{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:50:02Z","timestamp":1790887802392,"version":"4.1.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2014,3,1]],"date-time":"2014-03-01T00:00:00Z","timestamp":1393632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cigarette smoking causes acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction and is associated with delayed mucociliary clearance and chronic bronchitis. Roflumilast is a clinically approved phosphodiesterase 4 inhibitor that improves lung function in patients with chronic bronchitis. We hypothesized that its therapeutic benefit was related in part to activation of CFTR. Primary human bronchial epithelial (HBE) cells, Calu-3, and T84 monolayers were exposed to whole cigarette smoke (WCS) or air with or without roflumilast treatment. CFTR-dependent ion transport was measured in modified Ussing chambers. Airway surface liquid (ASL) was determined by confocal microscopy. Intestinal fluid secretion of ligated murine intestine was monitored ex vivo. Roflumilast activated CFTR-dependent anion transport in normal HBE cells with a half maximal effective concentration of 2.9 nM. Roflumilast partially restored CFTR activity in WCS-exposed HBE cells (5.3 \u00b1 1.1 \u03bcA\/cm2 vs. 1.2 \u00b1 0.2 \u03bcA\/cm2 [control]; P &amp;lt; 0.05) and was additive with ivacaftor, a specific CFTR potentiator approved for the treatment of CF. Roflumilast improved the depleted ASL depth of HBE monolayers exposed to WCS (9.0 \u00b1 3.1 \u03bcm vs. 5.6 \u00b1 2.0 \u03bcm [control]; P &amp;lt; 0.05), achieving 79% of that observed in air controls. CFTR activation by roflumilast also induced CFTR-dependent fluid secretion in murine intestine, increasing the wet:dry ratio and the diameter of ligated murine segments. Roflumilast activates CFTR-mediated anion transport in airway and intestinal epithelia via a cyclic adenosine monophosphate\u2013dependent pathway and partially reverses the deleterious effects of WCS, resulting in augmented ASL depth. Roflumilast may benefit patients with chronic obstructive pulmonary disease with chronic bronchitis by activating CFTR, which may also underlie noninfectious diarrhea caused by roflumilast.<\/jats:p>","DOI":"10.1165\/rcmb.2013-0228oc","type":"journal-article","created":{"date-parts":[[2013,10,9]],"date-time":"2013-10-09T16:43:22Z","timestamp":1381337002000},"page":"549-558","source":"Crossref","is-referenced-by-count":76,"title":["Cystic Fibrosis Transmembrane Conductance Regulator Activation by Roflumilast Contributes to Therapeutic Benefit in Chronic Bronchitis"],"prefix":"10.1093","volume":"50","author":[{"given":"James A.","family":"Lambert","sequence":"first","affiliation":[{"name":"Departments of Medicine"},{"name":"the Department of Biochemistry and Structural Biology at University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Vamsee","family":"Raju","sequence":"additional","affiliation":[{"name":"Departments of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li Ping","family":"Tang","sequence":"additional","affiliation":[{"name":"Departments of Medicine"},{"name":"the Cystic Fibrosis Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmel M.","family":"McNicholas","sequence":"additional","affiliation":[{"name":"Cell, Developmental, and Integrative Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Medicine"},{"name":"the Cystic Fibrosis Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford A.","family":"Courville","sequence":"additional","affiliation":[{"name":"Departments of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roopan F.","family":"Farris","sequence":"additional","affiliation":[{"name":"Departments of Medicine"},{"name":"Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George E.","family":"Coricor","sequence":"additional","affiliation":[{"name":"the Department of Biochemistry and Structural Biology at University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa H.","family":"Smoot","sequence":"additional","affiliation":[{"name":"Departments of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina M.","family":"Mazur","sequence":"additional","affiliation":[{"name":"the Cystic Fibrosis Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Dransfield","sequence":"additional","affiliation":[{"name":"Departments of Medicine"},{"name":"the UAB Lung Health Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme B.","family":"Bolger","sequence":"additional","affiliation":[{"name":"Departments of Medicine"},{"name":"Pharmacology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Rowe","sequence":"additional","affiliation":[{"name":"Departments of Medicine"},{"name":"Pediatrics"},{"name":"Cell, Developmental, and Integrative Biology and"},{"name":"the UAB Lung Health Center"},{"name":"the Cystic Fibrosis Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,3,1]]},"reference":[{"key":"2026030623192591800_bib1","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/S0140-6736(03)14416-9","article-title":"Chronic obstructive pulmonary disease","volume":"362","author":"Calverley","year":"2003","journal-title":"Lancet"},{"key":"2026030623192591800_bib2","doi-asserted-by":"crossref","first-page":"e39809","DOI":"10.1371\/journal.pone.0039809","article-title":"A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease","volume":"7","author":"Sloane","year":"2012","journal-title":"PLoS ONE"},{"key":"2026030623192591800_bib3","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1152\/physrev.00048.2006","article-title":"Pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease","volume":"87","author":"Yoshida","year":"2007","journal-title":"Physiol Rev"},{"key":"2026030623192591800_bib4","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1056\/NEJMra043184","article-title":"Cystic fibrosis","volume":"352","author":"Rowe","year":"2005","journal-title":"N Engl J Med"},{"key":"2026030623192591800_bib5","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0092-8674(00)81724-9","article-title":"Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease","volume":"95","author":"Matsui","year":"1998","journal-title":"Cell"},{"key":"2026030623192591800_bib6","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1056\/NEJMoa032158","article-title":"The nature of small-airway obstruction in chronic obstructive pulmonary disease","volume":"350","author":"Hogg","year":"2004","journal-title":"N Engl J Med"},{"key":"2026030623192591800_bib7","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1164\/ajrccm.153.5.8630597","article-title":"Association of chronic mucus hypersecretion with fev1 decline and chronic obstructive pulmonary disease morbidity. 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