TY - JOUR
T1 - β2-Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model
AU - Nguyen, Long P.
AU - Lin, Rui
AU - Parra, Sergio
AU - Omoluabi, Ozozoma
AU - Hanania, Nicola A.
AU - Tuvim, Michael J.
AU - Knoll, Brian J.
AU - Dickey, Burton F.
AU - Bond, Richard A.
PY - 2009/2/17
Y1 - 2009/2/17
N2 - 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.
AB - 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.
KW - Airway hyperresponsiveness
KW - Inflammation
KW - Inverse agonist
KW - Mucous metaplasia
KW - β-blocker
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U2 - 10.1073/pnas.0810902106
DO - 10.1073/pnas.0810902106
M3 - Article
C2 - 19171883
AN - SCOPUS:60549103882
SN - 0027-8424
VL - 106
SP - 2435
EP - 2440
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -