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

Philip R. Cooper, Reynold A. Panettieri

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)734-740
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume122
Issue number4
DOIs
StatePublished - Oct 2008

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Keywords

  • Airway smooth muscle
  • airway remodeling
  • asthma
  • chronic obstructive pulmonary disease

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