Distinct lung functional, histological and cell senescence signatures in the single and repetitive bleomycin mouse models of idiopathic pulmonary fibrosis.

This study aimed to comprehensively compare the lung disease phenotypes between single-dose and repetitive-dose bleomycin (BLEO)-induced mouse models of idiopathic pulmonary fibrosis (IPF). Male C57BL/6JRj mice were randomized and stratified to treatment according to body weight. Mice received either a single intratracheal instillation of BLEO (n = 14) or a repetitive regimen involving bi-weekly BLEO instillations over 4 weeks (n = 30). Two weeks after the last BLEO dose, mice were assigned as baseline (n = 13) or repetitive BLEO-IPF mice (terminated 8 weeks after baseline, n = 17). Saline-treated mice served as healthy controls (n = 10 per model). The repetitive BLEO-IPF mouse demonstrated sustained features of lung fibrosis, including persistent increases in lung hydroxyproline content, Ashcroft scores, and quantitative collagen levels 8 weeks after baseline. Histological analysis revealed ongoing pulmonary inflammation and accumulation of senescent myofibroblasts. Lung functional impairment was selective but persistent, with FEV0.1 being significantly reduced on study week 8. Lung transcriptome signatures in repetitive BLEO-IPF mice were comparable to those reported in end-stage IPF patients, albeit attenuated 8 weeks after baseline, suggesting initiation of reparative processes. The repetitive BLEO-IPF mouse model recapitulates histological features of progressive lung fibrosis with an evolving cellular senescence phenotype, offering a relevant preclinical platform for studying IPF pathophysiology and evaluating long-term effects of antifibrotic and senescence-targeted therapies.