Chronic treatment in vivo with β-adrenoceptor agonists induces dysfunction of airway β ₂-adrenoceptors and exacerbates lung inflammation in mice

BACKGROUND AND PURPOSE Inhalation of a β-adrenoceptor agonist (β-agonist) is first-line asthma therapy, used for both prophylaxis against, and acute relief of, bronchoconstriction. However, repeated clinical use of β-agonists leads to impaired bronchoprotection and, in some cases, adverse patient outcomes. Mechanisms underlying this β ₂- adrenoceptor dysfunction are not well understood, due largely to the lack of a comprehensive animal model and the uncertainty as to whether or not bronchorelaxation in mice is mediated by β ₂-adrenoceptors. Thus, we aimed to develop a mouse model that demonstrated functional β-agonist-induced β ₂-adrenoceptor desensitization in the context of allergic inflammatory airway disease. EXPERIMENTAL APPROACH We combined chronic allergen exposure with repeated β-agonist inhalation in allergen-treated BALB/C mice and examined the contribution of β ₂-adrenoceptors to albuterol-induced bronchoprotection using FVB/NJ mice with genetic deletion of β ₂-adrenoceptors (KO). Associated inflammatory changes - cytokines (ELISA), cells in bronchoalevolar lavage and airway remodelling (histology) and β ₂-adrenoceptor density (radioligand binding) - were also measured. KEY RESULTS β ₂-Adrenoceptors mediated albuterol-induced bronchoprotection in mice. Chronic treatment with albuterol induced loss of bronchoprotection, associated with exacerbation of the inflammatory components of the asthma phenotype. CONCLUSIONS AND IMPLICATIONS This animal model reproduced salient features of human asthma and linked loss of bronchoprotection with airway pathobiology. Accordingly, the model offers an advanced tool for understanding the mechanisms of the effects of chronic β- agonist treatment on β-adrenoceptor function in asthma. Such information may guide the clinical use of β-agonists and provide insight into development of novel β-adrenoceptor ligands for the treatment of asthma.