Transcriptomic and proteomic profiling of young and old mice in the bleomycin model reveals high similarity
Stephan Klee1, Sergio Picart-Armada2, Kathrin Wenger3
1Department Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Abstract:
The most common preclinical, in vivo model to study lung fibrosis is the bleomycin-induced lung fibrosis model in 2- to 3-mo-old mice. Although this model resembles key aspects of idiopathic pulmonary fibrosis (IPF), there are limitations in its predictability for the human disease. One of the main differences is the juvenile age of animals that are commonly used in experiments, resembling humans of around 20 yr. Because IPF patients are usually older than 60 yr, aging appears to play an important role in the pathogenesis of lung fibrosis. Therefore, we compared young (3 months) and old mice (21 months) 21 days after intratracheal bleomycin instillation. Analyzing lung transcriptomics (mRNAs and miRNAs) and proteomics, we found most pathways to be similarly regulated in young and old mice. However, old mice show imbalanced protein homeostasis as well as an increased inflammatory state in the fibrotic phase compared to young mice. Comparisons with published human transcriptomic data sets (GSE47460, GSE32537, and GSE24206) revealed that the gene signature of old animals correlates significantly better with IPF patients, and it also turned human healthy individuals better into "IPF patients" using an approach based on predictive disease modeling. Both young and old animals show similar molecular hallmarks of IPF in the bleomycin-induced lung fibrosis model, although old mice more closely resemble several features associated with IPF in comparison to young animals.
Insights
Aging mice better mimic human idiopathic pulmonary fibrosis (IPF) than young mice in a bleomycin-induced lung fibrosis model. Old mice exhibit increased inflammation and protein imbalance, aligning more closely with IPF patient gene signatures.
Area of Science:
- Pulmonary Medicine
- Fibrosis Research
- Aging Biology
Background:
- The bleomycin-induced lung fibrosis model is common but uses young mice, unlike older IPF patients.
- Aging is a critical factor in lung fibrosis pathogenesis, yet understudied in preclinical models.
Purpose of the Study:
- To compare young and old mice in a bleomycin-induced lung fibrosis model.
- To determine if aged animals better represent human idiopathic pulmonary fibrosis (IPF).
Main Methods:
- Intratracheal bleomycin instillation in young (3 months) and old (21 months) mice.
- Analysis of lung transcriptomics (mRNAs, miRNAs) and proteomics.
- Comparison with human IPF transcriptomic datasets (GSE47460, GSE32537, GSE24206).
Main Results:
- Most pathways were similarly regulated in young and old mice post-bleomycin.
- Old mice displayed imbalanced protein homeostasis and heightened inflammation during fibrosis.
- The gene signature of old mice correlated better with IPF patients and improved disease modeling.
Conclusions:
- While both young and old mice show IPF hallmarks, aged mice more accurately reflect human IPF features.
- Older animal models are crucial for understanding aging's role in lung fibrosis.
- This study highlights the importance of age in preclinical models for predicting human disease outcomes.
