Reduced glucocorticoid binding affinity in asthma is related to ongoing allergic inflammation.

Abstract

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.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: J D Spahn, D Y Leung, W Surs, R J Harbeck, S Nimmagadda, S J Szefler
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 151 Issue 6 Pg. 1709-14 (Jun 1995) ISSN: 1073-449X [Print] United States
• PMID: 7767511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Blood Proteins
• Eosinophil Granule Proteins
• Inflammation Mediators
• Receptors, Glucocorticoid
• Receptors, Interleukin-2
• Ribonucleases
• Prednisone
• Hydrocortisone
• Methylprednisolone

Topics

• Administration, Oral
• Adolescent
• Asthma (drug therapy, immunology, metabolism)
• Blood Proteins (analysis)
• Eosinophil Granule Proteins
• Female
• Humans
• Hydrocortisone (blood)
• Inflammation Mediators (analysis)
• Male
• Methylprednisolone (administration & dosage, therapeutic use)
• Prednisone (administration & dosage, therapeutic use)
• Radioligand Assay
• Receptors, Glucocorticoid (metabolism)
• Receptors, Interleukin-2 (analysis)
• Ribonucleases