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The ferret bleomycin-induced model of lung fibrosis shares features of human idiopathic pulmonary fibrosis

ABSTRACT: In the present study, we report a bleomycin-induced ferret PF model characterized by an irreversible decrease in pulmonary compliance and increase of opacification, accompanied by “honeycomb cyst-like” structures, “proximalization” of distal lung epithelium. Cellular and molecular analysis by single-nucleus RNA sequencing analysis 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+/KRT5low “basaloid-like” cells, were 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 KRT8high/KRT7low/SOX4+ to eventual KRT8high/KRT7high/SFN+/TP63+/KRT5low “basaloid-like” cells. Further, immunofluorescence analyses demonstrated KRT7 and KRT8 populations reside in close proximity to the ACTA2 positive myofibroblasts in fibrotic foci thereby driving fibrogenic phenotype in bleomycin injured ferret lungs. Collectively, our results provide evidence that the bleomycin ferrets can reproduce pathophysiological, cellular, and molecular features of human IPF disease, suggesting that they may be a reliable model for understanding mechanisms of IPF pathogenesis and for testing therapeutic strategies for treatment of IPF.

ORGANISM(S): Mustela putorius furo

PROVIDER: GSE279470 | GEO | 2025/06/16

REPOSITORIES: GEO

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Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group

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The ferret bleomycin-induced model of lung fibrosis shares features of human idiopathic pulmonary fibrosis

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