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.
Kraft, M; Vianna, E; Martin, RJ; Leung, DY
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