title: An inhaled dose of budesonide induces genes involved in transcription and signaling in the human airways: enhancement of anti- and proinflammatory effector genes.
abstract: Although inhaled glucocorticoids, or corticosteroids (ICS), are generally effective in asthma, understanding their anti-inflammatory actions in vivo remains incomplete. To characterize glucocorticoid-induced modulation of gene expression in the human airways, we performed a randomized placebo-controlled crossover study in healthy male volunteers. Six hours after placebo or budesonide inhalation, whole blood, bronchial brushings, and endobronchial biopsies were collected. Microarray analysis of biopsy RNA, using stringent (≥2-fold, 5% false discovery rate) or less stringent (≥1.25-fold,P≤0.05) criteria, identified 46 and 588 budesonide-induced genes, respectively. Approximately two third of these genes are transcriptional regulators (KLF9, PER1, TSC22D3, ZBTB16), receptors (CD163, CNR1, CXCR4, LIFR, TLR2), or signaling genes (DUSP1, NFKBIA, RGS1, RGS2, ZFP36). Listed genes were qPCR verified. Expression of anti-inflammatory and other potentially beneficial genes is therefore confirmed and consistent with gene ontology (GO) terms for negative regulation of transcription and gene expression. However, GO terms for transcription, signaling, metabolism, proliferation, inflammatory responses, and cell movement were also associated with the budesonide-induced genes. The most enriched functional cluster indicates positive regulation of proliferation, locomotion, movement, and migration. Moreover, comparison with the budesonide-induced expression profile in primary human airway epithelial cells shows considerable cell type specificity. In conclusion, increased expression of multiple genes, including the transcriptional repressor, ZBTB16, that reduce inflammatory signaling and gene expression, occurs in the airways and blood and may contribute to the therapeutic efficacy of ICS. This provides a previously lacking insight into the in vivo effects of ICS and should promote strategies to improve glucocorticoid efficacy in inflammatory diseases.
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Richard
authors.initials: R
authors.lastname: Leigh
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Mostafa
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: King
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Rider
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Suharsh
authors.initials: S
authors.lastname: Shah
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Curtis
authors.initials: C
authors.lastname: Dumonceaux
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Traves
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Andrew
authors.initials: A
authors.lastname: McWhae
authors.affiliation: Alberta Children's Hospital Research Institute University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Tyler
authors.initials: T
authors.lastname: Kolisnik
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Cora
authors.initials: C
authors.lastname: Kooi
authors.affiliation: Alberta Children's Hospital Research Institute University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Slater
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Kelly
authors.affiliation: Alberta Children's Hospital Research Institute University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Mark
authors.initials: M
authors.lastname: Bieda
authors.affiliation: Respiratory GMed AstraZeneca Gothenburg Molndal SE-43183 Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Miller-Larsson
authors.affiliation: Airways Inflammation Research Group Snyder Institute for Chronic Diseases University of Calgary Calgary Alberta T2N 4Z6.
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
keywords: Anti‐inflammatory; asthma; corticosteroid; gene expression; transactivation