Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium

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 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.Measurements and Main Results: The distal and proximal...