Beta2-adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2435-40. doi: 10.1073/pnas.0810902106. Epub 2009 Jan 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alprenolol / pharmacology
  • Animals
  • Asthma / genetics*
  • Asthma / pathology*
  • Bronchoconstrictor Agents / pharmacology
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Humans
  • Lung / pathology
  • Methacholine Chloride / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phenotype
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Signal Transduction


  • Bronchoconstrictor Agents
  • Receptors, Adrenergic, beta-2
  • Methacholine Chloride
  • Alprenolol