Rhinovirus-induced exacerbations of asthma: how is the β₂- adrenoceptor implicated?

Rhinovirus (RV) infections are the major cause of asthma exacerbations in children and adults. Under normal circumstances, asthmatic airway obstruction improves spontaneously or characteristically briskly in response to inhaled β₂-adrenergic receptor (β₂AR) agonists. During virus-associated exacerbations, an impaired response to β₂AR agonists is observed; the reason for this is not known. The objective of this study was to determine the effect of RV infection on airway smooth muscle β₂AR function. The human cell line Beas-2B and primary human bronchial epithelial cells (HBECs) were infected with RV (multiplicity of infection = 1). After 1 or 5 days for primary and Beas-2B cells, respectively, cell culture supernatants were harvested, UV-irradiated to inactivate RV, and applied to human airway smooth muscle cells for 3 days to assess modifications of β₂AR function. RV conditioned medium from Beas-2B and HBECs decreased β₂AR agonist–induced cAMP by 50 and 65%, respectively (n = 5; P < 0.05). When cAMP was induced independently of the β₂AR using forskolin, no impairment was found. Using flow cytometry, we demonstrated that this decrease was likely the result of β₂AR desensitization because membrane but not total cell receptor β₂AR was decreased. Pretreatment of HBECs and Beas-2B cells but not human airway smooth muscle cells with the corticosteroids dexamethasone or fluticasone abolished virus-mediated β₂AR loss of function. This study shows that epithelial infection with RV induces a decrease of β₂AR function on airway smooth muscle cells, potentially explaining the clinical observation of loss of β2AR agonist function during RV-induced asthma exacerbations.