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

Joanne L Wright,Anthony Tam,Andrew Churg,Jason H T Bates,Heinz Fehrenbach,S F Paul Man,Don D Sin

doi:10.1371/journal.pone.0164835

Joanne L Wright, Anthony Tam + Show 5 more

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https://doi.org/10.1371/journal.pone.0164835

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Abstract

Female smokers have increased risk of chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. We have shown previously that chronic smoke exposure for 6 months leads to increased airway wall remodeling in female C57BL/6 mice compared with male C57BL/6 mice. These differences, however, were not evident in female ovariectomized mice exposed to cigarette smoke. Herein, we report on the pulmonary function test results from the flexiVent system, which was used to determine the potential functional consequences of the histologic changes observed in these mice. We found that tissue damping (G) was increased in female compared to male or ovariectomized female mice after smoke exposure. At low oscillating frequencies, complex input resistance (Zrs) and impedance (Xrs) of the respiratory system was increased and decreased, respectively, in female but not in male or ovariectomized female mice after smoke exposure. Quasistatic pressure-volume curves revealed a reduction in inspiratory capacity in female mice but not in male or ovariectomized female mice after smoke exposure. The remaining lung function measurements including quasistatic compliance were similar amongst all groups. This is the first study characterizing a sexual dimorphism in respiratory functional properties in a mouse model of COPD. These findings demonstrate that increased airway remodeling in female mice following chronic smoke exposure is associated with increased tissue resistance in the peripheral airways. These data may explain the importance of female sex hormones and the increased risk of airway disease in female smokers.

Highlights

Chronic obstructive pulmonary disease (COPD) is a complex disease that includes both emphysema and airway remodelling, but these pathologic changes may be influenced by female sex hormones
Methacholine challenge was used as positive controls in all groups of mice to demonstrate that chronic smoke exposure was not associated with smooth muscle-dependent increase in Zrs (S2 Fig)
In patients with severe COPD, female smokers are at increased risk of small airways disease compared with male smokers [1]

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a complex disease that includes both emphysema and airway remodelling, but these pathologic changes may be influenced by female sex hormones. Epidemiological studies have shown that female smokers experience a more rapid loss in lung function compared with male smokers who smoke a similar number of cigarettes per day [2]. Van Winkle and colleagues have demonstrated that female mice demonstrated greater proximal airway injury than male mice after acute injection of napthalene, an important product in side-stream cigarette smoke [3]. Female A/J mice develop emphysema sooner than male A/J mice after 10 weeks and 16 weeks of cigarette smoke exposure, respectively [4]. These data have demonstrated important biological sex differences in emphysema and airways disease

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