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Publications

Journal Article Preprint Epublish

PubMed: 40462941 DOI: 10.1101/2025.05.08.652970

Ferret model of bleomycin-induced lung injury shares features of human idiopathic pulmonary fibrosis.

bioRxiv

Authors: Shuang Wu, Ian Drive, Meihui Luo, Hikaru Miyazaki, Smitha Shambhu, Dimitry Popov, Liyuan Yang, Jing Wang, Jia Ma, Junfeng Guo, Jarron Atha, Aleksandra Tata, Eric A Hoffman, Yujiong Wang, Purushothama Rao Tata, Martin B Jensen, John F Engelhardt, Vishwaraj Sontake, Xiaoming Liu

Affiliations

  • Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. 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.
  • Gordian Biotechnology, 486 Cabot Rd, South San Francisco, CA 94080, USA.
  • Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
  • Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
  • Department of Cell Biology, Duke University School of Medicine, Durham, NC 27708, USA.
  • 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.

Abstract

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 "honeycomb cyst-like" structures and "proximalization" 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 +/TP63 +/KRT5 low "basaloid-like" 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 high/KRT7 low/SOX4 + and eventually to KRT8 high/KRT7 high/SFN +/TP63 +/KRT5 low "basaloid-like" 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.

MeSH

Cells, Idiopathic Pulmonary Fibrosis, Bleomycin, Lung, Fibrosis, Lung Injury, Pulmonary Fibrosis, Therapeutics, Epithelium