Single cell RNA-sequencing meta-analysis identifies the molecular signature of smoking cessation on the human lung

Cigarette smokers have a greater risk for developing chronic obstructive pulmonary disease (COPD) and lung cancer because of smoking-induced lung injury. This injury is mitigated by smoking cessation, but former smokers are still more likely to develop these diseases than never smokers. This indicates that the lungs only partially recover with cessation, but what underlies this at a transcriptional level is unclear. To better understand the molecular impact of smoking cessation, we performed a meta-analysis of publicly available lung single cell RNA-sequencing (scRNA-seq) data from three studies, comprised of cells from 9 never, 5 active, and 7 former smokers. Genes in important cellular pathways were dysregulated in active smoker cells, including collagen genes in alveolar type 1 epithelial cells (AT1s), cytoskeleton genes in general capillary cells, and antigen presentation genes in macrophages. Cessation reduced antigen presentation gene dysregulation in some macrophages and fully resolved pathway dysregulation in AT1s. Cessation also had its own effects; former smoker capillary aerocytes had dysregulation of angiogenesis and cell junction genes despite having no dysregulated pathways in active smokers. Taken together, our findings shed light on how smoking permanently damages the lungs and heightens lung disease susceptibility in former smokers.