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

Titleβ2-Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model
Publication TypeJournal Article
AuthorsNguyen, Long P., Rui Lin, Sergio Parra, Ozozoma Omoluabi, Nicola A. Hanania, Michael J. Tuvim, Brian J. Knoll, Burton F. Dickey, and Richard A. Bond
JournalProceedings of the National Academy of Sciences
Volume106
Issue7
Pagination2435-2440
AbstractChronic regular use of β-adrenoceptor (β-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of β-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 β-AR-null and wild-type mice. Antigen challenge of β-AR-null mice produced results similar to what was observed with chronic β-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 β-AR inverse agonists are caused by inhibition of β-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 β-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, β-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.
URLhttp://www.pnas.org/content/106/7/2435.abstract
DOI10.1073/pnas.0810902106