The Old genetically heterogeneous Mouse Model Recapitulates Chronic and Persistent Idiopathic Pulmonary Fibrosis with Strong Senescence Signatures

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive lung disease that primarily afflicts people over the age of 65. IPF is characterized by lung scarring, an elevated senescence burden, and interstitial pneumonia, resulting in disability and mortality. The growing aging population worldwide, limited effectiveness of current treatments, and high economic burden underscore the need for robust models to investigate the underlying mechanisms and test novel interventions. Despite broad preclinical use, the bleomycin-induced murine model has notable limitations. Animals subjected to a single dose of bleomycin administration undergo recovery in weight and behavior between 21 and 28 days after administration, which is contrary to the progressive nature of IPF. Previous reports have shown that repetitive instillation of bleomycin phenocopies this aspect of the human disease. However, these methods are time-consuming and complex. Although IPF is typically associated with advanced age, most research is conducted in 6 to 8-week-old mice, which lack the age-related structural and metabolic deficits seen in humans. In this study, we report an improved model of IPF using 17-month-old UM-HET3 mice subjected to a single oropharyngeal bleomycin dosing that better mimics the persistent nature of the disease. Lung histology and immunohistochemistry (IHC) confirm persistence of fibrosis and senescence in mice 10 weeks after bleomycin administration. Furthermore, bulk RNA sequencing (RNA-Seq) analysis revealed a distinct set of gene expression signatures that is more consistent with chronic human fibrosis. This model offers greater insight into IPF pathogenesis, and we anticipate that it will enhance confidence in the human translatability of candidate therapeutic interventions.