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CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated Cl<jats:sup>\u2212<\/jats:sup> channel controlled in part by the adenosine A<jats:sub>2B<\/jats:sub> receptor. An alternative CFTR-independent mechanism of fluid secretion is regulated by ATP via the P2Y<jats:sub>2<\/jats:sub> receptor (P2Y<jats:sub>2<\/jats:sub>R) that activates Ca<jats:sup>2+<\/jats:sup>-regulated Cl<jats:sup>\u2212<\/jats:sup> channels (CaCC\/TMEM16) and inhibits Na<jats:sup>+<\/jats:sup> absorption. However, due to rapid ATP hydrolysis, steady-state ATP levels in CF airway surface liquid (ASL) are inadequate to maintain P2Y<jats:sub>2<\/jats:sub>R-mediated fluid secretion. Therefore, inhibiting airway epithelial ecto-ATPases to increase ASL ATP levels constitutes a strategy to restore airway surface hydration in CF. Using [\u03b3<jats:sup>32<\/jats:sup>P]ATP as radiotracer, we assessed the effect of a series of ATPase inhibitory compounds on the stability of physiologically occurring ATP concentrations. We identified the polyoxometalate [Co<jats:sub>4<\/jats:sub>(H<jats:sub>2<\/jats:sub>O)<jats:sub>2<\/jats:sub>(PW<jats:sub>9<\/jats:sub>O<jats:sub>34<\/jats:sub>)<jats:sub>2<\/jats:sub>]<jats:sup>10\u2212<\/jats:sup> (POM-5) as the most potent and effective ecto-ATPase inhibitor in CF airway epithelial cells. POM-5 caused long-lasting inhibition of ATP hydrolysis in airway epithelia, which was reversible upon removal of the inhibitor. Importantly, POM-5 markedly enhanced steady-state levels of released ATP, promoting increased ASL volume in CF cell surfaces. These results provide proof of concept for ecto-ATPase inhibitors as therapeutic agents to restore hydration of CF airway surfaces. As a test of this notion, cell-free sputum supernatants from CF subjects were studied and found to have abnormally elevated ATPase activity, which was markedly inhibited by POM-5. <\/jats:p>","DOI":"10.1152\/ajplung.00449.2019","type":"journal-article","created":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T15:47:02Z","timestamp":1575474422000},"page":"L356-L365","source":"Crossref","is-referenced-by-count":12,"title":["Inhibition of ATP hydrolysis restores airway surface liquid production in cystic fibrosis airway epithelia"],"prefix":"10.1152","volume":"318","author":[{"given":"Catharina","family":"van Heusden","sequence":"first","affiliation":[{"name":"Marsico Lung Institute\/UNC CF Research Center, University of North Carolina, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Button","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute\/UNC CF Research Center, University of North Carolina, Chapel 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