{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T03:47:15Z","timestamp":1778903235494,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K08442"],"award-info":[{"award-number":["17K08442"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K08175"],"award-info":[{"award-number":["18K08175"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal lung disease characterized by tissue scarring and declining lung function. The MUC5B promoter polymorphism rs35705950, a significant genetic predisposition for IPF, paradoxically associates with better survival and slower disease progression than other IPF genotypes. This study investigates the potential paradoxical protective effects of this MUC5B variant in lung fibrosis. For this purpose, we developed a transgenic mouse model overexpressing the human MUC5B rs35705950 variant in the proximal large airways. Lung fibrosis was induced through subcutaneous injection of bleomycin. Results demonstrated significantly reduced lung fibrosis severity in transgenic mice compared to wild-type mice, assessed by trichrome staining, Ashcroft scoring, and hydroxyproline levels. Additionally, transgenic mice showed significantly lower levels of inflammatory cells and cytokines (TNF\u03b1, IL-6, IFN\u03b3) and growth factors (PDGF, CTGF, IL-13) in the bronchoalveolar lavage fluid and lung tissues. There was also a significant decrease in mRNA expressions of fibrosis-related markers (periostin, fibronectin, Col1a1). In summary, this study reveals that mucin overexpression related to the MUC5B rs35705950 variant in the large airways significantly attenuates lung fibrosis and inflammatory responses in transgenic mice. These findings suggest that the rs35705950 variant modulates inflammatory and fibrotic responses in the proximal airways, which may contribute to the slower disease progression observed in IPF patients carrying this variant. Our study offers a possible explanation for the paradoxical beneficial effects of the MUC5B variant despite its role as a significant predisposing factor for IPF.<\/jats:p>","DOI":"10.3390\/cells13181523","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T05:45:12Z","timestamp":1726033512000},"page":"1523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Bleomycin-Induced Pulmonary Fibrosis in Transgenic Mice Carrying the Human MUC5B rs35705950 Variant"],"prefix":"10.3390","volume":"13","author":[{"given":"Suphachai","family":"Tharavecharak","sequence":"first","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":"Hajime","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Department 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":"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"},{"name":"Department of Diabetes, Endocrinology and Metabolism, 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"},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801, USA"}],"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":"Atsushi","family":"Tomaru","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":"Haruko","family":"Saiki","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":"Mei","family":"Uemura","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism, 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\/0000-0002-4894-6829","authenticated-orcid":false,"given":"Yurie","family":"Kogue","sequence":"additional","affiliation":[{"name":"Department 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":"Toshiyuki","family":"Ito","sequence":"additional","affiliation":[{"name":"Department 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 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 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":"Atsuro","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"},{"name":"Department of Diabetes, Endocrinology and Metabolism, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kota","family":"Nishihama","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryoichi","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osamu","family":"Hataji","sequence":"additional","affiliation":[{"name":"Respiratory Center, Matsusaka Municipal Hospital, Tonomachi1550, Matsusaka 515-8544, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0037-7049","authenticated-orcid":false,"given":"Tetsuya","family":"Nosaka","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsu","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department 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"}]},{"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":"Department 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"},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana\u2013Champaign, Urbana, IL 61801, USA"},{"name":"Respiratory Center, Matsusaka Municipal Hospital, Tonomachi1550, Matsusaka 515-8544, Mie, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lettieri, S., Bertuccio, F.R., Del Frate, L., Perrotta, F., Corsico, A.G., and Stella, G.M. (2023). The Plastic Interplay between Lung Regeneration Phenomena and Fibrotic Evolution: Current Challenges and Novel Therapeutic Perspectives. Int. J. Mol. 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