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

Abstract

In moderate‐to‐severe asthma, adding an inhaled long‐acting β2‐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 β2‐adrenoceptor density or biased β2‐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.

Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the Adverse and Therapeutic Effects ofβ2-Adrenoceptor Agonists

“…Thus, the net effect of regular SABA and LABA monotherapy could increase asthma severity and enhance mortality by preferentially enhancing proinflammatory gene expression. A genomic effect is also germane to the mechanism of action of ICS/LABA combination therapy, because glucocorticoids repress the expression of many of these adverse-effect genes (Newton and Giembycz, 2016) and protect against LABA-induced toxicity in asthmatic subjects (Cates et al, 2014). As a result, an ICS may tip the balance of a LABA away from side effects potentially toward therapeutic benefit.…”

“…An ICS can also augment, in an additive or synergistic manner, the expression of many LABA-induced genes that could be therapeutically desirable Newton and Giembycz, 2016). A recent microarraybased study using human airway epithelial cells identified many genes that are regulated in this way, including CRISPLD2, RGS2, and DUSP1 (Rider et al, under review).…”

Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation

“…This may, in part, explain the enhanced granulocyte (neutrophil/eosinophil) numbers observed in the BAL fluid of the HDM-exposed Rgs2 -/- animals. Furthermore, it is tempting to speculate that, in more severe neutrophilic asthma, the above effects of RGS2 could play a role in the enhanced clinical effectiveness of ICS/LABA combinations, compared to ICS as a monotherapy [42]. …”

“…For example, DUSP1, which acts to reduce MAPK signalling, is induced by glucocorticoids and LABAs and may also reduce expression of inflammatory genes and provide bronchoprotection [65–70]. In seeking to design improved glucocorticoids, and/or ICS/LABA combination therapies, we propose that strategies seeking to maximize expression of RGS2, and other beneficial gene products, may be therapeutically advantageous [42, 71]. …”

β2-Adrenoceptor Function in Asthma

“…The therapeutic value of combining long-acting β2-agonists with corticosteroids in the treatment of asthmatic patients is undeniable as evidenced by numerous reports showing better disease control, pulmonary function and reduced frequency of exacerbations (Newton & Giembycz, 2016). The mechanisms underlying the superior clinical benefits provided by the combination therapies have not been completely elucidated but several in vivo and in vitro studies have suggested that β2-agonists might possess antiinflammatory properties in addition to their bronchoprotective effect.…”