Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease

Tam, Anthony Raymond; Churg, Andrew; Wright, Joanne L.; Zhou, Shaoyu; Kirby, Miranda; Coxson, Harvey O.; Lam, Stephen; Man, S. F. Paul; Sin, Don D.

doi:10.1164/rccm.201503-0487oc

Cited by 125 publications

(133 citation statements)

References 35 publications

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“…It may be that: 1) the concentration of cigarette smoke per unit of area of airway, for the same level of exposure and same lung volume, is greater in women than in men, as women have a smaller airway to lung volume ratio than men (33); 2) there is a genetic predisposition for increased smoke-related lung damage among women that is linked to the X chromosome (34); and/or 3) there are hormonally-mediated differences in the metabolism of cigarette smoke (35,36). In a mouse model of COPD exposed to chronic cigarette smoke, female animals showed greater small airway wall remodelling, with increased oxidative stress and TGF-beta 1 signalling, than male mice and females ovariectomized before smoke exposure (37). This observation suggests that sex hormones are responsible for the differences in smoking-related risk of airflow obstruction between male and female smokers.…”

Section: Discussionmentioning

confidence: 99%

Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank

Amaral

Strachan

Burney

et al. 2017

Am J Respir Crit Care Med

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Section: Discussionmentioning

confidence: 99%

Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank

Amaral

Strachan

Burney

et al. 2017

Am J Respir Crit Care Med

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“…As described previously [5], adult male, female and ovariectomized C57BL/6 mice (12 weeks old) were obtained from Charles River (Montreal, PQ, Canada). Surgical ovariectomy of female mice was performed at Charles River four weeks prior to cigarette smoke exposure.…”

Section: Methodsmentioning

confidence: 99%

“…As described previously [5], we studied 6 groups of mice (n = 10 per group): 1) male control, 2) male smoke-exposed, 3) female control, 4) female smoked-exposed, 5) ovariectomized control, and 6) ovariectomized smoke-exposed. The smoke-exposed 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) for 5 days per week for 6 months.…”

Section: Methodsmentioning

confidence: 99%

“…In a recent study, we showed that chronic smoke exposure was associated with increased histological changes of small airway remodelling in female compared with male or female ovariectomized mice even though there were no significant sex-related differences in the histological burden of emphysema [5]. These findings were accompanied by corresponding increases in the real part of respiratory system impedance, Zrs , in the female mice.…”

Section: Introductionmentioning

confidence: 96%

“…This suggested the existence of a definable link between lung function and lung structure that may be modified by smoking and sex hormones. To further characterize the functional consequences of sex hormones on the airways and the lung parenchyma of mice exposed to long term cigarette smoke, we performed extensive physiological measurements in both male and female (ovariectomized as well as ovary intact) mice; the findings of these experiments have not been reported in detail previously [5]. These data are important because symptoms, quality of life and prognosis are determined to a large extent by lung function (as opposed to lung architecture) in human patients.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine

Brandsma

Berge

Hackett

et al. 2019

The Journal of Pathology

144

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Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease-modifying treatment. The biggest drawback of today's COPD treatment regimen is the 'one size fits all' pharmacological intervention, mainly based on disease severity and symptoms and not the individual's disease pathology. To halt the worrying increase in the burden of COPD, disease management needs to be advanced with a focus on personalized treatment. The main pathological feature of COPD includes a chronic and abnormal inflammatory response within the lungs, which results in airway and alveolar changes in the lung as reflected by (small) airways disease and emphysema. Here we discuss recent developments related to the abnormal inflammatory response, ECM and age-related changes, structural changes in the small airways and the role of sex-related differences, which are all relevant to explain the individual differences in the disease pathology of COPD and improve disease endotyping. Furthermore, we will discuss the most recent developments of new treatment strategies using biologicals to target specific pathological features or disease endotypes of COPD.

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Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease

Cited by 125 publications

References 35 publications

Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank

Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank

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

Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine

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