{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:05:59Z","timestamp":1790982359889,"version":"4.1.0"},"reference-count":83,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2012,10,1]],"date-time":"2012-10-01T00:00:00Z","timestamp":1349049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"explicit-label\"><jats:list-item><jats:p>The mechanisms of anion and fluid transport by airway submucosal glands are not well understood and may differ from those in surface epithelium.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>The Calu\u20103 cell line is often used as a model for submucosal gland serous cells and has cAMP\u2010stimulated fluid secretion; however, it does not actively transport chloride under short\u2010circuit conditions.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>In this study we show that fluid secretion requires chloride, bicarbonate and sodium, that chloride is the predominant anion in Calu\u20103 secretions, and that a large fraction of the basolateral chloride loading during cAMP stimulation occurs by Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>exchange.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>The results suggest a novel cellular model for anion and fluid secretion by Calu\u20103 and submucosal gland acinar cells<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><jats:p><jats:bold>Abstract\u2002<\/jats:bold>Anion and fluid secretion are both defective in cystic fibrosis (CF); however, the transport mechanisms are not well understood. In this study, Cl<jats:sup>\u2212<\/jats:sup>and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>secretion was measured using genetically matched CF transmembrane conductance regulator (CFTR)\u2010deficient and CFTR\u2010expressing cell lines derived from the human airway epithelial cell line Calu\u20103. Forskolin stimulated the short\u2010circuit current (<jats:italic>I<\/jats:italic><jats:sub>sc<\/jats:sub>) across voltage\u2010clamped monolayers, and also increased the equivalent short\u2010circuit current (<jats:italic>I<\/jats:italic><jats:sub>eq<\/jats:sub>) calculated under open\u2010circuit conditions.<jats:italic>I<\/jats:italic><jats:sub>sc<\/jats:sub>was equivalent to the HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>net flux measured using the pH\u2010stat technique, whereas<jats:italic>I<\/jats:italic><jats:sub>eq<\/jats:sub>was the sum of the Cl<jats:sup>\u2212<\/jats:sup>and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>net fluxes.<jats:italic>I<\/jats:italic><jats:sub>eq<\/jats:sub>and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>fluxes were increased by bafilomycin and ZnCl<jats:sub>2<\/jats:sub>, suggesting that some secreted HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>is neutralized by parallel electrogenic H<jats:sup>+<\/jats:sup>secretion.<jats:italic>I<\/jats:italic><jats:sub>eq<\/jats:sub>and fluid secretion were dependent on the presence of both Na<jats:sup>+<\/jats:sup>and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>. The carbonic anhydrase inhibitor acetazolamide abolished forskolin stimulation of<jats:italic>I<\/jats:italic><jats:sub>eq<\/jats:sub>and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>secretion, suggesting that HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>transport under these conditions requires catalysed synthesis of carbonic acid. Cl<jats:sup>\u2212<\/jats:sup>was the predominant anion in secretions under all conditions studied and thus drives most of the fluid transport. Nevertheless, 50\u201370% of Cl<jats:sup>\u2212<\/jats:sup>and fluid transport was bumetanide\u2010insensitive, suggesting basolateral Cl<jats:sup>\u2212<\/jats:sup>loading by a sodium\u2013potassium\u2013chloride cotransporter 1 (NKCC1)\u2010independent mechanism. Imposing a transepithelial HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>gradient across basolaterally permeabilized Calu\u20103 cells sustained a forskolin\u2010stimulated current, which was sensitive to CFTR inhibitors and drastically reduced in CFTR\u2010deficient cells. Net HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>secretion was increased by bilateral Cl<jats:sup>\u2212<\/jats:sup>removal and therefore did not require apical Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>exchange. The results suggest a model in which most HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>is recycled basolaterally by exchange with Cl<jats:sup>\u2212<\/jats:sup>, and the resulting HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>\u2010dependent Cl<jats:sup>\u2212<\/jats:sup>transport provides an osmotic driving force for fluid secretion.<\/jats:p>","DOI":"10.1113\/jphysiol.2012.236893","type":"journal-article","created":{"date-parts":[[2012,7,10]],"date-time":"2012-07-10T15:19:46Z","timestamp":1341933586000},"page":"5273-5297","source":"Crossref","is-referenced-by-count":38,"title":["Bicarbonate\u2010dependent chloride transport drives fluid secretion by the human airway epithelial cell line 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