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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

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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 7

Antiestrogens reverse the adverse effects of E2 on ASL volume homeostasis.

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Antiestrogens reverse the adverse effects of E2 on ASL volume homeostasi...
(A) Mean change in fura-2 emission ratio in JME cells exposed to ATP (10 μM) and vehicle or ATP and either 10 nM E2, E2 and 1 μM ICI182780, ICI182780, E2 with 10 μM TXN, and ICI182780, or 10 μM TXN. All n = 6. (B and C) ASL height measured by XZ confocal microscopy in non-CF and CF HBECs, respectively. 200 μM mucosal ATP addition (squares); 200 μM mucosal ATP and 200 μM mucosal TXN (circles); 200 μM mucosal ATP and 200 μM mucosal TXN and 10 nM serosal E2 (triangles). (D) ASL height over time in non-CF (closed symbols) and CF (open symbols) HBECs with TXN ± bumetanide. Squares, 200 μM mucosal TXN; triangles, 200 μM mucosal TXN and 10 μM serosal bumetanide. All data shown as mean ± SEM. *P < 0.05 compared with ATP or TXN alone. †P < 0.05 versus 0 minutes.

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