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PNAS 106 (7): 2435-2440

Copyright © 2009 by the National Academy of Sciences.

From the Cover


BIOLOGICAL SCIENCES / PHARMACOLOGY

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

Long P. Nguyena, Rui Lina, Sergio Parraa, Ozozoma Omoluabib, Nicola A. Hananiac, Michael J. Tuvimd, Brian J. Knolla, Burton F. Dickeyd, and Richard A. Bonda,1

aDepartment of Pharmacological and Pharmaceutical Sciences and bDepartment of Biology and Biochemistry, University of Houston, Science and Research Building 2, Houston, TX 77204; cSection of Pulmonary and Critical Care Medicine, Baylor College of Medicine, 1709 Dryden Road, Houston, TX 77030; and dDepartment of Pulmonary Medicine, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved December 12, 2008

Received for publication October 28, 2008.

Abstract: 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.

Key Words: airway hyperresponsiveness • β-blocker • inverse agonist • mucous metaplasia • inflammation


Author contributions: L.P.N., N.A.H., M.J.T., B.J.K., B.F.D., and R.A.B. designed research; L.P.N., R.L., S.P., and O.O. performed research; M.J.T. and B.F.D. contributed new reagents/analytic tools; L.P.N., N.A.H., M.J.T., B.J.K., B.F.D., and R.A.B. analyzed data; and L.P.N., N.A.H., B.J.K., B.F.D., and R.A.B. wrote the paper.

Conflict of interest statement: R.A.B. is a scientific founder and shareholder of Inverseon, Inc. S.P. is a shareholder of Inverseon, Inc.

This article is a PNAS Direct Submission.

See Commentary on page 2095.

1To whom correspondence should be addressed. E-mail: rabond{at}uh.edu

© 2009 by The National Academy of Sciences of the USA


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