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Review
. 2024 Jul 18;15(1):56.
doi: 10.1186/s13293-024-00633-z.

Sex differences in airway disease: estrogen and airway surface liquid dynamics

Brian J Harvey  1   2 , Noel G McElvaney  3
Affiliations
Review

Sex differences in airway disease: estrogen and airway surface liquid dynamics

Brian J Harvey et al. Biol Sex Differ. .

Abstract

Biological sex differences exist for many airway diseases in which females have either worse or better health outcomes. Inflammatory airway diseases such as cystic fibrosis (CF) and asthma display a clear male advantage in post-puberty while a female benefit is observed in asthma during the pre-puberty years. The influence of menstrual cycle stage and pregnancy on the frequency and severity of pulmonary exacerbations in CF and asthma point to a role for sex steroid hormones, particularly estrogen, in underpinning biological sex differences in these diseases. There are many ways by which estrogen may aggravate asthma and CF involving disturbances in airway surface liquid (ASL) dynamics, inappropriate hyper-immune and allergenic responses, as well as exacerbation of pathogen virulence. The deleterious effect of estrogen on pulmonary function in CF and asthma contrasts with the female advantage observed in airway diseases characterised by pulmonary edema such as pneumonia, acute respiratory distress syndrome (ARDS) and COVID-19. Airway surface liquid hypersecretion and alveolar flooding are hallmarks of ARDS and COVID-19, and contribute to the morbidity and mortality of severe forms of these diseases. ASL dynamics encompasses the intrinsic features of the thin lining of fluid covering the airway epithelium which regulate mucociliary clearance (ciliary beat, ASL height, volume, pH, viscosity, mucins, and channel activating proteases) in addition to innate defence mechanisms (pathogen virulence, cytokines, defensins, specialised pro-resolution lipid mediators, and metabolism). Estrogen regulation of ASL dynamics contributing to biological sex differences in CF, asthma and COVID-19 is a major focus of this review.

Keywords: Airway surface liquid; Asthma; COVID-19; Cystic fibrosis; Estrogen; Ion channels.

Plain language summary

Sex differences exist in many airway diseases in which females have either worse or better health outcomes. These include cystic fibrosis (CF) and asthma where females post-puberty have more frequent lung exacerbations and higher mortality. Lung infections and difficulty in breathing become worse in post-puberty in females and during the ovulation period of the menstrual cycle, and in pregnancy, indicating a role for sex hormones in underpinning sex differences in CF and asthma. Evidence also exists for sex differences with a female advantage in airway diseases which are characterised by flooding of the airways, as in pneumonia and COVID-19, where females have better lung function and lower risk of death than males. The female sex hormone estrogen plays an important role in determining the role of sex biology in airway disease severity and mortality. Estrogen can control the movement of salt and water in and out of the lung airway tubes and dehydrate the lung surface to make it more sticky with mucus, as observed in CF and asthma, thus worsening the condition. In contrast, estrogen can have beneficial effects in lowering the volume of water in the lungs in COVID-19 thus alleviating flooding of the airways. This review focusses on the biology of sex differences in CF, asthma and COVID-19, and the cellular mechanisms by which estrogen can have either detrimental or beneficial effects in these diseases.

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Conflict of interest statement

The authors declare they have no competing interests.

Figures

Fig. 1
Fig. 1
Sex differences in airway disease. A In cystic fibrosis, women have worse lung function exacerbations and higher mortality than men. Estrogen has aggravating effects on airway surface liquid dynamics in CF to reduce mucociliary clearance, increase mucus secretion and promote bacterial invasion and virulence. B In asthma, boys have worse lung exacerbations than girls pre-puberty, whereas women have more frequent and aggravated asthma episodes than men post-puberty. During pre-puberty, boys have dysanaptic lung development (larger and more hyperactive airways). During post-puberty, estrogen dehydrates the airway surface liquid and promotes mucus plugging of the airways and is hyper-allergenic whereas testosterone is hypo-allergenic. C In COVID-19, women have less severe morbidity and mortality than men. Sex steroids may account for this female advantage through several mechanism; X-linked genes offer enhanced immuno-protection and estrogen causes the suppression of ACE2-R expression. Together these responses reduce SARS-Cov-2 cellular invasion, inhibit inflammatory cytokines, activate the protective vasodilatory arm of RAS, and inhibit airway secretions to lower ASL height (ASLh) and reduce airway flooding. Testosterone, on the other hand, increases ACE2-R expression and is immuno-suppressant
Fig. 2
Fig. 2
Mortality and pulmonary exacerbations in airway diseases are sex-dependent. A Cystic fibrosis: Estimated median age of survival for a moving 5-year window with 95% confidence intervals, by sex, 1984 to 2020 in Canada. The sex difference in CF survival and mortality outcomes has been found in many other countries including Australia, France, UK and USA. Adapted and redrawn using data from Cystic Fibrosis Canada. (2022). The Canadian Cystic Fibrosis Registry 2020 Annual Data Report. Page 44, Retrieved on 10 October 2023 from https://www.cysticfibrosis.ca/Registry/2020AnnualDataReport.pdf. B Changes in estrogen and lung exacerbations are correlated throughout the menstrual cycle. Lung exacerbations (determined from Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) increase during peak plasma levels of 17β-estradiol (E2). During the menstruation phase, estrogen levels are low and pulmonary exacerbations are reduced. In the proliferative phase, estrogen begins to rise and peak just prior to ovulation when rates of pulmonary exacerbations are highest which then fall during ovulation and increase again during the luteal phase. Other factors contributing to lung exacerbations during high estrogen states include a more mucoid P. aeruginosa phenotype, elevated markers of inflammation (tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8) and free neutrophil elastase (NE). C Asthma prevalence percentage throughout life in developed countries. Graph based on the most up-to-date data available (2018) from the Global Health Data Exchange (https://ghdx.healthdata.org). D Asthma exacerbations (grey shaded area) according to phase of menstrual cycle and plasma E2 levels (red shaded area) when classified by symptom onset or day of emergency department visit. Asthma exacerbations began more often during the preovulatory (28%) and peri menstrual phases (27%) of the cycle than in the periovulatory or postovulatory phases. Hyper-immunoreactivity in follicular and luteal phases is shown in green shaded area corresponding to measured high TNFα, mast cells, hyper-eosinophilia and free neutrophil elastase. E Mean excess deaths associated with the Covid-19 pandemic worldwide classified by sex (female red stacks, male blue stacks) and age range. Data accessed 3 October 2023 from: https://www.statista.com/statistics/1306958/number-excess-deaths-covid-pandemic-by-age-and-gender-worldwide/. F Deaths attributable directly to COVID-19 grouped by age and sex from 8 representative countries (female red stacks, male blue stacks). The data from different countries show that male mortality is higher than females. The data for Peru, Italy, Spain, England, France, USA, and Mexico were obtained from Global Health 50/50 which was updated July 12 2023. The mortality data as of July 24 2023 for Sweden was taken from the Swedish Public Health Agency. Adapted and redrawn using data from: The COVID-19 Sex-Disaggregated Data Tracker. https://globalhealth5050.org/the-sex-gender-and-covid-19-project/the-data-tracker/?explore=variable&variable=Deaths. The Disaggregated Data Tracker is updated every month, the graph shows the last update when accessed on 3 October 2023
Fig. 3
Fig. 3
Ion transport generates the airway surface liquid height. Sodium ion absorption and chloride ion secretion generate an osmotic gradient for water flux across the airway epithelium. In healthy airways, the transepithelial transport of Na+ and Cl− is balanced so as to generate an optimal ASLh between 7 and 10 µm corresponding to the length of outstretched cilia. Sodium absorption occurs as a two-step process with sodium entry via ENaC Na+ channels in the apical membranes and then Na+ is pumped out of the cells into the blood side via Na/K-ATPase in the basolateral membranes. The electrical charge balance for Na+ absorption is generated by the activity of KATP (Kir6.1) potassium ion channels in the basolateral membranes. Inhibition of any one of these transporters (ENaC, Na/K-ATPase, KATP) will tend to decrease sodium and water absorption, and as a consequence increase ASLh, whereas stimulation of the Na+ transport pathways will decrease ASLh. Chloride ion secretion also occurs as a two-step process, with Cl− entering the airway epithelial cell across the basolateral membranes via the Na:K:2Cl cotransporter and then transported down an electrochemical gradient into the ASL via CFTR Cl− channels which support basal and cAMP-stimulated Cl− secretion. Calcium-activated CaCC Cl− channels are the pathway for calcium-activated Cl− secretion. The charge balance for CFTR-mediated Cl− secretion is provided by the cAMP activated KCNQ1:KCNE3 K+ channel, and for CaCC channels via calcium-activated KCNN4 K+ channels. Inhibition of any one the chloride ion secretion pathways will decrease water flux into the ASL and reduce ASLh, whereas stimulation of chloride ion secretion transporters will increase ASLh
Fig. 4
Fig. 4
ASL dynamics in airway diseases. A Cystic fibrosis is characterised by extremely low rates of Cl− secretion and a hyperabsorption of Na+ which can dehydrate the airway surface fluid and produce a low ASLh, dyskinetic ciliary beat, mucus plugging, inefficient mucociliary clearance and bacterial virulence. Estrogen (E2) exacerbates each one of these parameters and worsens CF lung disease in female patients. B The hallmarks of asthma are mucus hypersecretion, inflammation, and bronchoconstriction. ASLh may be normal in the asthmatic lung but mucociliary clearance is hampered by a viscous ASL and mucus plugging. Estrogen can aggravate this condition by inhibiting CFTR Cl− secretion and stimulating ENaC Na+ absorption, drawing water out of the airway fluid to further increase its viscosity as well as by stimulating mucus production and secretion. C In COVID-19, the SARS-CoV-2 virus causes severe lung inflammatory responses and fluid exudation which result in flooding of the alveoli and central airways. The hugely increased ASLh renders mucociliary clearance difficult leading to increased viral load and a vicious cycle of inflammation and airway flooding. Estrogen can alleviate ASL hydration, especially in the alveoli by stimulating Na+ absorption (which is inhibited by cytokines and TNFα in the inflammed airways), and contribute to better survival in female COVID-19 patients
Fig. 5
Fig. 5
Estrogen modulation of ASL height and cell signalling mechanisms. A Changes in ASL height produced by varying concentrations of estrogen (E2, 17β-oestradiol) in human female-derived bronchial epithelia. Low concentrations of E2 (in the range observed during the menstrual cycle) cause a rapid and sustained decrease in ASLh in normal epithelia but more so in CF epithelia to reach levels well below the height of outstretched cilia required for an effective mucociliary clearance. Adapted from [78]. B Cell signalling mechanisms for estrogen regulation of Na+ absorption and Cl− secretion which modulate ASLh. Estrogen signal transduction via a membrane estrogen receptor (mERα) stimulates Na+ absorption via transactivation of endothelial growth factor receptor EGFR, SRC kinase and matrix metalloproteases (MMP) to activate PLC and PKCδ, which in turn increase the expression and insertion of ENaC channel subunits into the apical membrane. Estrogen activation of PKCδ also phosphorylates the KCNQ1:KCNE3 K+ channel to cause its dissociation and reduced conductance which collapses the electrical driving force for Cl− secretion via CFTR. Estrogen also reduces intracellular Ca2+ and thereby inhibits Cl− secretion via CaCC and KCNN4. The rapid onset (< 1 min) of the effects of estrogen on sodium absorptive and chloride secretory ion transporters indicate a non-genomic mechanism of action, in addition to genomic responses on ion channel protein expression
Fig. 6
Fig. 6
Estrogen and dexamethasone regulation of airway Na+ absorption, Cl− secretion and ASL height. Estrogen inhibits CFTR and CaCC-mediated chloride ion secretion by inhibiting the activity of KCNQ1 and KCNN4 channels, respectively. Cl− secretion activated by cAMP agonists such as forskolin or adrenergic stimulation can be rapidly inhibited by dexamethasone or estrogen acting on KCNQ1 channels. Dexamethasone inhibition of KCNN4 channels reduces the calcium-activated Cl− secretion stimulated by purinergic (ATP) or muscarinergic (acetylcholine) agonists. Adapted and redrawn using data from [112, 161]. The diverse nature of the anti-secretory response indicates that estrogen and dexamethasone can reduce ASL height irrespective of the nature of chloride secretion transport pathways. Estrogen and dexamethasone can both stimulate Na+ absorption by increasing the expression of ENaC channel subunits into the apical membrane. The combined effects of pro-absorptive and anti-secretory actions of estrogen and dexamethasone result in increased water efflux out of the airways and lowering of ASL height which can be advantageous in reducing airway flooding in COVID-19 and alleviating morbidity and mortality in females
Fig. 7
Fig. 7
Estrogen regulated cell signalling underpinning sex differences in lung disease. Estrogen targets ion transport pathways mediating sodium absorption and chloride secretion in airway epithelial cells. Estrogen activates ENaC and stimulates Na+ and water flux out of the airways while inhibiting CFTR and CaCC ion channel mediated Cl− secretion and water flux into the airway. These ion transport responses synergise to lower ASL height. The rapid action of estrogen on ion channel activity indicate membrane-initiated ‘non-genomic’ signal transduction via membrane estrogen receptors such as mERα. Although the pro-absorptive and anti-secretory responses to estrogen are rapid, they are also long-lasting, most likely as a result of sustained protein kinase phosphorylation of the ion channels and delayed genomic activation of mRNA expression of ion channel subunits. Estrogen effects on ASLh may also synergise with the repression of pro-inflammatory cytokines and anti-inflammatory/pro-resolution actions which are transduced by genomic signalling via nuclear estrogen receptors.
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