Contribution of adaptive immune cells to COPD pathogenesis in a cigarette smoke induced mouse model

Chronic obstructive pulmonary disease (COPD) is caused by exposure to toxic gases and particles, most often cigarette smoke, leading to septal tissue damage, remodeling of small airways, airway obstruction, and a subsequent decline in lung function. The disease pathogenesis is related to an abnormal smoke-induced and antigen-driven inflammatory response of the lungs involving innate and specific immune cells. In this study, we characterized the dynamics of inflammatory cell recruitment after chronic cigarette smoke (CS) exposure in a COPD mouse model and focused on adaptive and innate immune cells.

Female C57BL/6 mice were exposed to a CS-concentration of 500mg/m3 total particulate matter every day for up to 6 months and analyzed on day 3, 7, 14, 28 and month 2, 4, 6. Two groups were also analyzed 1 and 2 months after the last exposure. Control animals were kept in a filtered air environment. Broncho-alveolar lavage fluid was obtained to perform differenzial cell counts and lung tissue was used to determine lymphocyte distribution by Flow cytometry. Air space enlargement was assessed by quantifying mean linear chord length via design-based stereology of hematoxylin-eosin-stained lung tissue slides.

Compared to control animals, CS-exposed mice showed significantly increased total BAL cell counts, due to elevated numbers of neutrophils and macrophages. Neutrophils were increased during the whole time course. After 14d of exposure, lymphocyte levels started to increase. Interestingly, inflammatory cells persisted even after smoking cessation. In lung tissue, there was an early upregulation of CD20+ B cells and Th17 cells and a delayed increase in Tregs after CS exposure. Stereological analysis of lung tissue revealed air space enlargement starting from 4 months of CS exposure with increased mean linear chord length persisting even 2 months after the last exposure.

These results demonstrate a time dependent recruitment of adaptive immune cells in a cigarette smoke-induced mouse model. Initial inflammatory processes might contribute to COPD pathogenesis at an early stage of smoke exposure, leading to a perpetuation and persistence of inflammation even 2 months after smoking cessation.