Molecular phenotyping of chronic bronchitis: mucin and inflammatory gene expression heterogeneity in COPD

Abstract

Introduction: Chronic bronchitis is a distinct phenotypic COPD subgroup, characterized by greater airway inflammation, mucus hypersecretion, and impaired outcomes. As in COPD overall, the chronic bronchitis subgroup is likely heterogeneous. MUC5AC and MUC5B, the major gel-forming airway mucins, are elevated in COPD overall. Here we explore airway epithelial mucin gene expression heterogeneity in COPD, and the associated adaptive immune responses. Methods: Airway epithelial brushings were collected from COPD participants by bronchoscopy at baseline (N=71) and 16 weeks after randomization to placebo (N=24) or Roflumilast (N=28). Gene expression was measured by multiplexed PCR. Signatures of IL-17 and Type 2 inflammation were generated using prespecified gene sets. Variables of interest were related by regression. Participant subsets were identified by cluster analyses. Results: MUC5AC and MUC5B gene expression were not correlated with each other, however cluster analysis revealed that participant subsets had relatively high expression of either MUC5AC or MUC5B. The IL-17 signature was associated with increasing MUC5B and decreasing MUC5AC expression (p=0.01 and p Conclusions: Our data suggest 2 COPD subgroups in which either MUC5AC or MUC5B gene expression is elevated. These subgroups are associated with specific inflammatory patterns. This suggests that mechanisms of mucus hypersecretion in COPD, and their underlying inflammatory pathways, are heterogeneous.