REDUCED GLUCOCORTICOID BINDING-AFFINITY IN ASTHMA IS RELATED TO ONGOING ALLERGIC INFLAMMATION

Recent studies indicate that chronic asthma is associated with a spect rum of glucocorticoid receptor(GCR) binding abnormalities that are cyt okine-inducible. These GCR abnormalities may contribute to poor asthma control and failure to respond to glucocorticoid (GC) therapy. The pu rpose of this study was to determine whether GCR defects are associate d with poorly controlled asthma, and whether diminished GCR binding is reversible following a course of GC therapy. We enrolled 12 patients with poorly controlled asthma characterized by nocturnal awakening wit h cough or wheezing, AM FEV(1) < 70%, or FEV(1), variability of > 25% requiring a short course of high dose GC therapy. GCR binding affinity was measured in peripheral blood mononuclear cells using a radioligan d binding assay before and after the GC course. Spirometry, serum cort isol, eosinophil cationic protein (ECP), and soluble IL-2 receptor (sI L-2R) levels were also performed before and after the GC course. At ba seline, all subjects had airflow obstruction that significantly improv ed (median FEV, increased from 65.0% to 89.5% of predicted, median FEV (1)/FVC ratio increased from 0.60 to 0.72) with therapy. A diminished GCR binding affinity at baseline was noted with an elevated median dis sociation constant (Kd) of 29.0 nM (interquartile range at the 25th an d 75th percentile [IQ] of 22.3 and 445 nM) compared with normal contro ls (Kd 8.0 nM [IQ 7.0, 9.2]). Following the GC course, a significant d ecrease in the Kd was seen. Serum ECP and sIL-2R levels at baseline we re elevated, with serum ECP demonstrating a significant reduction foll owing the GC course. in conclusion, these data support the hypothesis that GCR binding abnormalities noted in poorly controlled asthma are r eversible following a course of high dose GC therapy. The observed tre nd towards normalization may result from suppression of inflammation, contributing to increased GCR binding affinity and potentially resulti ng in heightened steroid responsiveness.