Abstract Rationale Endogenous antioxidant defense in epithelial progenitor cells, such as alveolar type 2 epithelial (ATII) cells, is essential for maintaining redox homeostasis and regenerative capacity. Previously, we demonstrated that carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) levels correlated with the severity of emphysema in chronic obstructive pulmonary disease (COPD). In COPD ATII cells, CEACAM6 levels were increased, paralleled by decreased heme oxygenase-1 (HO-1)-mediated antioxidant defense. However, the mechanistic role of CEACAM6 during COPD pathogenesis remains unclear. Methods A custom-designed adeno-associated virus (AAV) delivery system was employed to achieve CEACAM6 overexpression. Cigarette smoke (CS) was used to mimic COPD-relevant exposure in an ex vivo model of isolated, perfused, ventilated lungs (ILU) and an in vivo mouse pre-clinical model. Footprints of oxidative/nitrosative stress were traced using electron spin resonance spectroscopy (ESR) and protein immunoassays. Clinically relevant assessments in mice were performed using micro-computed tomography (µCT), in vivo lung function tests, non-invasive echocardiography, and right heart catheterization. Mouse lung tissues and bronchoalveolar lavage (BAL) were collected for immunofluorescence staining, immune cell profiling, and molecular examinations. Results Analyses of available human single-cell transcriptomic datasets revealed an enrichment of CEACAM6+/HO-1− cells in the intermediate ATII cell cluster of COPD lungs. In line with these findings, CEACAM6 gain-of-function decreased HO-1 levels in mouse ATII cells. Furthermore, mice with CEACAM6 overexpression exhibited increased reactive oxygen species (ROS) release and 3-nitrotyrosine formation in the lungs, accompanied by enhanced cell apoptosis/necrotic markers in ATII after CS exposure. Upon in vivo chronic CS exposure, CEACAM6-overexpressing mice showed an accelerated emphysema development compared to wildtype controls. Interestingly, increased CD4+ and CD8+ T cells were observed in BAL samples from CS-exposed mice with epithelial CEACAM6 gain-of-function. Such alterations in immune cell profiles can be linked to worsened pulmonary vascular remodeling, shown by increased right ventricular systolic pressure, in CS-exposed mice with CEACAM6 overexpression. Conclusion In summary, ectopic activation of CEACAM6 in ATII cells impairs the endogenous HO-1-mediated antioxidant defense. This leads to increased oxidative stress, worsened emphysema, enhanced inflammatory responses, and pathological pulmonary vascular alterations during CS exposure. These findings identify CEACAM6 as a biomarker of COPD susceptibility and a promising therapeutic target. Further studies will delineate the crosstalk between CEACAM6-enriched ATII cells and other lung cell types and define the broader pathogenic mechanisms. This abstract is funded by: the von Behring-Röntgen-Stiftung and the German research foundation (DFG)
Wu et al. (Fri,) studied this question.