TY - JOUR T1 - Glucocorticosteroids and β<sub>2</sub>-adrenoceptor agonists synergize to inhibit airway smooth muscle remodelling JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.112.195867 SP - jpet.112.195867 AU - Bart Gerrit Jan Dekkers AU - Adnan Pehlić AU - Raissa Mariani AU - I.Sophie T Bos AU - Herman Meurs AU - Johan Zaagsma Y1 - 2012/06/08 UR - http://jpet.aspetjournals.org/content/early/2012/06/08/jpet.112.195867.abstract N2 - Airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to increased airway narrowing in asthma. Increased ASM mass may be caused by exposure to mitogens, including platelet-derived growth factor (PDGF) and collagen type I, which induce a proliferative, hypocontractile ASM phenotype. By contrast, prolonged exposure to insulin induces a hypercontractile phenotype. Glucocorticosteroids and β2-adrenoceptor agonists synergize to increase glucocorticosteroid receptor translocation in ASM cells; however, the impact of this synergism on phenotype modulation is unknown. Using bovine tracheal smooth muscle, we investigated the effects of the glucocorticosteroids fluticasone (10 nM), budesonide (30 nM), dexamethasone (0.1-1 μM) and the combination of low concentrations of fluticasone (3-100 pM) and fenoterol (10 nM) on ASM phenotype switching in response to PDGF (10 ng/ml), collagen type I (50 μg/ml) and insulin (1 μM). All glucocorticosteroids inhibited PDGF- and collagen I-induced proliferation and hypocontractility, the effects of collagen I being less susceptible to glucocorticosteroid action. At 100-fold lower concentrations, fluticasone (100 pM) synergized with fenoterol to prevent PDGF- and collagen I-induced phenotype switching. This inhibition of ASM phenotype switching was associated with a normalization of the PDGF-induced decrease in the cell cycle inhibitors p21WAF1/CIP1 and p57KIP2. At this concentration, fluticasone also prevented the insulin-induced hypercontractile phenotype. At even lower concentrations, fluticasone (3 pM) synergized with fenoterol to inhibit this phenotype switch. Collectively, these findings indicate that glucocorticosteroids and β2-agonists synergistically inhibit ASM phenotype switching, which may contribute to the increased effectiveness of combined treatment with glucocorticosteroids and β2-agonists in asthma. ER -