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

Lingling Dong,1 Haipin Chen,2 Fei Li,3 Haitao Wang,1 Hongbin Zhou,1 Liming Cao,1 Yao Ye,1 Yilan Sun1 1Geriatric Medicine Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Hematology-Oncology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents’ Health and Diseases, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USACorrespondence: Yilan Sun, Geriatric Medicine Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, Zhejiang, 310014, People’s Republic of China, Tel +86-571-87666666, Email sunyilan@hmc.edu.cnBackground: 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. The diagram illustrates inflammatory reprogramming of fibroblasts in COPD. It is divided into four main processes: 1) Fibrotic remodeling involves TGFβ leading to fibroblast activation and extracellular matrix deposition. 2) Pro-inflammatory and tissue-injurious process involves IL-1β, IL-6, IL33 causing damage to epithelial and endothelial cells. 3) Immune cell recruitment involves CCL, CXCL acting as chemoattractants for macrophages and dendritic cells. 4) Immune cell activation involves CSF1, TNFSF13B activating mast cells, B cells and T cells. The diagram contrasts healthy lungs with COPD-affected lungs, highlighting the impact of these processes.COPD fibroblast reprogramming: fibrosis, immune recruitment, activation.Keywords: chronic obstructive pulmonary disease, fibroblasts, inflammatory state, immune response, fibrotic remodeling