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However, the model has significant limitations, including transient fibrosis that spontaneously resolves and its failure to fully recapitulate the epithelial remodeling in the lungs of patients with IPF. Thus, there remains an unmet need for a preclinical model with features that more closely resemble the human disease. Repetitive intratracheal instillation of bleomycin has previously been shown to recapitulate some of these features, but the instillation procedure is complex, and the long-term consequences on epithelial remodeling and fibrosis persistence and progression remain poorly understood. Here, we developed a simplified repetitive bleomycin instillation strategy consisting of three bi-weekly instillations that leads to persistent and progressive pulmonary fibrosis. Lung histology demonstrates increased collagen deposition, fibroblast accumulation, loss of type I and type II alveolar epithelial cells within fibrotic areas, bronchiolization of the lung parenchyma with CCSP+ cells, remodeling of the distal lung into cysts reminiscent of simple honeycombing, and accumulation of hyperplastic transitional KRT8+ epithelial cells. Micro\u2013computed tomographic imaging demonstrated significant traction bronchiectasis and subpleural fibrosis. Thus, the simplified repetitive bleomycin instillation strategy leads to progressive fibrosis and recapitulates the histological and radiographic characteristics of IPF. Compared with the single bleomycin instillation model, we suggest that the simplified repetitive instillation model may be better suited to address mechanistic questions about IPF pathogenesis and preclinical studies of antifibrotic drug candidates.<\/jats:p>","DOI":"10.1165\/rcmb.2020-0542ma","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T17:59:02Z","timestamp":1609955942000},"page":"669-676","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":117,"title":["Persistent, Progressive Pulmonary Fibrosis and Epithelial Remodeling in Mice"],"prefix":"10.1093","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8075-4325","authenticated-orcid":false,"given":"Elizabeth F.","family":"Redente","sequence":"first","affiliation":[{"name":"Program in Cell Biology, Department of Pediatrics, and"},{"name":"Department of Research, Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado"},{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart P.","family":"Black","sequence":"additional","affiliation":[{"name":"Program in Cell Biology, Department of Pediatrics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald S.","family":"Backos","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali N.","family":"Bahadur","sequence":"additional","affiliation":[{"name":"Bruker BioSpin Corporation, Billerica, Massachusetts; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-4530","authenticated-orcid":false,"given":"Stephen M.","family":"Humphries","sequence":"additional","affiliation":[{"name":"Department of Radiology, National Jewish Health, Denver, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine"},{"name":"Department of Radiology, National Jewish Health, Denver, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubin M.","family":"Tuder","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel L.","family":"Zemans","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and"},{"name":"Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9587-3335","authenticated-orcid":false,"given":"David W. 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