposure on the extra- and intracellular Wnt signaling pathways at the protein expression level.

Show MeSH
Related in: MedlinePlus