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

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited treatment options, partly due to a lack of effective disease models. This study presents a ferret model of pulmonary fibrosis (PF) induced by bleomycin, which replicates key characteristics of human IPF. The ferret model demonstrates an irreversible loss of pulmonary compliance, increased opacification, and structures resembling honeycomb cysts. Using single-nucleus RNA sequencing, we observed a significant shift in the distal lung epithelium toward a proximal phenotype. Cell trajectory analysis showed that AT2 cells transition into KRT8^high/KRT7^low/SOX4⁺ cells, and eventually into KRT8^high/KRT7^high/SFN⁺/TP63⁺/KRT5^low "basaloid-like" cells. These cells, along with KRT7 and KRT8 populations, are located over myofibroblasts in fibrotic areas, suggesting a role in fibrosis progression similar to that in human IPF. This model accurately reproduces the pathophysiological and molecular features of human IPF, making it a valuable tool for future research and therapeutic development.