title: Wnt/β-catenin signaling modulates human airway sensitization induced by β2-adrenoceptor stimulation.
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.
authors.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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Faisy
authors.affiliation: Unité Propre de Recherche de l'Enseignement Supérieur, Equipe d'Accueil 220, Université Versailles Saint-Quentin, Hôpital Foch, Suresnes, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Grassin-Delyle
authors.affiliation: Unité Propre de Recherche de l'Enseignement Supérieur, Equipe d'Accueil 220, Université Versailles Saint-Quentin, Hôpital Foch, Suresnes, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Blouquit-Laye
authors.affiliation: Unité Propre de Recherche de l'Enseignement Supérieur, Equipe d'Accueil 220, Université Versailles Saint-Quentin, Hôpital Foch, Suresnes, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Brollo
authors.affiliation: Unité Propre de Recherche de l'Enseignement Supérieur, Equipe d'Accueil 220, Université Versailles Saint-Quentin, Hôpital Foch, Suresnes, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Naline
authors.affiliation: Department of Thoracic Surgery, Hôpital Foch, Suresnes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Chapelier
authors.affiliation: Unité Propre de Recherche de l'Enseignement Supérieur, Equipe d'Accueil 220, Université Versailles Saint-Quentin, Hôpital Foch, Suresnes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000368:Aged; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005280:Fenoterol / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013997:Time Factors; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D051153:Wnt Proteins; D005280:Fenoterol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium