Glucagon-like peptide 1 receptor: A novel pharmacological target for treating human bronchial hyperresponsiveness

Paola Rogliani, Luigino Calzetta, Barbara Capuani, Francesco Facciolo, Mario Cazzola, Davide Lauro, Maria Gabriella Matera

Research output: Contribution to journalArticlepeer-review

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 (237.8± 7.5% and 274.9±3.9%, P<0.05 versus control, respectively) through selective activation of GLP1-R and in an epitheliumindependent 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 (148.4±1.3%, P<0.05 versus passively sensitized tissues) and restored the cAMP levels depleted by this procedure (1330.8±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.

Original languageEnglish
Pages (from-to)804-814
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume55
Issue number6
DOIs
Publication statusPublished - Dec 1 2016

Keywords

  • Asthma
  • Bronchial hyperresponsiveness
  • Exendin-4
  • Glucagon-like peptide 1 receptor
  • Human isolated bronchi

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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