Chronic effects of inhaled albuterol on beta-adrenoceptor system function in human respiratory cells

The in vivo effects of beta-adrenergic receptor (beta AR) agonists given ch ronically by metered-dose inhaler (MDI) on the molecular components of the beta-adreno-ceptor system expressed by human respiratory cells are poorly u nderstood. This study examined the effects of inhaled albuterol (180 mu g f our times daily for 7 days) on beta AR function of airway epithelial cells (AECs) and alveolar macrophages (AMs) freshly isolated from 10 normal subje cts. Responses were related to beta(2)AR genotype in codons 16 and 27, regi ons which affect chronic responses to beta(2)-agonists. In AEC, beta AR den sity and adenosine cyclic 3',5'-phosphate (cAMP) production in response to isoproterenol (ISO) were significantly lower in the albuterol versus placeb o treatment arm (p < 0.01 for both). Moreover, in AEC, albuterol treatment increased beta AR-kinase (beta ARK) protein immunoreactivity. In contrast, in AM, albuterol tended to decrease beta AR density and cAMP production but changes did not achieve statistical significance (p > 0.20 for both) and h ad no effect on beta ARK immunoreactivity. Changes in beta AR density occur red in all subjects but tended to be greater in subjects with the glycine 1 6 genotype. In cultured cells exposed to equal concentrations of beta-agoni st in vitro, the magnitude of beta AR down-regulation (p < 0.05) and cAMP d ensensitization (p < 0.05) was greater in AEC than AM. These results indica te that albuterol taken by inhalation in a therapeutically relevant dose fo r 1 week produces beta AR down-regulation, densensitizes the cAMP response of airway epithelial cells to a beta(2)-adrenergic agonist, and increases b eta ARK immunoreactivity. Greater densensitization of AEC than AM in respon se to chronic albuterol inhalation likely reflects cell type-specific respo nses.