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

Background: The mechanisms for heightened nocturnal inflammation in patients with nocturnal asthma (NA) are not well understood. Objective: We sought to determine the glucocorticoid receptor (GR) characteristics 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 and 4 AM in a random order separated by 1 week. GR binding affinity was measured in PBMCs by using a [³H]-dexamethasone (DX) radioligand binding assay and Scatchard analysis. The capacity of hydrocortisone (HC) and DX to suppress proliferation of PBMCs stimulated with PHA was also determined. Results: The subjects with NA exhibited a significantly lower GR binding affinity at 4 AM, detected by an elevated dissociation constant (Kd) of 22.2 ± 1.6 nmol/L compared with Kd at 4 PM (10.9 ± 0.7 nmol/L; P = .0001). The GR Kd 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 correlation 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 proliferation with HC and DX at 4 AM compared with that at 4 PM (P = .0004 and .03 for HC and DX, respectively). There were no circadian changes in suppression of PBMC proliferation in either the NNA or control groups. Conclusion: GR binding affinity and steroid responsiveness exhibit a circadian variation in subjects with NA, with a reduced GR binding affinity and suppression of PBMC proliferation at 4 AM that is not observed in normal subjects or asthmatic subjects without nocturnal exacerbation. These observations may contribute to nocturnal airway inflammation by inhibiting the antiinflammatory effects of glucocorticoids.