Portal de Periódicos da CAPES

β 2 -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

2009; National Academy of Sciences; Volume: 106; Issue: 7 Linguagem: Inglês

10.1073/pnas.0810902106

1091-6490

Long Nguyễn, Rui Lin, Sergio Parra, Ozozoma Omoluabi, Nicola A. Hanania, Michael J. Tuvim, Brian J. Knoll, Burton F. Dickey, Richard A. Bond,

Pharmacological Effects and Assays

Chronic regular use of beta(2)-adrenoceptor (beta(2)-AR) agonists in asthma is associated with a loss of disease control and increased risk of death. Conversely, we have found that administration of beta(2)-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, beta-AR inverse agonists can also activate signaling by novel pathways. To determine the mechanism of the beta-AR inverse agonists, we compared the asthma phenotype in beta(2)-AR-null and wild-type mice. Antigen challenge of beta(2)-AR-null mice produced results similar to what was observed with chronic beta(2)-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 beta(2)-AR inverse agonists are caused by inhibition of beta(2)-AR signaling rather than by the induction of novel signaling pathways. Chronic administration of alprenolol, a beta-blocker without inverse agonist properties, did not attenuate the asthma phenotype, suggesting that it is signaling by empty receptors, rather than agonist-induced beta(2)-AR signaling, that supports the asthma phenotype. In conclusion, our results demonstrate that, in a murine model of asthma, beta(2)-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.