Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patients with chronic obstructive pulmonary disease (COPD). It is capable of differentiating emphysema-related air trapping with nonemphysematous air trapping (small airway disease), which helps to identify the extent and localization of the disease. Most studies evaluating the gene expression in smokers and COPD patients related this to spirometric measurements, but none have investigated the relationship with CT-based measurements of lung structure. The current study aimed to examine gene expression profiles of brushed bronchial epithelial cells in association with the PRM-defined CT-based measurements of emphysema (PRM^Emph) and small airway disease (PRM^fSAD). Using the Top Institute Pharma (TIP) study cohort (COPD = 12 and asymptomatic smokers = 32), we identified a gene expression signature of bronchial brushings, which was associated with PRM^Emph in the lungs. One hundred thirty-three genes were identified to be associated with PRM^Emph. Among the most significantly associated genes, CXCL11 is a potent chemokine involved with CD8⁺ T cell activation during inflammation in COPD, indicating that it may play an essential role in the development of emphysema. The PRM^Emph signature was then replicated in two independent data sets. Pathway analysis showed that the PRM^Emph signature is associated with proinflammatory and notch signaling pathways. Together these findings indicate that airway epithelium may play a role in the development of emphysema and/or may act as a biomarker for the presence of emphysema. In contrast, its role in relation to functional small airways disease is less clear.