Persistence of alveolar fibroblast-derived ADAMTS4+ cells during delayed resolution of pulmonary fibrosis

Idiopathic pulmonary fibrosis is a severe interstitial lung disease with limited therapeutic options. This study traced fibroblast growth factor 10 (Fgf10+) alveolar fibroblasts (AFs) in aged mice subjected to bleomycin injury, analyzing histology and single-cell transcriptomics at peak fibrosis and during resolution phases. Ex vivo models and human lung tissue data were also examined. Results showed Fgf10+ AFs transitioning from lipofibroblasts (LIF) to myofibroblasts (MyoFBs) during fibrogenesis, and reversing during resolution. An ADAM metallopeptidase with thrombospondin type 1 motif 4 (Adamts4+) AF population was linked to delayed resolution. ADAMTS4 emerged as a key target in fibrotic lung diseases, highlighting its therapeutic potential. Overall design: Aged female Fgf10Cre-ERT2/+; tdTomatoflox mice received tamoxifen injections three successive injections two weeks prior to intratracheal instillation of saline or bleomycin. Lungs were collected on days 14, 30 and 60 post bleomycin injury for further analysis.