The Role of the Canonical Beta-2 Adrenoceptor Gs Pathway in Development of the Asthma Phenotype in Murine Models
Forkuo, Gloria S
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Asthma is a chronic inflammatory disease of the airways characterized by variable degrees of inflammation, mucous metaplasia and airway hyperresponsiveness (AHR). Asthma causes over a quarter million deaths per year and affects 300 million people worldwide. Current treatment modalities including inhaled β2-adrenoceptor (β2AR) agonists, and inhaled corticosteroids, the main bronchodilating and anti-inflammatory agents respectively are associated with serious and adverse side effects. Therefore, there is the need to develop novel therapies for the management of asthma. Using pharmacologic studies, we have previously shown in an allergen driven murine model of asthma that, chronic administration of certain “β-blockers” with inverse agonist properties such as nadolol, metoprolol, and ICI 118,551, but not the antagonists alprenolol, significantly attenuated three cardinal features of asthma: airway inflammation, mucous metaplasia and AHR. Also, in genetic studies, we established the requirement of the β2AR in development of the asthma phenotype where ovalbumin sensitized and challenged β2AR null mice, exhibited an attenuation of the asthma phenotype. These studies established the requirement of β2AR signaling in the development of the asthma phenotype in murine models. In mild asthmatics, clinical studies have also shown that, chronic administration of nadolol dose-dependently increased the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (FEV1). The β2AR can signal in the presence of a ligand or spontaneously (constitutively active receptors) in the absence of a ligand. It can also signal through at least two major pathways: the cAMP pathway and the β-arrestin pathway, which can lead to MAPK activation. This project was designed to study the role of constitutive versus ligand activation of the β2AR in development of the asthma phenotype in murine asthma models. We also investigated the pathways downstream of the β2AR required for the development of the asthma phenotype. Using pharmacologic and genetic studies, we have shown that ligand activation of the β2AR is required for the development of the asthma phenotype in murine asthma models. We also observed that, the Gs-cAMP pathway may demonstrate beneficial effects in a murine model of asthma.