Regional differences in airway susceptibility to cigarette smoke: An investigational case study of epithelial function and gene alterations in in vitro airway epithelial three-dimensional cultures

Cigarette smoke (CS) is a risk factor contributing to lung remodeling in chronic obstructive pulmonary disease (COPD). COPD is a heterogeneous disease because many factors contribute in varying degrees to the resulting airflow limitations in different regions of the respiratory tract. This heterogeneity makes it difficult to understand mechanisms behind COPD development. In the current study, we investigate the regional heterogeneity of the acute response to CS exposure between large and small airways using in vitro three-dimensional (3D) cultures. We used two in vitro 3D human airway epithelial tissues from large and small airway epithelial cells, namely, MucilAir™ and SmallAir™, respectively, which were derived from the same single healthy donor to eliminate donor differences. Impaired epithelial functions and altered gene expression were observed in SmallAir™ exposed to CS at the lower dose and earlier period following the last exposure compared with MucilAir™. In addition, severe damage in SmallAir™ was retained for a longer duration than MucilAir™. Transcriptomic analysis showed that although well-known CS-inducible biological processes (i.e. inflammation, cell fate, and metabolism) were disturbed with consistent activity in both tissues exposed to CS, we elucidated distinctively regulated genes in only MucilAir™ and SmallAir™, which were mostly related to catalytic and transporter activities. Our findings suggest that CS exposure elicited epithelial dysfunction through almost the same perturbed pathways in both airways; however, they expressed different genes related to metabolic and transporter activities in response to CS exposure which may contribute to cytotoxic heterogeneity to the response to CS in the respiratory tract.