Biased Signaling by Beta-2 Adrenergic Receptor Ligands in Murine Models of Asthma



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Asthma is a chronic inflammatory disorder of the airways that affects over 300 million people worldwide. Inhaled corticosteroids (ICS) and β2 adrenergic receptor (β2AR) agonists are the mainstay of asthma therapy. However, chronic use of ICS and β2AR agonists has been associated with adverse effects and loss of control of asthma symptoms. Clinical studies have shown the beneficial effects of chronic administration of the beta-blocker nadolol in attenuating forced expiratory volume (FEV1) in mild-asthmatics. However, not all beta-blockers are beneficial in the therapy of asthma. A clinical study published by Short and colleagues showed that chronic administration of the beta-blocker propranolol in a subset of moderate asthmatics did not improve FEV1. Similar to human studies, such discrepancy in the beneficial effects of beta-blockers has also been seen in murine models of asthma. Our previous studies have shown that certain beta-blockers with inverse agonist activity such as nadolol, ICI-118,551 and high-dose metoprolol are beneficial in attenuating the inflammation and AHR associated with the murine asthma phenotype. However, other beta-blockers that are not inverse agonists, such as alprenolol, were not as effective in attenuating the murine asthma phenotype. We have also reported that, β2AR knock out (β2AR KO) mice have an attenuated asthma phenotype, indicating the requirement of the β2AR for development of the murine asthma phenotype. Moreover, nadolol does not further attenuate the asthma phenotype in the β2AR KO mice, indicating that the beneficial effects of nadolol in the murine asthma phenotype are through its activity at the β2AR. The current project investigated the β2AR activation and the signaling pathways mediating the asthma phenotype in antigen-driven murine models. Using pharmacological and genetic models to we show that constitutive activation of the β2AR is not enough and ligand-activation of the receptor is required for development of the asthma phenotype. We used six β2AR ligands with varying signaling profiles to show the role of the non-canonical extracellular signal-regulated kinases (ERK1/2) activation pathway in development of the asthma phenotype; and suggest the subset of beta-blockers capable of shutting down β2AR-ERK1/2 signaling may have a role in the chronic management of asthma.



Biased signaling, Beta-2 adrenergic receptors, Asthma, Murine models


Portions of this document appear in: Thanawala, Vaidehi J., Gloria S. Forkuo, Nour Al-Sawalha, Zoulikha Azzegagh, Long P. Nguyen, Jason L. Eriksen, Michael J. Tuvim et al. "β2-Adrenoceptor agonists are required for development of the asthma phenotype in a murine model." American journal of respiratory cell and molecular biology 48, no. 2 (2013): 220-229. And in: Thanawala, Vaidehi J., Gloria S. Forkuo, Wayne Stallaert, Paul Leff, Michel Bouvier, and Richard Bond. "Ligand bias prevents class equality among beta-blockers." Current opinion in pharmacology 16 (2014): 50-57.