Sergio Parra

β2-Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Chronic regular use of β2-adrenoceptor (β2-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of β2-AR inverse agonists results in attenuation of the asthma phenotype in an allergen-driven murine model. Besides antagonizing agonist-induced signaling and reducing signaling by empty receptors, β-AR inverse agonists can also activate signaling by novel pathways. To determine the mechanism of the β-AR inverse agonists, we compared the asthma phenotype in β2-AR-null and wild-type mice. Antigen challenge of β2-AR-null mice produced results similar to what was observed with chronic β2-AR inverse agonist treatment, namely, reductions in mucous metaplasia, airway hyperresponsiveness (AHR), and inflammatory cells in the lungs. These results indicate that the effects of β2-AR inverse agonists are caused by inhibition of β2-AR signaling rather than by the induction of novel signaling pathways. Chronic administration of alprenolol, a β-blocker without inverse agonist properties, did not attenuate the asthma phenotype, suggesting that it is signaling by empty receptors, rather than agonist-induced β2-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, β2-AR signaling is required for the full development of three cardinal features of asthma: mucous metaplasia, AHR, and the presence of inflammatory cells in the lungs.

β‐Blockers have differential effects on the murine asthma phenotype

Our previous studies have shown the β2‐adrenoceptor and its endogenous ligand, adrenaline, are required for development of the asthma phenotype in murine asthma models. Chronic administration of some, but not other, β‐blockers attenuated the asthma phenotype and led us to hypothesize that biased signalling was the basis of their differential effects, experimentally and clinically.

β2-Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility

Significance Activation of β2-adrenoreceptors (β2ARs) on airway smooth muscle cells produces airway relaxation, and β2AR agonists are the most widely used bronchodilators for treating asthma. Paradoxically, murine models show β2AR activation is also required for expression of cardinal features of the asthma phenotype, including airway hyperresponsiveness (AHR), inflammation, and mucous metaplasia. However β2ARs are expressed on all the cell types implicated in the pathogenesis and maintenance of asthma, and which cell type(s) control these asthmatic effects is unknown. Here we show activation of β2AR signaling solely on airway epithelium is sufficient to restore/promote the cardinal features of asthma, including inflammation, mucous metaplasia, and AHR. These studies support the role of the airway epithelium as a master regulator of key features of asthma. The mostly widely used bronchodilators in asthma therapy are β2-adrenoreceptor (β2AR) agonists, but their chronic use causes paradoxical adverse effects. We have previously determined that β2AR activation is required for expression of the asthma phenotype in mice, but the cell types involved are unknown. We now demonstrate that β2AR signaling in the airway epithelium is sufficient to mediate key features of the asthmatic responses to IL-13 in murine models. Our data show that inhibition of β2AR signaling with an aerosolized antagonist attenuates airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus-production responses to IL-13, whereas treatment with an aerosolized agonist worsens these phenotypes, suggesting that β2AR signaling on resident lung cells modulates the asthma phenotype. Labeling with a fluorescent β2AR ligand shows the receptors are highly expressed in airway epithelium. In β2AR−/− mice, transgenic expression of β2ARs only in airway epithelium is sufficient to rescue IL-13–induced AHR, inflammation, and mucus production, and transgenic overexpression in WT mice exacerbates these phenotypes. Knockout of β-arrestin-2 (βarr-2−/−) attenuates the asthma phenotype as in β2AR−/− mice. In contrast to eosinophilic inflammation, neutrophilic inflammation was not promoted by β2AR signaling. Together, these results suggest β2ARs on airway epithelial cells promote the asthma phenotype and that the proinflammatory pathway downstream of the β2AR involves βarr-2. These results identify β2AR signaling in the airway epithelium as capable of controlling integrated responses to IL-13 and affecting the function of other cell types such as airway smooth muscle cells.

Differences in asthma study models and the effectiveness of β2‐adrenoceptor ligands: response to Lipworth et al.

These Tables list key protein targets and ligands in this article which are hyperlinked guidetopharmacology.org/, the common portal for data from the IUPHAR/BPS Guide to PHAR permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( Alexander et al., 20 LINKED ARTICLES This article is a reply to Lipworth BJ, Anderson WJ and Short PM (2016). From mouse to blockers in asthma. Br J Pharmacol 173: 248–249. doi: 10.1111/bph.13335, commentin Forkuo GS, Parra S, Knoll BJ, Bouvier M, Leff P and Bond RA (2015). Beta-blockers have d phenotype. Br J Pharmacol 172: 4833–4846. doi: 10.1111/bph.13253.