17β-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia

Abstract

Normal airways homeostatically regulate the volume of airway surface liquid (ASL) through both cAMP-and Ca 2+ -dependent regulation of ion and water transport. In cystic fibrosis (CF), a genetic defect causes a lack of cAMP-regulated CFTR activity, leading to diminished Cl -and water secretion from airway epithelial cells and subsequent mucus plugging, which serves as the focus for infections. Females with CF exhibit reduced survival compared with males with CF, although the mechanisms underlying this sex-related disadvantage are unknown. Despite the lack of CFTR, CF airways retain a limited capability to regulate ASL volume, as breathing-induced ATP release activates salvage purinergic pathways that raise intracellular Ca 2+ concentration to stimulate an alternate pathway to Cl -secretion. We hypothesized that estrogen might affect this pathway by reducing the ability of airway epithelia to respond appropriately to nucleotides. We found that uridine triphosphate-mediated (UTP-mediated) Cl -secretion was reduced during the periovulatory estrogen maxima in both women with CF and normal, healthy women. Estrogen also inhibited Ca 2+ signaling and ASL volume homeostasis in non-CF and CF airway epithelia by attenuating Ca 2+ influx. This inhibition of Ca 2+ signaling was prevented and even potentiated by estrogen antagonists such as tamoxifen, suggesting that antiestrogens may be beneficial in the treatment of CF lung disease because they increase Cl -secretion in the airways.

Sputum Biomarkers of Inflammation and Lung Function Decline in Children with Cystic Fibrosis

“…We focused on a panel of proteases, antiproteases, and cytokines because of their purported role in airway inflammation and supporting data in the CF literature and because we hypothesized that a change in airway proteolytic activity would relate to changes in lung function. Future studies need to consider other candidate biomarkers, such as high mobility group box protein-1 (35) or calprotectin (36), or explore the effects of other potential disease-modifying pathways, such as hormonal changes, which have been implicated in CF disease progression (37). It will also be important to compare the relative value of systemic biomarkers measured in blood and urine to local biomarkers assessed in sputum for monitoring CF disease activity and progression.…”

Bacterial host interactions in cystic fibrosis

“…Female CF patients have poorer survival rates than males. This has been attributed to estradiol reducing the ASL volume of CF epithelia in vitro [26]. More recently, treatment of P. aeruginosa-infected male CFTR-knockout mice with 17b-estradiol resulted in an increased secretion of pro-inflammatory-chemokines and chemoattractant-chemokines compared to controls [27], indicating that estrogens also have a direct effect on host response.…”

Pulmonary Inflammation in Cystic Fibrosis: Impact of Innate Immunity and Estrogen

“…As E 2 can play an antiinflammatory role in both CF and non-CF contexts, we hypothesized that, although uncontrolled chronic inflammation is damaging over a prolonged time period, surges of acute inflammation in the setting of an acute bacterial exacerbation in CF may, in fact, provide protection. This "protective" acute inflammatory burst is compromised during E 2 exposure in female patients with CF and, taken with the fact that E 2 compromises the ASL, high circulating E 2 levels in female patients can confer both a higher initial risk of infection and a subsequent blunted response to such infection [53]. Whether similar events occur during viral exacerbations remains to be determined.…”