{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:29:27Z","timestamp":1792466967186,"version":"4.5.0"},"reference-count":66,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":34,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"crossref","award":["Shwachman Award"],"award-info":[{"award-number":["Shwachman Award"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,22]]},"abstract":"<jats:p>\n                    Cystic fibrosis (CF) is a genetic disorder that disrupts CF transmembrane conductance regulator (CFTR) anion channels and impairs airway host defenses. Airway inflammation is ubiquitous in CF, and suppressing it has generally been considered to improve outcomes. However, the role of inflammation in people taking CFTR modulators, small-molecule drugs that restore CFTR function, is not well understood. We previously showed that inflammation enhances the efficacy of CFTR modulators. To further elucidate this relationship, we treated human \u0394F508-CF epithelia with TNF-\u03b1 and IL-17, two inflammatory cytokines that are elevated in CF airways. TNF-\u03b1+IL-17 enhanced CFTR modulator\u2013evoked anion secretion through mechanisms that raise intracellular Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    (Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    \/2Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    cotransport) and HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2013<\/jats:sup>\n                    (carbonic anhydrases and Na\n                    <jats:sup>+<\/jats:sup>\n                    \/HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2013<\/jats:sup>\n                    cotransport). This enhancement required p38 MAPK signaling. Importantly, CFTR modulators did not affect CF airway surface liquid viscosity under control conditions but prevented the rise in viscosity in epithelia treated with TNF-\u03b1+IL-17. Finally, antiinflammatory drugs limited CFTR modulator responses in TNF-\u03b1+IL-17\u2013treated epithelia. These results provide critical insights into mechanisms by which inflammation increases responses to CFTR modulators. They also suggest an equipoise between potential benefits and limitations of suppressing inflammation in people taking modulators, call into question current treatment approaches, and highlight a need for additional studies.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.181836","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T12:01:46Z","timestamp":1718712106000},"source":"Crossref","is-referenced-by-count":12,"title":["Epithelial responses to CFTR modulators are improved by inflammatory cytokines and impaired by antiinflammatory drugs"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7792-201X","authenticated-orcid":true,"given":"Tayyab","family":"Rehman","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA."},{"name":"Department of Internal Medicine, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7544-5109","authenticated-orcid":true,"given":"Alejandro A.","family":"Pezzulo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7777-4165","authenticated-orcid":true,"given":"Andrew L.","family":"Thurman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3537-9869","authenticated-orcid":true,"given":"Rachel L.","family":"Zemans","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, 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