{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:52:29Z","timestamp":1785412349994,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,14]]},"group-title":"Pathology","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["75N92024R00008"],"award-info":[{"award-number":["75N92024R00008"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 HL165404"],"award-info":[{"award-number":["R01 HL165404"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL160939"],"award-info":[{"award-number":["R01HL160939"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL153375"],"award-info":[{"award-number":["R01HL153375"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited therapeutic options. The development of effective therapies has been hindered by the lack of models that recapitulate key features of human disease. Here we report a bleomycin-induced ferret PF model characterized by an irreversible decrease in pulmonary compliance and an increase of opacification, accompanied by \u201choneycomb cyst-like\u201d structures and \u201cproximalization\u201d of distal lung epithelium. Cellular and molecular analysis by single-nucleus RNA sequencing revealed a significant shift in distal lung epithelium towards proximal epithelial phenotype. Importantly, a histopathological pattern of bronchiolization encompassing divergent atypical epithelial cells and KRT17\n                  <jats:sup>+<\/jats:sup>\n                  \/TP63\n                  <jats:sup>+<\/jats:sup>\n                  \/KRT5\n                  <jats:sup>low<\/jats:sup>\n                  \u201cbasaloid-like\u201d cells was present in the distal fibrotic lung lesions. Trajectory analysis revealed AT2 cells transition through multiple cell-states in bleomycin injured ferret lungs, particularly AT2 to KRT8\n                  <jats:sup>high<\/jats:sup>\n                  \/KRT7\n                  <jats:sup>low<\/jats:sup>\n                  \/SOX4\n                  <jats:sup>+<\/jats:sup>\n                  and eventually to KRT8\n                  <jats:sup>high<\/jats:sup>\n                  \/KRT7\n                  <jats:sup>high<\/jats:sup>\n                  \/SFN\n                  <jats:sup>+<\/jats:sup>\n                  \/TP63\n                  <jats:sup>+<\/jats:sup>\n                  \/KRT5\n                  <jats:sup>low<\/jats:sup>\n                  \u201cbasaloid-like\u201d cells. Further, immunofluorescence analyses demonstrated KRT7 and KRT8 populations reside overlaying the ACTA2-positive myofibroblasts in fibrotic foci, implying their pro-fibrogenic activity similar to human IPF lungs. Collectively, our results provide evidence that bleomycin-induced lung injury in ferrets recapitulates pathophysiological, cellular, and molecular features of human IPF, suggesting that they may be a reliable model for understanding mechanisms of IPF pathogenesis and for testing therapeutic strategies for treatment of IPF.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Take Home Message<\/jats:title>\n                  <jats:p>Bleomycin-induced acute lung injury in the ferret recapitulates pathophysiological, cellular, and molecular features of human IPF; thus the ferret may be a reliable species for studying mechanisms of IPF pathogenesis and testing therapeutic strategies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.08.652970","type":"posted-content","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T08:50:20Z","timestamp":1747212620000},"source":"Crossref","is-referenced-by-count":2,"title":["Ferret model of bleomycin-induced lung injury shares features of human idiopathic pulmonary fibrosis"],"prefix":"10.64898","author":[{"given":"Shuang","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Drive","sequence":"additional","affiliation":[{"name":"Gordian Biotechnology, 486 Cabot Rd, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meihui","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikaru","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Gordian Biotechnology, 486 Cabot Rd, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smitha","family":"Shambhu","sequence":"additional","affiliation":[{"name":"Gordian Biotechnology, 486 Cabot Rd, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitry","family":"Popov","sequence":"additional","affiliation":[{"name":"Gordian Biotechnology, 486 Cabot Rd, South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarron","family":"Atha","sequence":"additional","affiliation":[{"name":"Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Tata","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, 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