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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Steroids completely reverse albuterol-induced beta(2)-adrenergic receptor tolerance in human small airways.

Authors: Cooper, Philip R; Panettieri Jr, Reynold A

Published In J Allergy Clin Immunol, (2008 Oct)

Abstract: Evidence suggests that chronic stimulation of beta(2)-adrenergic receptors (beta(2)-ARs) induces receptor tolerance that limits the efficacy of beta-agonists in the treatment of asthma. The precise mechanisms that induce beta(2)-AR tolerance remain unclear.We sought to determine whether steroids modulate albuterol-induced beta(2)-AR tolerance in human small airways.beta(2)-AR responsiveness to isoproterenol was characterized in human precision-cut lung slices (PCLSs) precontracted to carbachol after pretreatment with albuterol.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 beta(2)-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 beta(2)-AR cell-surface number (P = .013), which was not significantly reversed by 1 hour of preincubation with dexamethasone.These data suggest that beta(2)-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 beta(2)-AR tolerance occurs might offer new therapeutic approaches to improve the efficacy of bronchodilators in asthma and chronic obstructive pulmonary disease.

PubMed ID: 18774166 Exiting the NIEHS site

MeSH Terms: Adrenergic beta-2 Receptor Agonists*; Adrenergic beta-Agonists/pharmacology*; Albuterol/pharmacology*; Anti-Inflammatory Agents/pharmacology*; Asthma/drug therapy; Asthma/metabolism; Asthma/physiopathology*; Bronchoconstriction/drug effects; Bronchodilator Agents/pharmacology; Dexamethasone/pharmacology*; Drug Resistance/drug effects*; Humans; Isoproterenol/pharmacology*; Lung*/metabolism; Lung*/physiopathology; Organ Culture Techniques; Pulmonary Disease, Chronic Obstructive/drug therapy; Pulmonary Disease, Chronic Obstructive/metabolism; Pulmonary Disease, Chronic Obstructive/physiopathology; Receptors, Adrenergic, beta-2/metabolism; Time Factors

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