Sex-Related Differences in Pulmonary Function following 6 Months of Cigarette Exposure: Implications for Sexual Dimorphism in Mild COPD

Tam, Anthony Raymond; Bates, Jason H. T.; Churg, Andrew; Wright, Joanne L.; Man, S. F. Paul; Sin, Don D.

doi:10.1371/journal.pone.0164835

Cited by 39 publications

(38 citation statements)

References 18 publications

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“…We have previously demonstrated that female mice have increased airway wall thickness, lymphoid follicle expression, oxidative stress and distal airway resistance after chronic smoke exposure compared to male mice, and these effects were attenuated with ovariectomy [23,24,26]. To extend previous findings that showed chronic cigarette smoke exposure altered the murine gut microbiome [42], we have systemically investigated specific sex-related effects in the cecal microbiome of mice in response to chronic smoke exposure.…”

Section: Discussionmentioning

confidence: 97%

“…The data reported in the present study were generated from mouse samples collected from a previous study where we examined the effect of sex-related differences on pulmonary function from chronic cigarette exposure [23]. In the current study, we report additional data focusing on the cecal microbiome and its contribution to changes in whole-body weight after chronic smoke exposure.…”

Section: Methodsmentioning

confidence: 99%

“…Adult male, female and ovariectomized C57BL/6 female mice (12 weeks old) were obtained from Charles River (Montreal, PQ, Canada) [23]. In brief, surgical ovariectomy of female mice was performed at Charles River four weeks prior to cigarette smoke exposure.…”

Section: Animalsmentioning

confidence: 99%

“…Two mice died in the smoke-exposed ovariectomized group from acute bronchospasm. All smoke exposures were conducted using our standard nose-only smoke exposure system [23][24][25][26].…”

Section: Smoke Exposurementioning

confidence: 99%

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Effects of sex and chronic cigarette smoke exposure on the mouse cecal microbiome

et al. 2020

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RationaleChronic smoke exposure is associated with weight loss in patients with Chronic Obstructive Pulmonary Disease (COPD). However, the biological contribution of chronic smoking and sex on the cecal microbiome has not been previously investigated. MethodsAdult male, female and ovariectomized mice were exposed to air (control group) or smoke for six months using a standard nose-only smoke exposure system. DNA was extracted from the cecal content using the QIAGEN QIAamp® DNA Mini Kit. Droplet digital PCR was used to generate total 16S bacterial counts, followed by Illumina MiSeq® analysis to determine microbial community composition. The sequencing data were resolved into Amplicon Sequence Variants and analyzed with the use of QIIME2 ® . Alpha diversity measures (Richness, Shannon Index, Evenness and Faith's Phylogenetic Diversity) and beta diversity (based on Bray-Curtis distances) were assessed and compared according to smoke exposure and sex.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

“…Two mice died in the smoke-exposed ovariectomized group from acute bronchospasm. All smoke exposures were conducted using our standard nose-only smoke exposure system [23][24][25][26].…”

Section: Smoke Exposurementioning

confidence: 99%

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Effects of sex and chronic cigarette smoke exposure on the mouse cecal microbiome

et al. 2020

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“…The smokeexposed groups were exposed to three cigarettes (one 1R1 and two 2R4F with the filters removed, or two 1R1 and one 2R4F with the filters removed on every other smoking day) per day for 5 days per week for 6 months. All smoke exposures were conducted using our standard nose-only smoke exposure system [5,14,15].…”

Section: Smoke Exposurementioning

confidence: 99%

Sex differences in lymphoid follicles in COPD airways

et al. 2020

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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. 3nitrotyrosine, 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.

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Impacts of anti‐inflammatory phosphodiesterase inhibitors on a murine model of chronic pulmonary inflammation

Zheng

Chen

Xiao-ling

et al. 2021

Pharmacology Res & Perspec

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Chronic obstructive pulmonary disease (COPD) often tends to respond poorly to glucocorticoid (GC) therapy. Reduced Histone deacetylase‐2 (HDAC‐2) activity is an important mechanism behind this GC insensitivity. In this study, we investigated the effects of three phosphodiesterase inhibitors (PDEIs), with an anti‐inflammatory propensity, on cigarette smoke (CS)‐induced pulmonary inflammation and HDAC‐2 activity. Male C57BL/6 mice were exposed to cigarette smoke (CS) over the course of 30 weeks. Administration of the PDEIs commenced from the 29th week and followed a schedule of once daily treatments, 5 days a week, for 2 weeks. Roflumilast (ROF) was administered intragastrically (5 mg·kg −1 ), while pentoxifylline (PTX) (10 mg·kg −1 ) and theophylline (THEO) (10 mg·kg −1 ) were administered intraperitoneally, either alone or in combination with a GC (triamcinolone acetonide or TRI, 5 mg·kg −1 , i.m., single injection). Lung morphometry, as well as the activity of HDAC‐2, pro‐inflammatory cytokines and reactive oxygen species (ROS) were assessed at the end of the 30‐week course. CS exposure was associated with a reduction in HDAC‐2 activity and the up‐regulation of ROS expression. PTX, ROF, and THEO administration led to the partial restoration of HDAC‐2 activity, which was favorably associated with the reduction of ROS expression. However, combining TRI to any of these PDEIs did not synergistically augment HDAC‐2 activity. Inactivation of HDAC‐2 due to long‐term CS exposure is closely related to exaggerated oxidative stress, and this reduced HDAC‐2 activity could partially be restored through the use of PDEIs. This finding provides a potential novel approach for further clinical research.

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Sex-Related Differences in Pulmonary Function following 6 Months of Cigarette Exposure: Implications for Sexual Dimorphism in Mild COPD

Cited by 39 publications

References 18 publications

Effects of sex and chronic cigarette smoke exposure on the mouse cecal microbiome

Effects of sex and chronic cigarette smoke exposure on the mouse cecal microbiome

Sex differences in lymphoid follicles in COPD airways

Impacts of anti‐inflammatory phosphodiesterase inhibitors on a murine model of chronic pulmonary inflammation

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