Chronic Effects of Inhaled Albuterol on β-Adrenoceptor System Function in Human Respiratory Cells

• Published in: The Journal of asthma Vol. 37; no. 4; pp. 361 - 370
• Main Authors: Kelsen, Steven G., Aksoy, Mark O., Brennan, Kathleen, Ciccolella, David, Borbely, Bernard
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01-01-2000; Taylor & Francis
• Subjects: Administration, Inhalation; Adrenergic agonists; Adrenergic beta-Agonists - pharmacology; Adrenergic receptor desensitization; Adult; Airway epithelial cells; Albuterol - pharmacology; Alveolar macrophages; Cross-Over Studies; Cyclic AMP - metabolism; Double-Blind Method; Down-Regulation - drug effects; Downregulation; Female; Humans; Macrophages, Alveolar - drug effects; Male; Receptors, Adrenergic, beta - drug effects; Respiratory Mucosa - drug effects; β-Adrenergic receptor kinase (βARK)
• ISSN: 0277-0903; 1532-4303
• DOI: 10.3109/02770900009055460

The in vivo effects of β-adrenergic receptor (βAR) agonists given chronically by metered-dose inhaler (MDI) on the molecular components of the β-adreno-ceptor system expressed by human respiratory cells are poorly understood. This study examined the effects of inhaled albuterol (180 μg four times daily for 7 days) on βAR function of airway epithelial cells (AECs) and alveolar macrophages (AMs) freshly isolated from 10 normal subjects. Responses were related to β2AR genotype in codons 16 and 27, regions which affect chronic responses to β2-agonists. In AEC, βAR density and adenosine cyclic 3′,5′-phosphate (cAMP) production in response to isoproterenol (ISO) were significantly lower in the albuterol versus placebo treatment arm (p < 0.01 for both). Moreover, in AEC, albuterol treatment increased βAR-kinase (βARK) protein immunoreactivity. In contrast, in AM, albuterol tended to decrease βAR density and cAMP production but changes did not achieve statistical significance (p > 0.20 for both) and had no effect on βARK immunoreactivity. Changes in (JAR density occurred in all subjects but tended to be greater in subjects with the glycine 16 genotype. In cultured cells exposed to equal concentrations of β-agonist in vitro, the magnitude of βAR down-regulation (p < 0.05) and cAMP densensiti-zation (p < 0.05) was greater in AEC than AM. These results indicate that albuterol taken by inhalation in a therapeutically relevant dose for 1 week produces pAR down-regulation, densensitizes the cAMP response of airway epithelial cells to a β2-adrenergic agonist, and increases PARK immunoreactivity. Greater densensitization of AEC than AM in response to chronic albuterol inhalation likely reflects cell type-specific responses.