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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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Newton R,Giembycz MA

doi

10.1111/bph.13628

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

3405-3430

issue

eissn

0007-1188

issn

1476-5381

journal_volume

173

pub_type

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