Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid responsiveness at night

Background: The mechanisms for heightened nocturnal inflammation in patient s with nocturnal asthma (NA) are not well understood. Objective: We sought to determine the glucocorticoid receptor (GR) characte ristics and steroid responsiveness in subjects with NA. Methods: Eleven subjects with NA, 12 subjects with nonnocturnal asthma (NNA ), and 16 nonasthmatic control subjects underwent blood sampling at 4 PM an d 4 AM in a random order separated by 1 week. GR binding affinity was measu red in PBMCs by using a [H-3]-dexamethasone (DX) radioligand binding assay and Scatchard analysis. The capacity of hydrocortisone (HC) and DX to suppr ess proliferation of PBMCs stimulated with PHA was also determined. Results: The subjects with NA exhibited a significantly lower CR binding af finity at 4 AM, detected by an elevated dissociation constant (Kd) of 22.2 +/- 1.6 nmol/L compared with Ed at 1 PM (10.9 +/- 0.7 nmol/L; P = .0001). T he GR lid of the NNA and control groups did not change significantly from 4 PM to 4 AM, Within the NA group, there was also a significant inverse corr elation between the absolute FEV1 at 4 AM and the Kd at 4 AM (r = -0.65, P = .04). PBMCs from subjects with NA exhibited less suppression of PBMC prol iferation with HC and DX at 4 AM compared with that at 4 PM (P = .0001 and .03 for HC and DX? respectively). There were no circadian changes in suppre ssion of PBMC proliferation in either the NNA or control groups. Conclusion: GR binding affinity and steroid responsiveness exhibit a circad ian variation in subjects with NA, with a reduced GR binding affinity and s uppression of PBMC proliferation at 4 AM that is not observed in normal sub jects or asthmatic subjects without nocturnal exacerbation. These observati ons may contribute to nocturnal airway inflammation by inhibiting the antii nflammatory effects of glucocorticoids.