In vivo modulation of glucocorticoid receptor mRNA by inhaled fluticasone propionate in bronchial mucosa and blood lymphocytes in subjects with mild asthma.
BACKGROUND
In vivo regulation of the glucocorticoid receptor (GR) by glucocorticoids provides a means of modulating sensitivity of targeted cells.


OBJECTIVE
We sought to determine the in vivo modulation of GR mRNA expression by fluticasone propionate (FP) in subjects with mild asthma.


METHODS
Ten atopic asthmatic subjects were treated with FP 250 microg twice daily for 4 weeks. Before and after treatment, the patients underwent fiberoptic bronchoscopy with endobronchial biopsy and sampling of venous blood for measurements of GR mRNA levels. A solution hybridization assay was used for quantitative analysis of GR mRNA. In addition, a 24-hour urinary cortisol excretion and an adrenocorticotropic hormone test before and after treatment with FP were performed.


RESULTS
A high interindividual variation in GR mRNA expression was seen. However, we detected a significant reduction of the GR mRNA levels in the endobronchial biopsy specimens after FP treatment (36.6 +/- 23.1 and 25.0 +/- 10.9 amol GR mRNA/microg RNA, respectively; P <.01). In the peripheral blood lymphocytes an even more striking downregulation of the GR by its cognate ligand was documented (30.3 +/- 26.5 and 8.8 +/- 5 amol GR mRNA/microg RNA, respectively; P <.001), possibly reflecting differences in glucocorticoid sensitivity between tissues. A small but significant reduction of the 24-hour urinary cortisol excretion was observed (233 +/- 109 and 157 +/- 66 nmol/L, respectively; P <.01), whereas the feedback regulation of glucocorticoid synthesis by means of the hypothalamic-pituitary-adrenal axis as assessed by the adrenocorticotropic hormone test remained normal after treatment with FP.


CONCLUSIONS
The results in this study confirm the potency of the inhaled corticosteroid FP and provide evidence for a considerable tissue-specific interindividual variation in the expression of the GR.
Andersson
O
O
Department of Lung Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden.
Cassel
T N
TN
Grönneberg
R
R
Brönnegård
M
M
Stierna
P
P
Nord
M
M
D000324:Adrenocorticotropic Hormone; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage* / Q000494:pharmacology; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D000068298:Fluticasone; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D009092:Mucous Membrane / Q000378:metabolism; D010366:Peak Expiratory Flow Rate; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014598:Uteroglobin
D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D011506:Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C556389:SCGB1A1 protein, human; D000324:Adrenocorticotropic Hormone; D014598:Uteroglobin; D000068298:Fluticasone; D006854:Hydrocortisone