{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T09:38:21Z","timestamp":1777887501869,"version":"3.51.4"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["ARM"],"abstract":"<jats:p>Purpose: A high-salt extracellular environment promotes fibrosis in multiple organs by inducing oxidative stress, fibroblast activation, and extracellular matrix remodeling. In the lung, sodium accumulation may result from impaired epithelial ion transport. Transforming growth factor-\u03b21 (TGF-\u03b21), a key profibrotic cytokine, downregulates epithelial sodium and chloride channels, promoting sodium retention and fibrotic remodeling. This study investigated whether antifibrotic drugs can prevent TGF-\u03b21-induced suppression of sodium channel expression in the lung epithelium. Methods: Human A549 alveolar epithelial cells and primary alveolar epithelial cells were cultured with or without TGF-\u03b21 in the presence or absence of nintedanib or pirfenidone. Expression of epithelial sodium channel (ENaC) subunits (SCNN1A, SCNN1B, SCNN1G, SCNN1D) and CFTR was analyzed. In vivo, lung tissues from TGF-\u03b21 transgenic mice and wild-type controls were examined following intranasal administration of pirfenidone. Results: TGF-\u03b21 markedly reduced the expression of all ENaC subunits and CFTR in vitro. Nintedanib prevented suppression of SCNN1A, SCNN1D, and SCNN1G, whereas pirfenidone prevented suppression of SCNN1A, SCNN1B, and SCNN1G. In TGF-\u03b21 transgenic mice, Scnn1a, Scnn1b, and Scnn1g expression was significantly decreased compared with wild-type controls. Pirfenidone administration dose-dependently restored expression of these ENaC subunits in vivo. Conclusions: Antifibrotic drugs partially prevent TGF-\u03b21-induced suppression of epithelial sodium channels, preserving epithelial ion homeostasis. Restoration of ENaC expression may represent a novel mechanism by which antifibrotic therapy mitigates sodium-associated lung fibrosis.<\/jats:p>","DOI":"10.3390\/arm94030030","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:46:11Z","timestamp":1777455971000},"page":"30","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antifibrotic Drugs Regulate the Expression of Epithelial Sodium Channels in the Lungs"],"prefix":"10.3390","volume":"94","author":[{"given":"Toshiyuki","family":"Ito","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4141-0538","authenticated-orcid":false,"given":"Hajime","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Toda","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Fridman D\u2019Alessandro","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2164-5775","authenticated-orcid":false,"given":"Corina N.","family":"D\u2019Alessandro-Gabazza","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yurie","family":"Kogue","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuki","family":"Tsuruga","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohito","family":"Okano","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuki","family":"Furuhashi","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruko","family":"Saiki","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Tomaru","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5748-1499","authenticated-orcid":false,"given":"Esteban C.","family":"Gabazza","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"},{"name":"Microbiome Research Center, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taro","family":"Yasuma","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"},{"name":"Microbiome Research Center, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsu","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"},{"name":"Microbiome Research Center, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1021\/acs.jafc.5b05897","article-title":"Liver Fibrosis Can Be Induced by High Salt Intake through Excess Reactive Oxygen Species (ROS) Production","volume":"64","author":"Wang","year":"2016","journal-title":"J. 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