{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:26:39Z","timestamp":1768566399848,"version":"3.49.0"},"posted":{"date-parts":[[2024,8,29]]},"group-title":"Pharmacology and Toxicology","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T00:00:00Z","timestamp":1724889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The combination of elexacaftor\/tezacaftor\/ivacaftor (ETI, Trikafta) reverses the primary defect in Cystic Fibrosis (CF) by improving CFTR mediated Cl\n                  <jats:sup>-<\/jats:sup>\n                  and HCO\n                  <jats:sub>3<\/jats:sub>\n                  <jats:sup>-<\/jats:sup>\n                  secretion by airway epithelial cells (AEC), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, has numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression we exposed primary human AEC to ETI for 48 hours and interrogated the transcriptome by RNA-seq and qPCR. ETI increased defensin gene expression (\n                  <jats:italic>DEFB1<\/jats:italic>\n                  ) an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI also decreased\n                  <jats:italic>MMP10<\/jats:italic>\n                  and\n                  <jats:italic>MMP12<\/jats:italic>\n                  gene expression, suggesting that ETI may reduce proteolytic induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase (\n                  <jats:italic>HMOX1<\/jats:italic>\n                  ). qPCR analysis confirmed\n                  <jats:italic>DEFB1, HMOX1, MMP10<\/jats:italic>\n                  and\n                  <jats:italic>MMP12<\/jats:italic>\n                  gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation and MHC Class II antigen presentation. Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug induced increases in\n                  <jats:italic>DEFB1<\/jats:italic>\n                  , and that ETI may reduce lung damage by reducing\n                  <jats:italic>MMP10<\/jats:italic>\n                  and\n                  <jats:italic>MMP12<\/jats:italic>\n                  gene expression, which is predicted to reduce matrix metalloprotease activity. Moreover, pathway analysis also identified several genes responsible for the ETI induced reduction in inflammation observed in people with CF.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>New and Noteworthy<\/jats:title>\n                  <jats:p>Gene expression responses by CF AEC exposed to ETI suggest that in addition to improving CFTR channel function, ETI is likely to increase resistance to bacterial infection by increasing levels of beta defensin 1 (hBD-1). ETI may also reduce lung damage by suppressing MMP10, and reduce airway inflammation by repressing proinflammatory cytokine secretion by AEC cells.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.08.28.610162","type":"posted-content","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T01:35:26Z","timestamp":1724981726000},"source":"Crossref","is-referenced-by-count":0,"title":["Gene expression responses of CF airway epithelial cells exposed to elexacaftor\/tezacaftor\/ivacaftor (ETI) suggest benefits beyond improved CFTR channel function"],"prefix":"10.64898","author":[{"given":"Thomas 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