title: Glucagon-Like Peptide 1 Receptor: A Novel Pharmacological Target for Treating Human Bronchial Hyperresponsiveness.
abstract: 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.
authors.affiliation: 1 Department of Systems Medicine, Respiratory Medicine, and.
authors.forename: Paola
authors.initials: P
authors.lastname: Rogliani
authors.affiliation: 1 Department of Systems Medicine, Respiratory Medicine, and.
authors.forename: Luigino
authors.initials: L
authors.lastname: Calzetta
authors.affiliation: 2 Department of Systems Medicine, Endocrinology and Diabetes, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Capuani
authors.affiliation: 3 Thoracic Surgery Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facciolo
authors.affiliation: 1 Department of Systems Medicine, Respiratory Medicine, and.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: 2 Department of Systems Medicine, Endocrinology and Diabetes, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Lauro
authors.affiliation: 4 Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, Italy; and.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Matera
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000378:metabolism* / Q000628:therapy*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D058990:Molecular Targeted Therapy; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011724:Pyridazines / Q000494:pharmacology; D015398:Signal Transduction; D014688:Venoms / Q000494:pharmacology
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D011724:Pyridazines; D014688:Venoms; D000077270:Exenatide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; C066436:zardaverine
keywords: asthma; bronchial hyperresponsiveness; exendin-4; glucagon-like peptide 1 receptor; human isolated bronchi