A Single Cell Atlas of the COPD Lung Identifies Inflammatory Reprogramming in Fibroblasts.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation, structural remodeling, and irreversible airflow limitation, but the cellular mechanisms that sustain chronic inflammatory remodeling remain poorly understood. Methods: We integrated newly generated single cell transcriptomic data with publicly available datasets, comprising 6 healthy controls and 10 patients with COPD. Gene expression programs, intercellular communication, pseudotime trajectories, and transcription factor regulatory networks were assessed to define fibroblast associated changes in COPD lung tissue. Results: Fibroblasts exhibited the strongest outgoing signaling activity among lung parenchymal cells and showed the greatest increase in outgoing signaling in COPD. Across multiple fibroblast subpopulations, fibroblasts from COPD lungs acquired a shared proinflammatory and immunoregulatory state associated with inflammatory activation, tissue injury, and fibrotic remodeling. This state was characterized by increased expression of inflammatory mediators and enhanced potential to promote immune cell recruitment and activation. Regulatory analyses further suggested that this inflammatory program was accompanied by extensive remodeling of transcription factor networks in fibroblasts. Conclusion: These findings identify fibroblasts as key immunoregulatory cells in COPD lung tissue and suggest that fibroblast associated inflammatory programs may contribute to the maintenance of chronic inflammatory remodeling. Fibroblast centered inflammatory pathways may represent potential targets for future mechanistic and translational studies.