Extracellular Zinc and ATP Restore Chloride Secretion across Cystic Fibrosis Airway Epithelia by Triggering Calcium Entry

Abstract

] i was measured in non-polarized human CF (IB3-1) and non-CF (16HBE14o ؊ ) airway epithelial cells. Primary human CF and non-CF airway epithelial monolayers as well as Calu-3 monolayers were used to assess anion secretion. In vivo nasal potential difference measurements were performed in non-CF and two different CF mouse (⌬F508 homozygous and bitransgenic gut-corrected but lung-null) models. Zinc and ATP induced a sustained, reversible, and reproducible increase in cytosolic Ca 2؉ in CF and non-CF cells with chemistry and pharmacology most consistent with activation of P2X purinergic receptor channels. P2X purinergic receptor channel-mediated Ca 2؉ entry stimulated sustained Cl ؊ and HCO 3 ؊ secretion in CF and non-CF epithelial monolayers. In non-CF mice, zinc and ATP induced a significant Cl ؊ secretory response similar to the effects of agonists that increase intracellular cAMP levels. More importantly, in both CF mouse models, Cl ؊ permeability of nasal epithelia was restored in a sustained manner by zinc and ATP. These effects were reversible and reacquirable upon removal and readdition of agonists. Our data suggest that activation of P2X calcium entry channels may have profound therapeutic benefit for CF that is independent of cystic fibrosis transmembrane conductance regulator genotype.

Non-diluted seawater enhances nasal ciliary beat frequency and wound repair speed compared to diluted seawater and normal saline

“…Indeed, calcium ions are well known for their implication in ciliary beat regulation 45, 46, 47. Potassium, magnesium, and zinc ions have been shown to assist in epithelial wound repair 48, 49, 50. Diluted seawater solutions contain far lower mineral content due to dilution.…”

Proteomic and ionomic profiling reveals significant alterations of protein expression and calcium homeostasis in cystic fibrosis cells

“…Finally, it should be reminded that it is known that extracellular Zn 2+ improves Ca 2+ mediated Cl À efflux by regulation of ATP-gated P2 purinergic ionotropic receptors (P2X). 47 Activation of P2X Ca 2+ entry channels may have therapeutic benefit for CF independently of the CFTR genotype. 48 Our data show that Ca and Zn are strongly correlated in IB3-1 cells, suggesting that there could be a further Zn-activated mechanism resulting in increased [Ca 2+ ] i .…”

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

“…Further, there is evidence that Zn stabilizes lipid membranes and prevents peroxidation. Some alternative chloride channels that are Zn sensitive might even be targets for CF therapy [157].…”