TY - JOUR
T1 - Reduced glucocorticoid binding affinity in asthma is related to ongoing allergic inflammation
AU - Spahn, Joseph D.
AU - Leung, Donald Y.M.
AU - Surs, Wendy
AU - Harbeck, Ronald J.
AU - Nimmagadda, Sai
AU - Szefler, Stanley J.
PY - 1995/6
Y1 - 1995/6
N2 - Recent studies indicate that chronic asthma is associated with a spectrum of glucocorticoid receptor (GCR) binding abnormalities that are cytokine- inducible. These GCR abnormalities may contribute to poor asthma control and failure to respond to glucocorticoid (GC) therapy. The purpose of this study was to determine whether GCR defects are associated 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 with cough or wheezing, AM FEV1 < 70%, or FEV1 variability of > 25% requiring a short course of high dose GC therapy. GCR binding affinity was measured in peripheral blood mononuclear cells using a radioligand binding assay before and after the GC course. Spirometry, serum cortisol, eosinophil cationic protein (ECP), and soluble IL-2 receptor (sIL-2R) levels were also performed before and after the GC course. At baseline, all subjects had airflow obstruction that significantly improved (median FEV1 increased from 65.0% to 89.5% of predicted, median FEV1/FVC ratio increased from 0.60 to 0.72) with therapy. A diminished GCR binding affinity at baseline was noted with an elevated median dissociation constant (Kd) of 29.0 nM (interquartile range at the 25th and 75th percentile [IQ] of 22.3 and 44.5 nM) compared with normal controls (Kd 8.0 nM [IQ 7.0, 9.2]). Following the GC course, a significant decrease in the Kd was seen. Serum ECP and sIL-2R levels at baseline were elevated, with serum ECP demonstrating a significant reduction following the GC course. In conclusion, these data support the hypothesis that GCR binding abnormalities noted in poorly controlled asthma are reversible following a course of high dose GC therapy. The observed trend towards normalization may result from suppression of inflammation, contributing to increased GCR binding affinity and potentially resulting in heightened steroid responsiveness.
AB - Recent studies indicate that chronic asthma is associated with a spectrum of glucocorticoid receptor (GCR) binding abnormalities that are cytokine- inducible. These GCR abnormalities may contribute to poor asthma control and failure to respond to glucocorticoid (GC) therapy. The purpose of this study was to determine whether GCR defects are associated 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 with cough or wheezing, AM FEV1 < 70%, or FEV1 variability of > 25% requiring a short course of high dose GC therapy. GCR binding affinity was measured in peripheral blood mononuclear cells using a radioligand binding assay before and after the GC course. Spirometry, serum cortisol, eosinophil cationic protein (ECP), and soluble IL-2 receptor (sIL-2R) levels were also performed before and after the GC course. At baseline, all subjects had airflow obstruction that significantly improved (median FEV1 increased from 65.0% to 89.5% of predicted, median FEV1/FVC ratio increased from 0.60 to 0.72) with therapy. A diminished GCR binding affinity at baseline was noted with an elevated median dissociation constant (Kd) of 29.0 nM (interquartile range at the 25th and 75th percentile [IQ] of 22.3 and 44.5 nM) compared with normal controls (Kd 8.0 nM [IQ 7.0, 9.2]). Following the GC course, a significant decrease in the Kd was seen. Serum ECP and sIL-2R levels at baseline were elevated, with serum ECP demonstrating a significant reduction following the GC course. In conclusion, these data support the hypothesis that GCR binding abnormalities noted in poorly controlled asthma are reversible following a course of high dose GC therapy. The observed trend towards normalization may result from suppression of inflammation, contributing to increased GCR binding affinity and potentially resulting in heightened steroid responsiveness.
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U2 - 10.1164/ajrccm.151.6.7767511
DO - 10.1164/ajrccm.151.6.7767511
M3 - Article
C2 - 7767511
AN - SCOPUS:0029020726
SN - 1073-449X
VL - 151
SP - 1709
EP - 1714
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 6
ER -