BACKGROUND Female 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. METHODS Lymphoid 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. RESULTS Lymphoid 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. CONCLUSIONS Chronic 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.

中文翻译：

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COPD气道淋巴滤泡的性别差异。

背景技术与吸烟史相似的男性吸烟者相比，女性吸烟者患慢性阻塞性肺疾病（COPD）的风险增加。患有严重COPD的患者的肺部常发现三级淋巴滤泡，但以前尚未研究过与性别相关的差异。我们确定了女性性激素对慢性香烟烟雾诱导的COPD样病理小鼠淋巴样聚集物表达的影响。方法对暴露于空气或香烟中6个月的雄性，雌性和卵巢切除的小鼠进行形态计量学测定，测定其淋巴样聚集体计数，总聚集体截面积和泡沫巨噬细胞计数。通过免疫荧光染色和基因表达分析，评估了小鼠肺组织中B细胞活化因子（BAFF）的蛋白表达和氧化应激标记。在人COPD肺的肺组织切片上进行定量组织学评估卵泡形成。结果与雄性小鼠相比，雌性小鼠肺组织中的淋巴滤泡和泡沫性巨噬细胞计数以及总卵泡横截面积有所不同，并且这些差异通过卵巢切除术得以消除。这些淋巴样聚集体的CD45，CD20，CD21和BAFF表达均为阳性。Mmp12和Cxcl2基因表达的差异增加与烟暴露后雌性小鼠而非雄性小鼠实质组织中泡沫巨噬细胞的增加相关。雌性小鼠的实质组织未能响应烟暴露而诱导抗氧化剂相关基因，这种作用通过卵巢切除术得以恢复。3-硝基酪氨酸是氧化应激的稳定标志物，与Mmp12和Cxcl2基因表达呈正相关。过氧化氢诱导小鼠巨噬细胞系中的BAFF蛋白。在人的肺组织中，患有严重COPD的女性吸烟者与男性相比，淋巴滤泡的数量增加。结论与男性小鼠相比，慢性烟雾暴露增加了雌性小鼠淋巴样聚集的风险，这是在氧化环境中介导的雌性激素和BAFF表达的。与Mmp12和Cxcl2基因表达正相关。过氧化氢诱导小鼠巨噬细胞系中的BAFF蛋白。在人的肺组织中，患有严重COPD的女性吸烟者与男性相比，淋巴滤泡的数量增加。结论与男性小鼠相比，慢性烟雾暴露增加了雌性小鼠淋巴样聚集的风险，这是在氧化环境中介导的雌性激素和BAFF表达的。与Mmp12和Cxcl2基因表达正相关。过氧化氢诱导小鼠巨噬细胞系中的BAFF蛋白。在人的肺组织中，患有严重COPD的女性吸烟者与男性相比，淋巴滤泡的数量增加。结论与男性小鼠相比，慢性烟雾暴露增加了雌性小鼠淋巴样聚集的风险，这是在氧化环境中介导的雌性激素和BAFF表达的。