Glucocorticosteroids and β₂-Adrenoceptor Agonists Synergize to Inhibit Airway Smooth Muscle Remodeling

Abstract

Airway remodeling, 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. In contrast, prolonged exposure to insulin induces a hypercontractile phenotype. Glucocorticosteroids and ␤ 2 -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), and dexamethasone (0.1-1 M) 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 g/ml), and insulin (1 M). All glucocorticosteroids inhibited PDGF-and collagen I-induced proliferation and hypocontractility, with 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 p21 WAF1/CIP1 and p57 KIP2 . At this concentration, fluticasone also prevented the insulininduced hypercontractile phenotype. At even lower concentrations, fluticasone (3 pM) synergized with fenoterol to inhibit this phenotype switch. Collectively, these findings indicate that glucocorticosteroids and ␤ 2 -agonists synergistically inhibit ASM phenotype switching, which may contribute to the increased effectiveness of combined treatment with glucocorticosteroids and ␤ 2 -agonists in asthma.

Salmeterol Efficacy and Bias in the Activation and Kinase-Mediated Desensitization of β2-Adrenergic Receptors

“…Furthermore, the use of salmeterol in the clinic is now strictly indicated for use as an add-on to therapy with steroids. It has been appreciated that use of PDE4 inhibitors in the treatment of asthma and chronic obstructive pulmonary disease may be clinically important and synergize with glucocorticoids and LABA treatment to reduce the frequency of exacerbations, as recently discussed (Kaur et al, 2008;Nino et al, 2010;Cooper et al, 2011;Holden et al, 2011;Dekkers et al, 2012;Manetsch et al, 2013;Moodley et al, 2013;Theron et al, 2013;Giembycz and Newton, 2014;BinMahfouz et al, 2015). Our findings showing the dramatic effects of PDE inhibition on cAMP levels after either long-term or short-term salmeterol treatment support the importance of developing multidrug therapy that includes PDE inhibitors, LABAs, and steroids.…”

Concurrent Agonism of Adenosine A2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

“…Thus, RGS2, a GTPase-activating protein, terminates signaling from G q -linked GPCRs and is reported to be bronchoprotective and could also have antiinflammatory activity (Holden et al, 2011). In contrast, p57 kip2 is a cell cycle kinase inhibitor that could suppress airway remodeling (Dekkers et al, 2012) by arresting mitogenesis. Fig.…”

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

“…Previous work on families of receptor tyrosine kinases such as endothelial growth factor (EGF) receptors (171,214,270,284), insulin receptors (54,55,90,128,224,271), or plateletderived growth factor (PDGF) receptors (123) has shown a role for these receptors in airway contractility and/or remodeling. However, a number of recent studies have found that the Trk family of receptors (RTK class VII; Fig.…”