Distal-to-Proximal Re-patterning of Small Airway Epithelium in Smoking-associated Chronic Obstructive Pulmonary Disease

The proximal-distal patterning program determines unique structural and functional properties of proximal and distal airways in the adult lung. Based on the knowledge that remod-eling of distal airways is the major pathologic feature of chronic obstructive pulmonary disease (COPD), and that small airway epithelium (SAE), which covers distal airways, is the primary site of the initial smoking-induced changes relevant to COPD pathogenesis, we hypothesized that in COPD smokers, the SAE transcriptome loses its region-specific biologic identity and takes on the transcriptional pattern of the proximal airways. By analyzing human airway epithelium col-lected by bronchoscopic brushings from proximal and distal airways of healthy smokers, proxi-mal and distal airway epithelial transcriptome signatures were identified. Dramatic smoking-dependent suppression of distal signature paralleled by acquisition of the proximal airway epithe-lial phenotype was found in the SAE of COPD smokers. Distal-proximal re-patterning observed in the SAE of smokers in vivo was reproduced in vitro by stimulating SAE basal cells (BC), the stem/progenitor cells of the SAE, with EGF, a growth factor up-regulated in airway epithelium by smoking. Together, this study identifies distal-proximal SAE re-patterning as a characteristic feature of small airway disordering in COPD smokers potentially driven by EGF/EGFR-mediated reprogramming of SAE BC stem/progenitor cells. In this study, distal and proximal human airway epithelial transcriptome signatures were identified by genome-wide analysis of the epithelial samples obtained by bronchoscopic brushings from the distal and proximal airways of healthy nonsmokers. Expression of the identified distal and proximal signatures were then analyzed in the small airway epithelium (SAE) of smokers with COPD compared to that of healthy smokers and healthy nonsmokers. A dramatic smoking-dependent suppression of the distal signature expression accompanied by up-regulation of the proximal signature genes was observed in the SAE of COPD smokers, a novel pathologic feature of COPD-associated small airway disordering designated “distal-proximal re-patterning” of the SAE.