Inflammaging increases susceptibility to cigarette smoke-induced COPD.

Chronic obstructive pulmonary disease (COPD) is related to an abnormal chronic inflammatory response of the lung to mainly cigarette smoke (CS) and the disease risk is increased in aged individuals. The source of this chronic inflammation is due to the repeated and progressive activation of immune cells. We hypothesize that in a chronic CS-induced mouse model, the predisposition to COPD pathogenesis in aged mice is characterized by an elevated immune response compared to young animals. We measured several characteristics of COPD in young and old mice (2 and 12 months of age) exposed to CS for 3 months. CS-exposed aged mice exhibited increased lung compliance (0.061 ± 0.008 vs. 0.055 ± 0.006 ml/cm H2O, p < 0.01), emphysema development (35.36 ± 0.71 vs. 25.31 ± 0.005 µm; p < 0.01) and airway remodeling (2.15 ± 0.37 vs. 1.09 ± 0.64 µm3/µm2; p < 0.01) compared to control animals, which was not seen in CS-exposed young mice. Quantification of lung tissue inflammation revealed a significantly greater volume of inducible bronchus-associated lymphoid tissue structures in aged mice after CS exposure (5.94 ± 2.89 vs. 2.37 ± 1.69 µm3/µm2; p < 0.01). Our results indicate that age-induced lung inflammation is further elevated after CS exposure in old mice, potentially via an age-induced change in immune cell susceptibility to CS thereby accelerating the pathophysiological hallmarks of COPD.

Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD.

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decline in lung function, caused by exposure to exogenous particles, mainly cigarette smoke (CS). COPD is initiated and perpetuated by an abnormal CS-induced inflammatory response of the lungs, involving both innate and adaptive immunity. Specifically, B cells organized in iBALT structures and macrophages accumulate in the lungs and contribute to CS-induced emphysema, but the mechanisms thereof remain unclear. Here, we demonstrate that B cell-deficient mice are significantly protected against CS-induced emphysema. Chronic CS exposure led to an increased size and number of iBALT structures, and increased lung compliance and mean linear chord length in wild-type (WT) but not in B cell-deficient mice. The increased accumulation of lung resident macrophages around iBALT and in emphysematous alveolar areas in CS-exposed WT mice coincided with upregulated MMP12 expression. In vitro coculture experiments using B cells and macrophages demonstrated that B cell-derived IL-10 drives macrophage activation and MMP12 upregulation, which could be inhibited by an anti-IL-10 antibody. In summary, B cell function in iBALT formation seems necessary for macrophage activation and tissue destruction in CS-induced emphysema and possibly provides a new target for therapeutic intervention in COPD.