Abstract
BackgroundFemale smokers have increased risk for chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. Tertiary lymphoid follicles are often found in the lungs of patients with severe COPD but sex-related differences have not been previously investigated. We determined the impact of female sex hormones on chronic cigarette smoke-induced expression of lymphoid aggregates in mice with COPD-like pathologies.MethodsLymphoid aggregate counts, total aggregate cross-sectional area and foamy macrophage counts were determined morphometrically in male, female, and ovariectomized mice exposed to air or cigarette smoke for 6 months. B-cell activating factor (BAFF) protein expression and markers of oxidative stress were evaluated in mouse lung tissues by immunofluorescence staining and gene expression analyses. Quantitative histology was performed on lung tissue sections of human COPD lungs to evaluate follicle formation.ResultsLymphoid follicle and foamy macrophage counts as well as the total follicle cross-sectional area were differentially increased in lung tissues of female mice compared to male mice, and these differences were abolished by ovariectomy. These lymphoid aggregates were positive for CD45, CD20, CD21 and BAFF expression. Differential increases in Mmp12 and Cxcl2 gene expression correlated with an increase in foamy macrophages in parenchymal tissues of female but not male mice after smoke exposure. Parenchymal tissues from female mice failed to induce antioxidant-related genes in response to smoke exposure, and this effect was restored by ovariectomy. 3-nitrotyrosine, a stable marker of oxidative stress, positively correlated with Mmp12 and Cxcl2 gene expression. Hydrogen peroxide induced BAFF protein in mouse macrophage cell line. In human lung tissues, female smokers with severe COPD demonstrated increased numbers of lymphoid follicles compared with males.ConclusionsChronic smoke exposure increases the risk of lymphoid aggregate formation in female mice compared with male mice, which is mediated female sex hormones and BAFF expression in an oxidative environment.
Highlights
Female smokers have increased risk for chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure
Female mice have more lung-associated lymphoid aggregates than male mice with chronic smoke exposure, and these differences disappeared following ovariectomy To identify whether there was any sexual dimorphism in lymphoid aggregate formation in mice with COPD-like pathologies, lung tissues of male, female and ovariectomized mice exposed to air or smoke for 6 months were stained with Hematoxylin and Eosin (H&E) for histological assessment
We observed a differential increase in the total number of lymphoid aggregates per cm2 in lung tissues of female versus male mice with chronic smoke exposure, and these differences disappeared with ovariectomy (Fig. 1d-f)
Summary
Female smokers have increased risk for chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. Chronic obstructive pulmonary disease (COPD) is the third most prevalent cause of mortality in North America and Western Europe, and imposes a tremendous economic burden to the healthcare system [1] Both men and women develop COPD, females are at a greater risk of developing significant COPD with lower. We have shown previously that there is a 6 to 7 fold increase in the percentage of small airways containing lymphoid follicles among patients with COPD (compared with smokers without COPD) [6]. These lymphoid follicles contain B-cells, follicular dendritic cells and Tcells [7]. Our primary hypothesis was that females would have increased expression of lymphoid follicles in the airways of COPD lungs and that ovariectomy would prevent the formation of these lymphoid aggregates in mice
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