{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T09:34:03Z","timestamp":1770975243526,"version":"3.50.1"},"reference-count":79,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["CRC \u20102021 \u201000289"],"award-info":[{"award-number":["CRC \u20102021 \u201000289"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The airway epithelium serves as the first line of defense against inhaled insults present in the external environment by acting as a physical barrier and through host defense mechanisms. Proper maintenance of these host defense mechanisms relies on the regulation of airway surface liquid (ASL) composition and properties, a process that is tightly controlled by various ion transporters, including the cystic fibrosis transmembrane conductance regulator (CFTR) protein. With evidence suggesting dysfunctional CFTR\u2010mediated bicarbonate secretion leads to airway acidification, resulting in impaired host defenses, there is increased interest in improving ASL pH. The aim of our study was to determine whether pharmacological interventions, via cAMP and CFTR modulators, lead to an increase in pH. Human airway epithelial (Calu\u20103) cells were exposed to various combinations of cAMP and CFTR modulating agents to assess their effectiveness at elevating apical base secretions (apical fluid) pH. Our results show that pharmacological interventions with cAMP elevating agents and CFTR modulator VX\u2010770 led to significant increases in pH, with combinations leading to greater increases compared to single drug interventions. Our study suggests that cAMP and CFTR modulation has potential as a therapeutic strategy for elevating ASL pH and may be beneficial for respiratory diseases with ASL abnormalities.<\/jats:p>","DOI":"10.14814\/phy2.70747","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T05:17:02Z","timestamp":1770182222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of\n                    <scp>cAMP<\/scp>\n                    and\n                    <scp>CFTR<\/scp>\n                    modulation on apical fluid\n                    <scp>pH<\/scp>\n                    in human airway Calu\u20103 cells"],"prefix":"10.14814","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2952-6877","authenticated-orcid":false,"given":"Jenny P.","family":"Nguyen","sequence":"first","affiliation":[{"name":"Division of Respirology, Department of Medicine, Firestone Institute for Respiratory Health McMaster University  Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Milad","sequence":"additional","affiliation":[{"name":"Division of Respirology, Department of Medicine, Firestone Institute for Respiratory Health McMaster University  Hamilton Ontario Canada"},{"name":"McMaster Immunology Research Centre McMaster University  Hamilton Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2429-4165","authenticated-orcid":false,"given":"Jeremy A.","family":"Hirota","sequence":"additional","affiliation":[{"name":"Division of Respirology, Department of Medicine, Firestone Institute for Respiratory Health McMaster University  Hamilton Ontario Canada"},{"name":"McMaster Immunology Research Centre McMaster University  Hamilton Ontario Canada"},{"name":"Division of Respiratory Medicine, Department of Medicine University of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Biology University of Waterloo  Waterloo Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"issue":"15","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.121468","article-title":"Ivacaftor\u2010induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis","volume":"3","author":"Abou Alaiwa M. H.","year":"2018","journal-title":"JCI Insight"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0909825"},{"issue":"1","key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41525-017-0015-6","article-title":"Phenotypic profiling of CFTR modulators in patient\u2010derived respiratory epithelia","volume":"2","author":"Ahmadi S.","year":"2017","journal-title":"NPJ Genomic Medicine"},{"issue":"52","key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"18703","DOI":"10.1073\/pnas.1422091112","article-title":"pH modulates the activity and synergism of the airway surface liquid antimicrobials \u03b2\u2010defensin\u20103 and LL\u201037","volume":"111","author":"Alaiwa M. H. A.","year":"2014","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_9_6_1","volume-title":"ALYFTREK (Vanzacaftor\/Tezacaftor\/Deutivacaftor) Package Insert","year":"2025"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1712984"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90155-6"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2014.02.009"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(14)70132-8"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21440"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90446-6"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2634339100"},{"issue":"3","key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1165\/rcmb.2002-0247OC","article-title":"Adenosine receptors and phosphodiesterase inhibitors stimulate Cl\u2014secretion in Calu\u20103 cells","volume":"29","author":"Cobb B. R.","year":"2003","journal-title":"American Journal of Respiratory Cell and Molecular Biology"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0156OC"},{"issue":"20","key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"9262","DOI":"10.1073\/pnas.88.20.9262","article-title":"Immunocytochemical localization of the cystic fibrosis gene product CFTR","volume":"88","author":"Crawford I.","year":"1991","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"1","key":"e_1_2_9_17_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-83189-x","article-title":"PHAIR: A biosensor for pH measurement in air\u2013liquid interface cell culture","volume":"11","author":"Dabaghi M.","year":"2021","journal-title":"Scientific Reports"},{"issue":"47","key":"e_1_2_9_18_1","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2307551120","article-title":"Dynamic regulation of airway surface liquid pH by TMEM16A and SLC26A4 in cystic fibrosis nasal epithelia with rare mutations","volume":"120","author":"Delpiano L.","year":"2023","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"1","key":"e_1_2_9_19_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1172\/JCI115582","article-title":"Localization of cystic fibrosis transmembrane conductance regulator in chloride secretory epithelia","volume":"89","author":"Denning G. M.","year":"1992","journal-title":"Journal of Clinical Investigation"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.393637"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50641-1"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.164944"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201600223R"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2015-207588"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00141514"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(24)00407-7"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13641"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.131087598"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2001.281.5.C1504"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215982110"},{"issue":"1","key":"e_1_2_9_31_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-98122-5","article-title":"Combined agonists act synergistically to increase mucociliary clearance in a cystic fibrosis airway model","volume":"11","author":"Joo N. S.","year":"2021","journal-title":"Scientific Reports"},{"key":"e_1_2_9_32_1","volume-title":"KALYDECO (Ivacaftor) Package Insert","year":"2025"},{"issue":"3","key":"e_1_2_9_33_1","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S2213-2600(24)00411-9","article-title":"Vanzacaftor\u2013tezacaftor\u2013deutivacaftor versus elexacaftor\u2013tezacaftor\u2013ivacaftor in individuals with cystic fibrosis aged 12\u2009years and older (SKYLINE trials VX20\u2010121\u2010102 and VX20\u2010121\u2010103): Results from two randomised, active\u2010controlled, phase 3 trials","volume":"13","author":"Keating C.","year":"2025","journal-title":"The Lancet Respiratory Medicine"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1807120"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2018-0158OC"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0215217"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201010518"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0228OC"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.09.037"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.04.046"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw7611"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231911396"},{"issue":"11","key":"e_1_2_9_43_1","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1172\/JCI0216112","article-title":"Thiazolidinone CFTR inhibitor identified by high\u2010throughput screening blocks cholera toxin\u2010induced intestinal fluid secretion","volume":"110","author":"Ma T.","year":"2002","journal-title":"The Journal of Clinical Investigation"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12726"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908639"},{"issue":"2","key":"e_1_2_9_46_1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1085\/jgp.200409059","article-title":"Discovery of glycine hydrazide pore\u2010occluding CFTR inhibitors: Mechanism, structure\u2010activity analysis, and in\u00a0vivo efficacy","volume":"124","author":"Muanprasat C.","year":"2004","journal-title":"The Journal of General Physiology"},{"issue":"1","key":"e_1_2_9_47_1","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1073\/pnas.0135434100","article-title":"A macromolecular complex of \u03b22 adrenergic receptor, CFTR, and ezrin\/radixin\/moesin\u2010binding phosphoprotein 50 is regulated by PKA","volume":"7","author":"Naren A. P.","year":"2003","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"1","key":"e_1_2_9_48_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-79555-w","article-title":"Modulation of cAMP metabolism for CFTR potentiation in human airway epithelial cells","volume":"11","author":"Nguyen J. P.","year":"2021","journal-title":"Scientific Reports"},{"issue":"6","key":"e_1_2_9_49_1","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1165\/rcmb.2018-0414ED","article-title":"Ion the prize: Defining the complexities of airway epithelial cell ion transport functions","volume":"60","author":"Nguyen J. P.","year":"2019","journal-title":"American Journal of Respiratory Cell and Molecular Biology"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2021.105253"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.080267"},{"key":"e_1_2_9_52_1","volume-title":"ORKAMBI (Lumacaftor\/Ivacaftor) Package Insert","year":"2025"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11130"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)42339-3"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1105185"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI150398"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12081104"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2475911"},{"issue":"20","key":"e_1_2_9_59_1","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.123616","article-title":"Increased expression of ATP12A proton pump in cystic fibrosis airways","volume":"3","author":"Scudieri P.","year":"2018","journal-title":"JCI Insight"},{"issue":"6","key":"e_1_2_9_60_1","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1073\/pnas.78.6.3363","article-title":"Forskolin: Unique diterpene activator of adenylate cyclase in membranes and in intact cells","volume":"78","author":"Seamon K. B.","year":"1981","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad5589"},{"issue":"21","key":"e_1_2_9_62_1","doi-asserted-by":"crossref","first-page":"5273","DOI":"10.1113\/jphysiol.2012.236893","article-title":"Bicarbonate\u2010dependent chloride transport drives fluid secretion by the human airway epithelial cell line Calu\u20103","volume":"590","author":"Shan J.","year":"2012","journal-title":"Journal of Physiology"},{"issue":"1","key":"e_1_2_9_63_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-019-42751-4","article-title":"Airway surface liquid acidification initiates host defense abnormalities in cystic fibrosis","volume":"9","author":"Simonin J.","year":"2019","journal-title":"Scientific Reports"},{"issue":"4","key":"e_1_2_9_64_1","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1172\/JCI115696","article-title":"cAMP stimulates bicarbonate secretion across normal, but not cystic fibrosis airway epithelia","volume":"89","author":"Smith J. J.","year":"1992","journal-title":"Journal of Clinical Investigation"},{"key":"e_1_2_9_65_1","volume-title":"SYMDEKO (Tezacaftor\/Ivacaftor) Package Insert","year":"2025"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI83922"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709846"},{"key":"e_1_2_9_68_1","volume-title":"TRIKAFTA (Elexacaftor\/Tezacaftor\/Ivacaftor) Package Insert","year":"2025"},{"issue":"10","key":"e_1_2_9_69_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/ajplung.00395.2014","article-title":"Roflumilast combined with adenosine increases mucosal hydration in human airway epithelial cultures after cigarette smoke exposure","volume":"308","author":"Tyrrell J.","year":"2015","journal-title":"American Journal of Physiology. Lung Cellular and Molecular Physiology"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(22)00504-5"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904709106"},{"issue":"15","key":"e_1_2_9_72_1","doi-asserted-by":"crossref","first-page":"18843","DOI":"10.1073\/pnas.1105787108","article-title":"Correction of the F508del\u2010CFTR protein processing defect in\u00a0vitro by the investigational drug VX\u2010809","volume":"108","author":"Van Goor F.","year":"2011","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"19","key":"e_1_2_9_73_1","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.2174\/13816128113199990321","article-title":"CFTR inhibitors","volume":"19","author":"Verkman A. S.","year":"2013","journal-title":"Current Pharmaceutical Design"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01661-2015"},{"issue":"18","key":"e_1_2_9_75_1","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1056\/NEJMc1510466","article-title":"Lumacaftor\u2010ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR","volume":"373","author":"Wainwright C. E.","year":"2015","journal-title":"The New England Journal of Medicine"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/38514"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2316675121"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073384"},{"key":"e_1_2_9_79_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3389\/fphar.2023.1293578","article-title":"Putting bicarbonate on the spot: Pharmacological insights for CFTR correction in the airway epithelium","volume":"14","author":"Zajac M.","year":"2023","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1815287115"}],"container-title":["Physiological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.70747","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.14814\/phy2.70747","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.70747","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:17:20Z","timestamp":1770970640000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.14814\/phy2.70747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":79,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.14814\/phy2.70747"],"URL":"https:\/\/doi.org\/10.14814\/phy2.70747","archive":["Portico"],"relation":{},"ISSN":["2051-817X","2051-817X"],"issn-type":[{"value":"2051-817X","type":"print"},{"value":"2051-817X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2]]},"assertion":[{"value":"2025-10-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70747"}}