Why are women more vulnerable to chronic obstructive pulmonary disease?

Keywords::

• COPD
• FEV₁
• inflammation
• smoking
• women

Epidemiology of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is one of the leading health problems around the world. Globally, more than 200 million individuals aged 45 years and older are affected and 3 million die annually across the world from this disease. By 2020, COPD will become the third leading cause of mortality, trailing only behind ischemic heart disease and stroke [1]. The major risk factor for COPD is cigarette smoking. Although men have traditionally smoked more than women, there are more women with self-reported COPD than men in the western world and in 2000, the number of women dying of COPD surpassed that of men in the USA [2]. The mechanisms behind these observations are largely unknown. However, in a recent meta-analysis, we showed that female smokers experience a faster decline in lung function after the age of 45 years compared with male smokers [3]. Prescott et al. reported similar findings from two independent sample populations, the Copenhagen City Heart Study and Glostrup Population Studies, in which female smokers demonstrated faster decline in lung function and a higher risk of hospitalization for COPD compared with male smokers after controlling for pack years of smoking [4]. These observations were replicated in an independent study in which smoking-related decline in forced expiratory volume in 1 s (FEV₁) was threefold higher in women with FEV₁/forced vital capacity <0.70 compared with men with FEV₁/forced vital capacity <0.70 [5]. In the largest randomized controlled trial of its kind, the TORCH study showed that although female COPD patients had lower risk of total mortality, they had more symptoms and experienced increased risk of exacerbations [6]. Together, these data raise the possibility that female smokers may be biologically more susceptible to COPD than male smokers. In this concise editorial, we review several putative mechanisms to explain the enhanced risk of COPD in female smokers.

Dysanapsis

One of the leading hypotheses is the concept of dysanapsis [7]. It is well known that the airway lumen in adult females is on average narrower than that of males. Interestingly, before puberty, the reverse is true, suggesting that there are differential rates of growth of airways and lungs between men and women. The concept that airway size increases disproportionately to the growth in lung size, leading to wide variations in maximal expiratory flow rates, was first proposed by Green et al. and is called ‘dysanapsis’ [8]. An observational study comparing airway size (as estimated by using maximal expiratory flow/static recoil pressure at 50% vital capacity) to lung size (as estimated by using vital capacity) in healthy adult men and women found that the male upper airways were on average 17% larger in diameter than that in women [7]. In a subset of individuals matched for total lung capacity, Martin et al. found that there was a significant reduction in tracheal cross-sectional area by 29% in women compared with men [9]. However, these studies had a major limitation in that lung size was estimated using indirect rather the more accurate direct measurements [7,8]. In a more recent study using computed tomography (CT), investigators showed that women harbored significantly smaller conducting airways than those in men, matched for lung size [10]. A similar study, using multidetector CT scanning, showed that female smokers had thicker wall area and smaller luminal area in all anatomically matched airways compared with male smokers [11]. Dysanapsis explains why following puberty, women are at increased risk of airway disease. However, it cannot explain why when adolescent girls smoke their lung growth is stunted, whereas smoking in adolescent boys appears to have little to no effect on rate of lung growth [12].

Increased risk of airway inflammation & mucus hypersecretion

An alternative (but not mutually exclusive) hypothesis is that female airways may be more susceptible to inflammation and mucus hypersecretion in response to an irritant such as cigarette smoke. Using lung tissue obtained at lung volume reduction surgery, Martinez et al. have shown that female COPD patients demonstrated more airway disease than their male counterparts, characterized by smaller airway lumen, disproportionately thicker airway walls and less extensive emphysematous changes in the adjacent parenchyma for the same degree of lung function impairment [13]. They also showed that in these very advanced COPD cases, the small airways (i.e., those <2 mm in diameter) undergo extensive remodeling, leading to a marked increase in airway wall tissue volume in all layers including epithelium, lamina propria, smooth muscle and adventitia [14]. Airway inflammation appears to start very early. Using multidetector CT scanning, we found that all female smokers in their 20s demonstrated CT evidence for bronchiolitis (i.e., inflammation in the small airways) and systemic inflammation [15]. In a separate study, Gosselink et al. found using PCR of laser-captured microdissected tissue that small airways of COPD patients expressed growth factors that promoted tissue proliferation in airway remodeling [16]. These data have been complemented by observations in C57/B6 mice that were exposed to daily cigarette smoke for 6 months. These experiments have shown that the smoke-exposed airways overexpress profibrotic factors, especially those related to the TGF-β signaling pathway, matrix protein and platelet-derived growth factors, leading to airway remodeling [17]. Whether female airways demonstrate differential molecular responses to cigarette smoke remains unknown. Moreover, it is known that similar to female smokers, all young male smokers develop bronchiolitis [18]. Thus, differential inflammatory response to cigarette smoke is probably insufficient in explaining gender differences in susceptibility to COPD.

With COPD progression, airway remodeling worsens and is accompanied by mucus hypersecretion, which may dysregulate normal ciliary clearance. Mucus secretion from human airways consists primarily of mucin 5AC (MUC5AC), which is produced predominantly by goblet cells on the surface epithelium, and mucin 5B (MUC5B), which is produced predominantly by submucosal glands [19]. Choi et al. demonstrated, using normal human nasal epithelial cells cultured in air–liquid interface, that 17β-estradiol upregulates the MUC5B gene and hence protein expression by stimulating the cAMP response element binding protein [20]. In addition to these processes, estrogens may affect post-translational modification of mucin structure, which plays an important role in mucin maturation. For instance, post-translational modification of glycoproteins with fucose is essential to embryonic growth and development, fertility and immune function [21]. We have shown recently using normal human bronchial epithelial cells in air–liquid interface that 17β-estradiol may be a novel mediator of mucin 5AC by post-translationally fucosylating this protein, making this protein bigger and altering its rheology. Collectively, these data suggest that females have enhanced risk of mucus hypersecretion that may adversely impact on COPD symptoms and prognosis.

Sex differences in particle deposition in the lungs

There may also be sex differences in the way in which smoke and particles are inhaled and deposited in the female versus male lungs. Deposition of inhaled particles in the lungs depends on particle size, breathing pattern and lung structure. In general, particle deposition is greatly enhanced in the proximal airways as particle size and breathing rate increase. By contrast, particle deposition in the distal airways takes place when the particle size becomes small (usually less than 5 µm in mass mean aerodynamic diameter), tidal volume increases and respiratory rate decreases [22]. Although it has not been well studied, anecdotal reports suggest that female smokers tend to inhale more deeply and hold their breath longer than male smokers, which may explain the increased inflammation and airway remodeling in the small airways of female COPD patients. However, this explanation is not fully satisfactory. Jaques and Kim demonstrated that women have greater lung deposition of ultrafine particles, which are on average 0.05 µm in diameter, than men under controlled breathing conditions (i.e., with the same tidal volume and respiratory rate) [23]. Thus, it remains largely a mystery why women experience increased particle deposition in the lungs compared with men.

Summary & five-year view

Gender differences in susceptibility to COPD are probably multifactorial. Differential rates of growth in airway size and caliber, inflammatory and repair responses in the airway and particle deposition of fine and ultrafine particles may contribute in some way to the increased vulnerability of female smokers to COPD. However, there remains many unanswered questions. For instance, it is not known why adolescent girls who smoke experience stunted lung growth, while teenage boys who smoke do not experience this impairment. Furthermore, it is not clear how female sex hormones (or male sex hormones) regulate key pathways in the airways to increase the susceptibility of the female lungs to COPD changes. It is also not certain how and why particle deposition of ultrafine and fine (but not large) particles is increased in the female lungs (compared with male lungs) even when tidal volume and respiratory rate are fully controlled and lung volumes are accounted for. Finally, the impact of menopause and the aging process on the risk of COPD in the female population is mostly unknown and unexplored. With the growing number of female smokers around the world (and the epidemic of COPD in the female population), there is a pressing need to address these and other questions relevant to sexual dimorphism in COPD.

Financial & competing interests disclosure

DD Sin is supported by a Canada Research Chair in chronic obstructive pulmonary disease. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.