Glucocorticoid receptor-binding characteristics in severe asthma

Abstract

The cellular mechanisms associated with severe asthma are still poorly understood. This study investigated the association between glucocorticoid-receptor (GR) alterations and continuous oral glucocorticoid therapy requirement in severe asthma.GR-binding affinity (Kd) and receptor number (n) in peripheral blood monocytes (PBM) obtained from 10 normal subjects, 10 untreated, intermittent asthmatics and 10 severe asthmatics were assessed. Moreover, one ability of dexamethasone to inhibit regulated on activation, T-cells expressed and secreted (RANTES) release by these cells in vitro was investigated. GR-binding characteristics were studied in PBM using a 3 H dexamethasone ligand-binding assay and Scatchard analysis. RANTES release was measured in the supernatant of PBM at 24 h using an enzyme-linked immunosorbent assay.No significant differences in Kd and n were found between the three groups of patients. Dexamethasone in vitro was able to inhibit RANTES release (mean ¡ SEM), with the same concentration/response curve in intermittent, untreated asthmatics (0.47 ¡ 0.22 versus 1.64 ¡ 0.31 ng?mL -1 ) and severe asthmatics (1.49 ¡ 0.64 versus 2.59 ¡ 0.77 ng?mL -1). This study showed that, despite long-term treatment with oral glucocorticoids, there was no evidence of abnormalities in glucocorticoid receptor-binding characteristics in severe asthma, and moreover, it was demonstrated that glucocorticoid receptors were functional in vitro. Eur Respir J 2003; 21: 985-988.

IL‐13‐inducedMUC5ACproduction and goblet cell differentiation is steroid resistant in human airway cells

“…The concentration of Dex tested in this study was physiologically relevant. Dex 0.04 μg/mL significantly inhibited ‘regulated on activation, normal T cells expressed and secreted’ release by peripheral blood monocytes from severe asthmatics . In a clinical setting, the peak plasma concentration (Cmax) of Dex when administered at 1 mg orally is 0.084 ± 0.036 μg/mL .…”

Severe asthma in adults: What are the important questions?

“…Rather, reduced responsiveness, often described as corticosteroid-dependent asthma, 76 is more common, where large doses of ICS and even OCS are needed to control asthma 77,78 Poor responsiveness to corticosteroid is likely to be multifactorial, varying by phenotype, changing over time and duration of disease, with environmental conditions and within different cell types. However, treatment of eosinophilic severe asthma with a large dose of OCS can lead to a clinically meaningful response.…”

Corticosteroid Design for the Treatment of Asthma: Structural Insights and the Therapeutic Potential of Soft Corticosteroids

“…From a therapeutic perspective it is also promising that long-term treatment with glucocorticoids seems to cause no significant alterations in GR binding characteristics even, for example, in subjects with severe asthma [37]. Typically, experimental GR binding affinities are obtained with rat cytosol preparations by determining the concentration necessary to inhibit by 50% the binding of a given concentration of 3 H-DEX (IC 50 ).…”