In vitro and in vivo modulation of alpha- and beta-glucocorticoid-receptor mRNA in human bronchial epithelium.
Despite the central role bronchial epithelial cells play in asthmatic reactions, and the widespread use of inhaled corticosteroids in asthma, no information is available on the effect of glucocorticoids on glucocorticoid- receptor (GR) gene expression. In this study, the effect of budesonide on alpha- and beta-GR gene expression in human bronchial epithelial cells was investigated in vitro and in vivo. A bronchial epithelial cell line was exposed in vitro to budesonide, and a dose- and time-dependent synchronous downregulation of alpha- and beta-GR mRNA was observed. A 1-h exposure resulted in a reversible and reduced downregulation as compared with continuous exposure. In healthy volunteers (n = 10), no difference on average was present in GR mRNA expression before or after 4 wk of budesonide inhalation in either bronchial epithelial cells or alveolar macrophages. The time between the last inhalation and sampling of cells ranged from 0.5 to 8 h. However, a significant downregulation of alpha-GR mRNA was observed when the time between the last inhalation and sampling of cells was more than 2 h. Normalization of the downregulation of GR mRNA expression in bronchial epithelial cells is explained by the pharmacokinetics of inhaled budesonide in the human lung.
Korn
S H
SH
Department of Pulmonology, University of Limburg, Maastricht, The Netherlands.
Wouters
E F
EF
Wesseling
G
G
Arends
J W
JW
Thunnissen
F B
FB
D000287:Administration, Topical; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019819:Budesonide; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D009693:Nucleic Acid Hybridization; D011282:Pregnenediones / Q000494:pharmacology*; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000235:genetics
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011282:Pregnenediones; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D019819:Budesonide