GLP1-R: a Novel Pharmacological Target for Treating Human Bronchial Hyperresponsiveness

Asthma is associated with several comorbidities such as Type 2 Diabetes Mellitus (T2DM) which may lead to bronchial hyperersponsiveness (BHR). Since glucagon-like peptide 1 regulates glucose homeostasis, we pharmacologically investigated the influence of the glucagon-like peptide 1 receptor (GLP1-R) agonist exendin-4 on the bronchial 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 asthmatic and diabetic patients, respectively. GLP1-R activation modulated the bronchial contractile tone induced by transmural stimulation (Emax -56.7±3.6%, onset of action 28.2±4.4 min). Exendin-4 prevented the BHR induced by both high glucose stimulation and passive sensitization (-37.8±7.5% and -74.9±3.9%, P<0.05 vs. control, respectively) through selective activation of GLP1-R and in an epithelium independent manner. The cAMP-dependent protein kinase A (PKA) inhibitor KT5720 reduced the protective role of exendin-4 (P>0.05 vs. passively sensitized tissues). The GLP1-R stimulation by overnight incubation with exendin-4 induced the over-expression of adenylyl cyclase isoform V (+48.4±1.3%, P<0.05 vs. passively sensitized tissues) and restored the cAMP levels depleted by this procedure (+330.8±63.3%, P<0.05 vs. passively sensitized tissues). In conclusion, GLP1-R may represent a novel target for treating BHR by activating the cAMP-dependent PKA pathway in human airways, and GLP1-R agonists could be used as a 'new' class to treat asthmatic patients and T2DM patients with BHR.