Smoking-dependent distal-to-proximal repatterning of the adult human small airway epithelium

Jing Yang, Wu Lin Zuo, Tomoya Fukui, Ion Wa Chao, Kazunori Gomi, Busub Lee, Michelle R. Staudt, Robert J. Kaner, Yael Strulovici-Barel, Jacqueline Salit, Ronald Crystal, Renat Shaykhiev

Research output: Contribution to journalArticle

22 Citations (Scopus)


Rationale: Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder. Objectives: 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). Methods: 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 withCOPDcompared 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. Measurements and Main Results: 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 upregulated in the SAE of smokers, during differentiation of SAE BCs in vitro. Conclusions: 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.

Original languageEnglish
Pages (from-to)340-352
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number3
Publication statusPublished - 1 Aug 2017
Externally publishedYes



  • Basal cells
  • Chronic obstructive pulmonary disease
  • Differentiation
  • Stem cells
  • Transcriptome

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Yang, J., Zuo, W. L., Fukui, T., Chao, I. W., Gomi, K., Lee, B., Staudt, M. R., Kaner, R. J., Strulovici-Barel, Y., Salit, J., Crystal, R., & Shaykhiev, R. (2017). Smoking-dependent distal-to-proximal repatterning of the adult human small airway epithelium. American Journal of Respiratory and Critical Care Medicine, 196(3), 340-352.