| First Author | Thanawala VJ | Year | 2013 |
| Journal | Am J Respir Cell Mol Biol | Volume | 48 |
| Issue | 2 | Pages | 220-9 |
| PubMed ID | 23204390 | Mgi Jnum | J:205089 |
| Mgi Id | MGI:5543997 | Doi | 10.1165/rcmb.2012-0364OC |
| Citation | Thanawala VJ, et al. (2013) beta2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model. Am J Respir Cell Mol Biol 48(2):220-9 |
| abstractText | beta(2)-Adrenoceptor (beta2AR) agonists are the most effective class of bronchodilators and a mainstay of asthma management. The first potent beta2AR agonist discovered and widely used in reversing the airway constriction associated with asthma exacerbation was the endogenous activator of the beta2AR, epinephrine. In this study, we demonstrate that activation of the beta2AR by epinephrine is paradoxically required for development of the asthma phenotype. In an antigen-driven model, mice sensitized and challenged with ovalbumin showed marked elevations in three cardinal features of the asthma phenotype: inflammatory cells in their bronchoalveolar lavage fluid, mucin over production, and airway hyperresponsiveness. However, genetic depletion of epinephrine using mice lacking the enzyme to synthesize epinephrine, phenylethanolamine N-methyltransferase, or mice that had undergone pharmacological sympathectomy with reserpine to deplete epinephrine, had complete attenuation of these three cardinal features of the asthma phenotype. Furthermore, administration of the long-acting beta2AR agonist, formoterol, a drug currently used in asthma treatment, to phenylethanolamine N-methyltransferase-null mice restored the asthma phenotype. We conclude that beta2AR agonist-induced activation is needed for pathogenesis of the asthma phenotype. These findings also rule out constitutive signaling by the beta2AR as sufficient to drive the asthma phenotype, and may help explain why chronic administration of beta2AR agonists, such as formoterol, have been associated with adverse outcomes in asthma. These data further support the hypothesis that chronic asthma management may be better served by treatment with certain "beta-blockers." |
