title: Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid responsiveness at night.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Medicine and Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kraft
authors.forename: E
authors.initials: E
authors.lastname: Vianna
authors.forename: R J
authors.initials: RJ
authors.lastname: Martin
authors.forename: D Y
authors.initials: DY
authors.lastname: Leung
mesh_terms: D000328:Adult; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D011446:Prospective Studies; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: D011965:Receptors, Glucocorticoid