title: Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.
abstract: Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder.
  
  
  
  On the basis of the concept of proximal-distal patterning that determines regional specialization of the airway epithelium during lung development, we hypothesized that a similar program operates in the adult human lung being altered by smoking, leading to decreased regional identity of the small airway epithelium (SAE).
  
  
  
  The proximal and distal airway signatures were identified by comparing the transcriptomes of large and small airway epithelium samples obtained by bronchoscopy from healthy nonsmokers. The expression of these signatures was evaluated in the SAE of healthy smokers and smokers with COPD compared with that of healthy nonsmokers. The capacity of airway basal stem cells (BCs) to maintain region-associated phenotypes was evaluated using the air-liquid interface model.
  
  
  
  The distal and proximal airway signatures, containing 134 and 233 genes, respectively, were identified. These signatures included known developmental regulators of airway patterning, as well as novel regulators such as epidermal growth factor receptor, which was associated with the proximal airway phenotype. In the SAE of smokers with COPD, there was a dramatic smoking-dependent loss of the regional transcriptome identity with concomitant proximalization. This repatterning phenotype was reproduced by stimulating SAE BCs with epidermal growth factor, which was up-regulated in the SAE of smokers, during differentiation of SAE BCs in vitro.
  
  
  
  Smoking-induced global distal-to-proximal reprogramming of the SAE represents a novel pathologic feature of COPD and is mediated by exaggerated epidermal growth factor/epidermal growth factor receptor signaling in SAE BCs.
authors.affiliation: 1 Department of Genetic Medicine and.|2 Department of Respiratory Medicine, West China Hospital, Sichuan University, Sichuan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: 1 Department of Genetic Medicine and.
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Zuo
authors.affiliation: 1 Department of Genetic Medicine and.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fukui
authors.affiliation: 1 Department of Genetic Medicine and.
authors.forename: IonWa
authors.initials: I
authors.lastname: Chao
authors.affiliation: 3 Department of Medicine, Weill Cornell Medical College, New York, New York; and.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Gomi
authors.affiliation: 3 Department of Medicine, Weill Cornell Medical College, New York, New York; and.
authors.forename: Busub
authors.initials: B
authors.lastname: Lee
authors.affiliation: 1 Department of Genetic Medicine and.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Staudt
authors.affiliation: 1 Department of Genetic Medicine and.|3 Department of Medicine, Weill Cornell Medical College, New York, New York; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kaner
authors.affiliation: 1 Department of Genetic Medicine and.
authors.forename: Yael
authors.initials: Y
authors.lastname: Strulovici-Barel
authors.affiliation: 1 Department of Genetic Medicine and.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Salit
authors.affiliation: 1 Department of Genetic Medicine and.|3 Department of Medicine, Weill Cornell Medical College, New York, New York; and.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.affiliation: 1 Department of Genetic Medicine and.
authors.forename: Renat
authors.initials: R
authors.lastname: Shaykhiev
mesh_terms: D000328:Adult; D004848:Epithelium / Q000503:physiopathology; D005260:Female; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D012907:Smoking / Q000503:physiopathology*
keywords: basal cells; chronic obstructive pulmonary disease; differentiation; stem cells; transcriptome