Abstract
Male cystic fibrosis (CF) patients survive longer than females and lung exacerbations in CF females vary during the estrous cycle. Estrogen has been reported to reduce the height of the airway surface liquid (ASL) in female CF bronchial epithelium. Here we investigated the effect of 17β-estradiol on the airway surface liquid height and ion transport in normal (NuLi-1) and CF (CuFi-1) bronchial epithelial monolayers. Live cell imaging using confocal microscopy revealed that airway surface liquid height was significantly higher in the non-CF cells compared to the CF cells. 17β-estradiol (0.1–10 nM) reduced the airway surface liquid height in non-CF and CF cells after 30 min treatment. Treatment with the nuclear-impeded Estrogen Dendrimer Conjugate mimicked the effect of free estrogen by reducing significantly the airway surface liquid height in CF and non-CF cells. Inhibition of chloride transport or basolateral potassium recycling decreased the airway surface liquid height and 17β-estradiol had no additive effect in the presence of these ion transporter inhibitors. 17β-estradiol decreased bumetanide-sensitive transepithelial short-circuit current in non-CF cells and prevented the forskolin-induced increase in ASL height. 17β-estradiol stimulated an amiloride-sensitive transepithelial current and increased ouabain-sensitive basolateral short-circuit current in CF cells. 17β-estradiol increased PKCδ activity in CF and non-CF cells. These results demonstrate that estrogen dehydrates CF and non-CF ASL, and these responses to 17β-estradiol are non-genomic rather than involving the classical nuclear estrogen receptor pathway. 17β-estradiol acts on the airway surface liquid by inhibiting cAMP-mediated chloride secretion in non-CF cells and increasing sodium absorption via the stimulation of PKCδ, ENaC and the Na+/K+ATPase in CF cells.
Highlights
In a study from 2010, Chotirmall et al showed that estrogen inhibited the NF-kB signalling pathway, leading to a decrease in IL-8 secretion in cystic fibrosis (CF) bronchial epithelial cells
We found that physiological concentrations of estrogen decreased airway surface liquid (ASL) height in both non-CF and CF bronchial epithelial cell lines but that it is still higher in non-CF cells than in CF cells
The E2-induced decrease in ASLh might seem modest, the height of the ASL in normal human bronchial epithelium has been shown to be in the range of 7 to 9 mm and this height is critical for efficient mucociliary clearance
Summary
17b-estradiol (E2) is the most potent circulating estrogen hormone during the reproductive years of women. CF male mice treated with estrogen showed an aggravation of P. aeruginosa, induced pneumonia, an up-regulation of the immune adaptative Th17 response and a decrease in the innate antibacterial immune response compared to untreated CF male mice [24] From these studies it appears that estrogen is deleterious to CF female lung function and that the deterioration of the CF condition seen in girls at puberty is due to an elevation of estrogen levels in the body. In this study we uncover an anti-secretory and pro-absortive effect of estrogen in non-CF and CF airway epithelia, respectively These responses occur via inhibition of Cl2 transport and K+ recycling (anti-secretion in non-CF) and stimulation of ENaC and Na+/K+ ATPase (in CF) that decrease ASL hydration in both cell types. These ion transporter and ASL responses to estrogen occur as a non-genomic effect via ERa and may underlie estrogen effects in vivo to exacerbate lung function especially in CF, when secretion is already compromised through the lack of functional CFTR
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