A Single-Cell Transcriptional Landscape of Emphysema: Heterogeneous Cellular Dynamics in Centrilobular, Panlobular, and Paraseptal Subtypes

Abstract

Emphysema is a chronic lung disease characterized by irreversible alveolar destruction, with distinct imaging subtypes—centrilobular emphysema (CLE), panlobular emphysema (PLE), and paraseptal emphysema (PSE). The cellular and molecular mechanisms driving subtype-specific pathogenesis remain poorly understood. Here, we performed single-cell RNA sequencing on emphysematous lung tissues from nine patients (three per subtype) to map the transcriptional landscape across CLE, PLE, and PSE. Profiling 84,704 high-quality cells, we identified eight major cell types, and subsequent subclustering uncovered subtype-enriched populations and transcriptional features. CLE was characterized by upregulated inflammatory pathways in ciliated cells and activated macrophage–epithelial/fibroblast crosstalk, suggesting an airway-derived infection and inflammatory phenotype. In PLE, the proportions of Natural Killer T (NKT) cells and Group 1 innate lymphoid cells (ILC1s) with enhanced cytotoxicity were increased, and mesothelial cells showed upregulation of extracellular matrix (ECM)-related genes, indicating dysfunction in innate immune cells and abnormal repair of mesothelial cells. PSE showed pronounced ECM remodeling signatures, with an increased proportion of systemic venous endothelial cells and enhanced fibroblast–epithelial interactions. Collectively, our findings reveal that CLE is predominantly driven by airway-originated inflammation, PSE exhibits a fibrosis-like remodeling phenotype, and PLE represents an intermediate state of innate immune activation and matrix dysregulation, providing a single-cell resolution framework for subtype-specific therapeutic targeting.