• Anthony Tam, Andrew Churg, Joanne L Wright, Steven Zhou, Miranda Kirby, Harvey O Coxson, Stephen Lam, S F Paul Man, and Don D Sin.
• 1 Centre for Heart Lung Innovation, St. Paul's Hospital.
• Am. J. Respir. Crit. Care Med. 2016 Apr 15; 193 (8): 825-34.

RationaleAfter adjustment for the amount of smoking, women have a 50% increased risk of chronic obstructive pulmonary disease (COPD) compared with men. The anatomic basis and/or mechanism(s) of these sex-related differences in COPD are unknown.ObjectivesTo characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodeling and emphysema in a mouse model of COPD.MethodsAirway remodeling and emphysema were determined morphometrically in male, female, and ovariectomized mice exposed to 6 months of cigarette smoke. Antioxidant- and transforming growth factor (TGF)-β-related genes were profiled in airway tissues. The selective estrogen receptor modulator tamoxifen was also administered during smoke exposure in a short-term model. Airway wall thickness of male and female human smokers at risk of or with mild COPD was measured using optical coherence tomography.Measurements And Main ResultsSmall airway wall remodeling was increased in female but not male or ovariectomized mice and was associated with increased distal airway resistance, down-regulation of antioxidant genes, increased oxidative stress, and activation of TGF-β1. These effects were prevented by ovariectomy. Use of tamoxifen as a therapeutic intervention mitigated smoke-induced increase in oxidative stress in female mice. Compared with male human smokers, female human smokers had significantly thicker airway walls.ConclusionsThe excess risk of small airway disease in female mice after chronic smoke exposure was associated with increased oxidative stress and TGF-β1 signaling and also was related to the effects of female sex hormones. Estrogen receptor antagonism might be of value in reducing oxidative stress in female smokers.

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