Because age matters – A comparative multi-omics analysis of young and old mice in the Bleomycin-induced lung fibrosis model

Abstract

The Bleomycin (Bleo)-induced lung fibrosis is the most commonly used model to study lung fibrosis in mice. This model resembles a number of key pathological aspects in the fibrotic phase that are found in human IPF patients. However, mice used in experiments are often 3 months of age, which is comparable to a 20-year-old human. On the other hand, patients suffering from IPF are usually older than 60 years. With increasing age, a number of changes occur that are not found in young adolescents, such as impairment of the innate and adaptive immune system (immuno-aging), stem cell exhaustion and changes in the extracellular matrix.

We here compared both young (3 months) and old mice (21 months; equivalent of 60-65 years in humans) in the model of Bleo-induced lung fibrosis. We used a multi-omics approach (transcriptomics, proteomics, lipidomics and metabolomics) to analyse lung tissue and plasma. Our results show that young and old mice are highly similar in regard to fibrotic changes when analyzing the mice 21 days after Bleo instillation, as assessed by lung function measurements, µCT and expression of fibrosis-associated markers in the lung. However, we also identified significant differences between both age groups during the fibrotic phase. We found an upregulation of T- and B-cell markers in old Bleo-treated mice compared to young mice. Furthermore, old mice showed a downregulation of proteins required for proper protein folding and ribosomal proteins, indicating potential unfolded protein response and mitochondrial stress. Comparison with human data sets will help to answer if we can model human lung fibrosis more closely using the Bleo model in aged mice.