Asthma is associated with several comorbidities, such as type 2 diabetes mellitus, which may lead to bronchial hyperresponsiveness (BHR). Because glucagon-like peptide (GLP) 1 regulates glucose homeostasis, we pharmacologically investigated the influence of the GLP1 receptor (GLP1-R) agonist, exendin-4, on BHR induced in human isolated airways. The effect of exendin-4 was assessed in human isolated airways undergoing overnight passive sensitization and high-glucose stimulation, two conditions mimicking ex vivo the BHR typical of patients with asthma and diabetes, respectively. GLP1-R activation modulated the bronchial contractile tone induced by transmural stimulation (maximum effect -56.7 ± 3.6%; onset of action, 28.2 ± 4.4 min). Exendin-4 prevented BHR induced by both high-glucose stimulation and passive sensitization (-37.8 ± 7.5% and -74.9 ± 3.9%, P < 0.05 versus control, respectively) through selective activation of GLP1-R and in an epithelium-independent manner. The cAMP-dependent protein kinase A inhibitor, KT5720, reduced the protective role of exendin-4 (P > 0.05 versus passively sensitized tissues). The GLP1-R stimulation by overnight incubation with exendin-4 induced the overexpression of adenylyl cyclase isoform V (+48.4 ± 1.3%, P < 0.05 versus passively sensitized tissues) and restored the cAMP levels depleted by this procedure (+330.8 ± 63.3%, P < 0.05 versus passively sensitized tissues). In conclusion, GLP1-R may represent a novel target for treating BHR by activating the cAMP-dependent protein kinase A pathway in human airways, and GLP1-R agonists could be used as a "new" class to treat patients with asthma and patients with type 2 diabetes mellitus with BHR.
Rogliani, P., Calzetta, L., Capuani, B., Facciolo, F., Cazzola, M., Lauro, D., et al. (2016). Glucagon-like peptide 1 receptor: A novel pharmacological target for treating human bronchial hyperresponsiveness. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 55(6), 804-814.
|Tipologia:||Articolo su rivista|
|Citazione:||Rogliani, P., Calzetta, L., Capuani, B., Facciolo, F., Cazzola, M., Lauro, D., et al. (2016). Glucagon-like peptide 1 receptor: A novel pharmacological target for treating human bronchial hyperresponsiveness. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 55(6), 804-814.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/10 - Malattie dell'Apparato Respiratorio|
Settore MED/13 - Endocrinologia
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1165/rcmb.2015-0311OC|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2016|
|Titolo:||Glucagon-like peptide 1 receptor: A novel pharmacological target for treating human bronchial hyperresponsiveness|
|Autori:||Rogliani, P; Calzetta, L; Capuani, B; Facciolo, F; Cazzola, M; Lauro, D; Matera, M|
|Appare nelle tipologie:||01 - Articolo su rivista|