{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T22:22:45Z","timestamp":1758925365160},"reference-count":89,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,7,1]]},"abstract":"<jats:p>Airway submucosal glands contribute to airway surface liquid (ASL) composition and volume, both important for lung mucociliary clearance. Serous acini generate most of the fluid secreted by glands, but the molecular mechanisms remain poorly characterized. We previously described cholinergic-regulated fluid secretion driven by Ca2+-activated Cl\u2212 secretion in primary murine serous acinar cells revealed by simultaneous differential interference contrast (DIC) and fluorescence microscopy. Here, we evaluated whether Ca2+-activated Cl\u2212 secretion was accompanied by secretion of HCO3\u2212, possibly a critical ASL component, by simultaneous measurements of intracellular pH (pHi) and cell volume. Resting pHi was 7.17 \u00b1 0.01 in physiological medium (5% CO2\u201325 mM HCO3\u2212). During carbachol (CCh) stimulation, pHi fell transiently by 0.08 \u00b1 0.01 U concomitantly with a fall in Cl\u2212 content revealed by cell shrinkage, reflecting Cl\u2212 secretion. A subsequent alkalinization elevated pHi to above resting levels until agonist removal, whereupon it returned to prestimulation values. In nominally CO2\u2013HCO3\u2212-free media, the CCh-induced acidification was reduced, whereas the alkalinization remained intact. Elimination of driving forces for conductive HCO3\u2212 efflux by ion substitution or exposure to the Cl\u2212 channel inhibitor niflumic acid (100 \u03bcM) strongly inhibited agonist-induced acidification by &amp;gt;80% and &amp;gt;70%, respectively. The Na+\/H+ exchanger (NHE) inhibitor dimethylamiloride (DMA) increased the magnitude (greater than twofold) and duration of the CCh-induced acidification. Gene expression profiling suggested that serous cells express NHE isoforms 1\u20134 and 6\u20139, but pharmacological sensitivities demonstrated that alkalinization observed during both CCh stimulation and pHi recovery from agonist-induced acidification was primarily due to NHE1, localized to the basolateral membrane. These results suggest that serous acinar cells secrete HCO3\u2212 during Ca2+-evoked fluid secretion by a mechanism that involves the apical membrane secretory Cl\u2212 channel, with HCO3\u2212 secretion sustained by activation of NHE1 in the basolateral membrane. In addition, other Na+-dependent pHi regulatory mechanisms exist, as evidenced by stronger inhibition of alkalinization in Na+-free media.<\/jats:p>","DOI":"10.1085\/jgp.200810017","type":"journal-article","created":{"date-parts":[[2008,6,30]],"date-time":"2008-06-30T19:48:39Z","timestamp":1214855319000},"page":"161-183","update-policy":"http:\/\/dx.doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["HCO3\u2212 Secretion by Murine Nasal Submucosal Gland Serous Acinar Cells during Ca2+-stimulated Fluid Secretion"],"prefix":"10.1085","volume":"132","author":[{"given":"Robert J.","family":"Lee","sequence":"first","affiliation":[{"name":"1Department of Physiology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janice M.","family":"Harlow","sequence":"additional","affiliation":[{"name":"1Department of Physiology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria P.","family":"Limberis","sequence":"additional","affiliation":[{"name":"3Department of Pathology and Laboratory Medicine, Division of Medical Genetics, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James M.","family":"Wilson","sequence":"additional","affiliation":[{"name":"3Department of Pathology and Laboratory Medicine, Division of Medical Genetics, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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