{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:37:44Z","timestamp":1790080664525,"version":"4.0.1"},"reference-count":64,"publisher":"Wiley","issue":"S7","license":[{"start":{"date-parts":[[2015,5,6]],"date-time":"2015-05-06T00:00:00Z","timestamp":1430870400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Institutes of Health (NIH)\/National Heart, Lung, and Blood Institute","award":["1K08HL107142-05"],"award-info":[{"award-number":["1K08HL107142-05"]}]},{"DOI":"10.13039\/100000062","name":"NIH\/National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["5P30DK072482-04"],"award-info":[{"award-number":["5P30DK072482-04"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Laryngoscope"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:sec><jats:title>Objective\/Hypothesis<\/jats:title><jats:p>Ineffective mucociliary clearance (MCC) is a common pathophysiologic process that underlies airway inflammation and infection. A dominant fluid and electrolyte secretory pathway in the nasal airways is governed by the cystic fibrosis transmembrane conductance regulator (CFTR). Decreased transepithelial Cl<jats:sup>\u2212<\/jats:sup> transport secondary to an acquired CFTR deficiency may exacerbate respiratory epithelial dysfunction by diminishing MCC and increasing mucus viscosity. The objectives of the present study are to 1) develop a model of acquired CFTR deficiency in sinonasal epithelium using hypoxia, 2) investigate whether the polyphenol resveratrol promotes CFTR\u2010mediated anion transport, 3) explore resveratrol mechanism of action and determine therapeutic suitability for overcoming acquired CFTR defects, and 4) test the drug in the hypoxic model of acquired CFTR deficiency in preparation for a clinical trial in human sinus disease. We hypothesize that hypoxia will induce depletion of airway surface liquid (ASL) secondary to acquired CFTR deficiency and that resveratrol will restore transepithelial Cl<jats:sup>\u2212<\/jats:sup> secretion and recover ASL hydration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design<\/jats:title><jats:p>Basic science.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Murine nasal septal (MNSE) and human sinonasal epithelial (HSNE) cultures were incubated under hypoxic conditions (1% O<jats:sub>2<\/jats:sub>, 5% CO<jats:sub>2<\/jats:sub>) and transepithelial ion transport (change in short\u2010circuit current\u2009=\u2009\u0394I<jats:sub>SC<\/jats:sub>) evaluated in Ussing chambers. Resveratrol was tested using primary cells and HEK293 cells expressing human CFTR by Ussing chamber and patch clamp techniques under both phosphorylating and nonphosphorylating conditions. CFTR activation was evaluated in human explants and by murine in vivo (nasal potential difference) assessment. Cellular cyclic adenosine monophosphate (cAMP) (ELISA) and subsequent CFTR regulatory domain (R\u2010D) phosphorylation (gel\u2010shift assay) were also evaluated. Effects of hypoxia and resveratrol on ASL were tested using confocal laser scanning microscopy (CLSM) and micro\u2010optical coherence tomography (\u00b5OCT).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hypoxia significantly decreased \u0394I<jats:sub>SC<\/jats:sub> (in \u00b5A\/cm<jats:sup>2<\/jats:sup>) attributable to CFTR at 12 and 24 hours of exposure in both MNSE (13.55\u2009\u00b1\u20090.46 [12 hours]; 12.75\u2009\u00b1\u20090.07 [24 hours] vs. 19.23\u2009\u00b1\u20090.18 [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) and HSNE (19.55\u2009\u00b1\u20090.56 [12 hours]; 17.67\u2009\u00b1\u20091.13 [24 hours] vs. 25.49\u2009\u00b1\u20091.48 [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). We have shown that resveratrol (100 \u03bcM) enhanced CFTR\u2010dependent Cl<jats:sup>\u2212<\/jats:sup> secretion in HSNE to an extent comparable to the recently Food and Drug Administration\u2010approved CFTR potentiator, ivacaftor. Cl<jats:sup>\u2212<\/jats:sup> transport across human sinonasal explants (78.42\u2009\u00b1\u20091.75 vs. 1.75\u2009\u00b1\u20091.5 [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) and in vivo murine nasal epithelium (\u22124\u2009\u00b1\u20091.8 vs. \u22120.8\u2009\u00b1\u20091.7 mV [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) were also significantly increased by the drug. No increase in cAMP or CFTR R\u2010D phosphorylation was detected. Inside\u2010out patches showed increased CFTR open probability (NPo\/<jats:italic>N<\/jats:italic> (<jats:italic>N<\/jats:italic>\u2009=\u2009channel number]) compared to controls in both MNSE (0.329\u2009\u00b1\u20090.116 vs. 0.119\u2009\u00b1\u20090.059 [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) and HEK293 cells (0.22\u2009\u00b1\u20090.048 vs. 0.125\u2009\u00b1\u20090.07 [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). ASL thickness was decreased under hypoxic conditions when measured by CLSM (4.19\u2009\u00b1\u20090.44 vs. 6.88\u2009\u00b1\u20090.67 [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). A 30\u2010minute apical application of resveratrol increased ASL depth in normal epithelium (8.08\u2009\u00b1\u20091.68 vs. 6.11\u2009\u00b1\u20090.47 [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Furthermore, hypoxia\u2010induced abnormalities of fluid and electrolyte secretion in sinonasal epithelium were restored with resveratrol treatment (5.55\u2009\u00b1\u20090.74 vs. 3.13\u2009\u00b1\u20090.17 [control]; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CFTR activation with a leading edge Cl<jats:sup>\u2212<\/jats:sup> secretagogue such as resveratrol represents an innovative approach to overcoming acquired CFTR defects in sinus and nasal airway disease. This exciting new strategy bears further testing in non\u2010CF individuals with chronic rhinosinusitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Level of Evidence<\/jats:title><jats:p>N\/A. <jats:italic>Laryngoscope<\/jats:italic>, 125:S1\u2013S13, 2015<\/jats:p><\/jats:sec>","DOI":"10.1002\/lary.25335","type":"journal-article","created":{"date-parts":[[2015,5,6]],"date-time":"2015-05-06T16:27:42Z","timestamp":1430929662000},"source":"Crossref","is-referenced-by-count":39,"title":["Resveratrol ameliorates abnormalities of fluid and electrolyte secretion in a hypoxia\u2010Induced model of acquired <scp>CFTR<\/scp> deficiency"],"prefix":"10.1002","volume":"125","author":[{"given":"Bradford A.","family":"Woodworth","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery University of Alabama at Birmingham Birmingham Alabama U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,5,6]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/000348941112000701"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0194-5998(95)70152-4"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1067\/mhn.2002.129815"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.154.6.8970383"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2687"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1998.274.2.L258"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(99)77250-4"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110894"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCP.0000000000000107"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.2500\/ajra.2013.27.3981"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.2500\/ajra.2013.27.3919"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.2500\/ajra.2012.26.3705"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra043184"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2002.282.1.L12"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.20223"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00305-08"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00338-07"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203154200"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00376.2004"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039809"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200508-1330OC"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001325"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.23278"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.20930"},{"key":"e_1_2_6_26_1","first-page":"103","article-title":"Mucociliary transport in chronic rhinosinusitis","volume":"20","author":"Baroody FM","year":"2007","journal-title":"Clin Allergy Immunol"},{"key":"e_1_2_6_27_1","first-page":"59","article-title":"Hypoxia induced chemokine expression in nasal epithelial cells: development of an in vitro model for chronic rhinosinusitis","volume":"23","author":"Pahl A","year":"2006","journal-title":"ALTEX"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/ACI.0b013e3282f3f488"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI0213870"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2010.12.002"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0909825"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904709106"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1373908"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.279.1.C108"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004240050424"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0896(03)00435-8"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101892200"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00351.2002"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.279.6.C1838"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-004-4422-3"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2004.02.022"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00465.2010"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2009.01.005"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00110.2004"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.12.6509"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.2144\/000112531"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.2500\/ajra.2009.23.3285"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.2500\/ajr.2008.22.3178"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.2500\/ajr.2008.22.3125"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.2500\/ajr.2007.21.3068"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21335"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0104090"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0215OC"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072398"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081589"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.20871"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2009\u20100281OC"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.otohns.2010.05.021"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.06.026"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0909825"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2007.03.002"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.1098"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.10-0179"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.21921"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.21798"}],"container-title":["The Laryngoscope"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Flary.25335","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lary.25335","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T10:01:04Z","timestamp":1695981664000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/lary.25335"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,5,6]]},"references-count":64,"journal-issue":{"issue":"S7","published-print":{"date-parts":[[2015,10]]}},"alternative-id":["10.1002\/lary.25335"],"URL":"https:\/\/doi.org\/10.1002\/lary.25335","archive":["Portico"],"relation":{},"ISSN":["0023-852X","1531-4995"],"issn-type":[{"value":"0023-852X","type":"print"},{"value":"1531-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,5,6]]}}}