17beta-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia.
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.
Coakley
Ray D
RD
Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Sun
Hengrui
H
Clunes
Lucy A
LA
Rasmussen
Julia E
JE
Stackhouse
James R
JR
Okada
Seiko F
SF
Fricks
Ingrid
I
Young
Steven L
SL
Tarran
Robert
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D020545:Respiratory Mucosa; D012737:Sex Factors; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D014867:Water / Q000378:metabolism*
C505032:CFTR protein, human; D002712:Chlorides; D004965:Estrogen Antagonists; D014867:Water; D013629:Tamoxifen; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004958:Estradiol; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D002118:Calcium