Beta2-adrenoceptor signaling is required for the development of an asthma phenotype in a murine model.
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.
Nguyen
Long P
LP
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Science and Research Building 2, Houston, TX 77204, USA.
Lin
Rui
R
Parra
Sergio
S
Omoluabi
Ozozoma
O
Hanania
Nicola A
NA
Tuvim
Michael J
MJ
Knoll
Brian J
BJ
Dickey
Burton F
BF
Bond
Richard A
RA
D000526:Alprenolol / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000473:pathology*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction
D016085:Bronchoconstrictor Agents; D018343:Receptors, Adrenergic, beta-2; D016210:Methacholine Chloride; D000526:Alprenolol