Understanding how long-acting β2-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma - an update

In moderate-to-severe asthma, adding an inhaled long-acting (2)-adenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) provides better disease control than simply increasing the dose of ICS. Acting on the glucocorticoid receptor (GR, gene NR3C1), ICSs promote anti-inflammatory/anti-asthma gene expression. In vitro, LABAs synergistically enhance the maximal expression of many glucocorticoid-induced genes. Other genes, including dual-specificity phosphatase 1(DUSP1) in human airways smooth muscle (ASM) and epithelial cells, are up-regulated additively by both drug classes. Synergy may also occur for LABA-induced genes, as illustrated by the bronchoprotective gene, regulator of G-protein signalling 2 (RGS2) in ASM. Such effects cannot be produced by either drug alone and may explain the therapeutic efficacy of ICS/LABA combination therapies. While the molecular basis of synergy remains unclear, mechanistic interpretations must accommodate gene-specific regulation. We explore the concept that each glucocorticoid-induced gene is an independent signal transducer optimally activated by a specific, ligand-directed, GR conformation. In addition to explaining partial agonism, this realization provides opportunities to identify novel GR ligands that exhibit gene expression bias. Translating this into improved therapeutic ratios requires consideration of GR density in target tissues and further understanding of gene function. Similarly, the ability of a LABA to interact with a glucocorticoid may be suboptimal due to low (2)-adrenoceptor density or biased (2)-adrenoceptor signalling. Strategies to overcome these limitations include adding-on a phosphodiesterase inhibitor and using agonists of other Gs-coupled receptors. In all cases, the rational design of ICS/LABA, and derivative, combination therapies requires functional knowledge of induced (and repressed) genes for therapeutic benefit to be maximized.