17β-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia
Ray D. Coakley, … , Steven L. Young, Robert Tarran
Ray D. Coakley, … , Steven L. Young, Robert Tarran
Published November 20, 2008
Citation Information: J Clin Invest. 2008;118(12):4025-4035. https://doi.org/10.1172/JCI33893.
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Research Article

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 Ca2+-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 Ca2+ 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 Ca2+ signaling and ASL volume homeostasis in non-CF and CF airway epithelia by attenuating Ca2+ influx. This inhibition of Ca2+ 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.

Authors

Ray D. Coakley, Hengrui Sun, Lucy A. Clunes, Julia E. Rasmussen, James R. Stackhouse, Seiko F. Okada, Ingrid Fricks, Steven L. Young, Robert Tarran

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Figure 1

UTP-activated Cl– secretion changes with the menstrual cycle.

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UTP-activated Cl– secretion changes with the menstrual cycle. Female...
Females with and without CF calculated their high– and low–E2 level days based on the onset of menses, and nasal PDs were recorded at these times. White bars represent low–E2 level days and black bars represent high–E2 level days. (A and B) Typical traces showing sequential addition of amiloride, a low Cl– solution, and UTP on low and high days respectively. T, time. (C) Paired mean basal nasal PDs measured on low– and high–E2 level days (n = 12). (D) Paired mean changes in nasal PD in normal subjects on low- and high-level E2 days following amiloride addition and following perfusion of a low Cl– solution and a low Cl– solution containing 100 μM UTP added in the continued presence of amiloride to measure the UTP-activated Cl– secretory response (n = 12). In a separate experiment, perfusion of a low Cl– solution containing amiloride with 100 μM ISO in a subset of the subjects tested in A–C (n = 6). (E and F) Typical traces showing sequential addition of amiloride, a low Cl– solution with 100 μM ISO, and UTP on low- and high-level E2 days, respectively, in CF subjects. (G) Paired mean basal CF nasal PDs measured on low– and high–E2 level days (n = 10). (H) Paired mean changes in nasal PD in CF patients following amiloride addition and following perfusion of a low Cl– solution containing 100 μM ISO and a low Cl– solution containing 100 μM UTP added in the continued presence of amiloride to measure the UTP-activated Cl– secretory response (n = 10). *P < 0.05 difference in UTP secretion between low– and high–E2 level days. †P < 0.05 compared with non-CF.