Steroids completely reverse albuterol-induced β2-adrenergic receptor tolerance in human small airways

Received 17 March 2008; received in revised form 28 July 2008; accepted 30 July 2008. published online 09 September 2008.

Background

Evidence suggests that chronic stimulation of β2-adrenergic receptors (β2-ARs) induces receptor tolerance that limits the efficacy of β-agonists in the treatment of asthma. The precise mechanisms that induce β2-AR tolerance remain unclear.

Objective

We sought to determine whether steroids modulate albuterol-induced β2-AR tolerance in human small airways.

Methods

β2-AR responsiveness to isoproterenol was characterized in human precision-cut lung slices (PCLSs) precontracted to carbachol after pretreatment with albuterol.

Results

Incubation of PCLSs with albuterol for 3, 6, or 12 hours attenuated subsequent isoproterenol-induced relaxation in a dose- and time-dependent manner. A 40% decrease (P < .0001) in maximum relaxation and a 45% decrease (P = .0011) in airway sensitivity from control values occurred after the maximum time and concentration of albuterol incubation. Desensitization was not evident when airways were relaxed to forskolin. Dexamethasone pretreatment of PCLSs (1 hour) prevented albuterol-induced β2-AR desensitization by increasing the maximum drug effect (P = .0023) and decreasing the log half-maximum effective concentration values (P < .0001) from that of albuterol alone. Albuterol (12-hour incubation) decreased the β2-AR cell-surface number (P = .013), which was not significantly reversed by 1 hour of preincubation with dexamethasone.

Conclusion

These data suggest that β2-AR desensitization occurs with prolonged treatment of human small airways with albuterol through mechanisms upstream of protein kinase A and that steroids prevent or reverse this desensitization. Clarifying the precise molecular mechanisms by which β2-AR tolerance occurs might offer new therapeutic approaches to improve the efficacy of bronchodilators in asthma and chronic obstructive pulmonary disease.

Key words: Airway smooth muscle, airway remodeling, asthma, chronic obstructive pulmonary disease

Abbreviations used: β2-AR, β2-Adrenergic receptor, COPD, Chronic obstructive pulmonary disease, EC50, Half-maximum effective concentration, Emax, Maximum drug effect, PCLS, Precision-cut lung slices, SABA, Short-acting β2-adrenergic receptor agonist

Department of Medicine and the Airways Biology Initiative, University of Pennsylvania School of Medicine, Philadelphia, Pa

Reprint requests: Reynold A. Panettieri, Jr, MD, Airways Biology Initiative TRL, Suite 1200, 125 South 31st St, Philadelphia, PA 19104.

Supported by HL080676, HL064063, HL081824, and ES013508.

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

PII: S0091-6749(08)01375-4

doi:10.1016/j.jaci.2008.07.040

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