Shuang Wu, Ian D. Driver, 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 Borch Jensen, John F. Engelhardt, Vishwaraj Sontake, Xiaoming Liu
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.