title: A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment.
abstract: BACKGROUND
  Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function.
  
  
  OBJECTIVE
  We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy.
  
  
  METHODS
  Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays.
  
  
  RESULTS
  We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts.
  
  
  CONCLUSIONS
  Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.
authors.affiliation: Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Steiling
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.forename: Kahkeshan
authors.initials: K
authors.lastname: Hijazi
authors.forename: Roberta
authors.initials: R
authors.lastname: Florido
authors.forename: Joshua
authors.initials: J
authors.lastname: Campbell
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Ji
authors.initials: J
authors.lastname: Xiao
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.forename: Grant
authors.initials: G
authors.lastname: Duclos
authors.forename: Eduard
authors.initials: E
authors.lastname: Drizik
authors.forename: Huiqing
authors.initials: H
authors.lastname: Si
authors.forename: Catalina
authors.initials: C
authors.lastname: Perdomo
authors.forename: Charles
authors.initials: C
authors.lastname: Dumont
authors.forename: Harvey O
authors.initials: HO
authors.lastname: Coxson
authors.forename: Yuriy O
authors.initials: YO
authors.lastname: Alekseyev
authors.forename: Don
authors.initials: D
authors.lastname: Sin
authors.forename: Peter
authors.initials: P
authors.lastname: Pare
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.forename: Annette
authors.initials: A
authors.lastname: McWilliams
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sterk
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: George T
authors.initials: GT
authors.lastname: O'Connor
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Bild
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics*; D000368:Aged; D000704:Analysis of Variance; D000730:Androstadienes; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D001993:Bronchodilator Agents / Q000494:pharmacology; D001999:Bronchoscopy; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D000068298:Fluticasone; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012129:Respiratory Function Tests; D012907:Smoking / Q000009:adverse effects*; D059467:Transcriptome / Q000187:drug effects / Q000502:physiology*
chemical_list: D000730:Androstadienes; D001993:Bronchodilator Agents; D051701:Activating Transcription Factor 4; D000068298:Fluticasone