Rosiglitazone reverses salbutamol‐induced β₂‐adrenoceptor tolerance in airway smooth muscle

Abstract

BACKGROUND AND PURPOSEb2-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)g agonist rosiglitazone modulated salbutamol-induced b2-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACHAn in vivo model of homologous b2-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent b2-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTSIn tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of b2-adrenoceptor gene and a marked decrease in b-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored b2-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPARg agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro b2-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and b2-adrenoceptor expression. 14 -prostaglandin J2 restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONSThese data suggest a potential pharmacodynamic interaction between PPARg agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease. AbbreviationsBSMC, human bronchial smooth muscle cells; EMSA, electrophoretic mobility shift assay; PPAR, peroxisome-proliferator-activated receptor

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…Certainly, therapeutic agents such as corticosteroids and even ␤ 2 -agonists can reduce proliferation (19,86). Furthermore, peroxisome proliferatoractivated receptor (PPAR)-␥ ligands can blunt ASM proliferation, migration, and ECM formation (63,72,73,250,293), and this mechanism may be of interest, given its emerging role in lung development and injury (180,220,247,260). Finally, there is increasing interest in atypical anti-inflammatory stimuli such as vitamin D (44,50).…”

Synergistic interaction between PPAR ligands and salbutamol on human bronchial smooth muscle cell proliferation

“…Another relevant finding of the present study is that the synergistic effect induced by PPARγ agonists + salbutamol was comparable with that observed for the combination dexamethasone + salbutamol, suggesting that PPARγ agonists might be used instead of steroids to design β 2 ‐adrenoceptor agonist‐based combination schedules in steroid‐resistant airway diseases. In support of this proposal, rosiglitazone produced improvements in lung function in smokers with asthma, showing a reduced response to inhaled corticosteroids (Spears et al ., ), and preserved airway smooth muscle responsiveness to salbutamol following homologous desensitization (Fogli et al ., ).…”

“…As β 2 ‐adrenoceptor agonists affect cell proliferation by increasing cAMP (Tomlinson et al ., ), it could be that homologous β 2 ‐adrenoceptor desensitization abolished the inhibitory effect of β 2 ‐adrenoceptor agonists, therefore limiting their anti‐remodelling potential. We have previously demonstrated that the PPARγ agonists, rosiglitazone and PGJ 2 , reverse salbutamol‐induced tolerance in homologously desensitized BSMC, restoring cAMP synthesis to a level comparable with that of control (Fogli et al ., ), a property that could preserve the antiproliferative action of β 2 ‐adrenoceptor agonists. However, such an effect occurred at a concentration 20‐fold higher than that used in combination experiments and it is unlikely that this mechanism could account for the synergistic interaction observed in the present study.…”

“…Several lines of evidence suggest that PPARg ligands may have anti-inflammatory effects in asthma and are endowed with anti-proliferative and antiangiogenic properties in epithelial lung cancers (Denning and Stoll, 2006). Furthermore, PPARg agonists reversed b2-adrenoceptor tolerance induced by prolonged exposure of human bronchial smooth muscle cells (BSMCs) to salbutamol (Fogli et al, 2011), thus supporting the potential combined benefit of PPARg agonists and drugs currently used in the treatment of asthma.…”

“…An interesting point that should be considered in this regard comes from recently published findings showing that homologous b2-adrenoceptor desensitization induced by exposing BSMCs to salbutamol 1 mM for 24 h (i.e. a condition similar to that used in combination studies) significantly increased nuclear PPARg translocation (Fogli et al, 2011). Such a mechanism might account for a more effective antiproliferative effect of the combined drugs compared with each drug alone due to the sensitizing effect of salbutamol on the PPARg agonist-induced cell growth inhibition.…”