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Updated: Nov 1, 2025
A Mouse Model of Pulmonary Fibrosis Induced by Nasal Bleomycin Nebulization
Published on: January 20, 2023
Genes, other than Muc5b, play a role in bleomycin-induced lung fibrosis
Evgenia Dobrinskikh1, Alani M Estrella1, Corinne E Hennessy1
1Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function MUC5B promoter variant rs35705950 is the dominant genetic risk factor for IPF, yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of MUC5B. Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is Muc5b dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for Muc5b expression and lung fibrosis 3 wk after intratracheal bleomycin administration. Although we identified strains with low Muc5b expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high Muc5b expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between Muc5b expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with Muc5b and cause lung fibrosis.
Insights
Idiopathic pulmonary fibrosis (IPF) risk is linked to MUC5B, but its low penetrance suggests other genes are involved. This study explored MUC5B dependence in bleomycin-induced lung fibrosis across diverse mouse strains.
Area of Science:
- Genetics
- Pulmonary Medicine
- Immunology
Background:
- Idiopathic pulmonary fibrosis (IPF) is a severe genetic lung disease with low penetrance for the MUC5B promoter variant.
- MUC5B concentration in bronchoalveolar epithelia correlates with lung fibrosis severity in mice.
- Understanding factors influencing IPF penetrance is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the dependence of bleomycin-induced lung injury and fibrosis on Muc5b expression in genetically diverse mouse strains.
- To identify genetic factors that interact with MUC5B to influence lung fibrosis.
Main Methods:
- Eight Diversity Outbred (DO) mouse founder strains were used.
- Mice were administered intratracheal bleomycin to induce lung injury.
- Muc5b expression and lung fibrosis were quantified 3 weeks post-administration.
Main Results:
- Significant variation in Muc5b expression and fibrosis severity was observed across mouse strains.
- Some strains showed a correlation between high Muc5b and extensive fibrosis, while others did not.
- Hierarchical clustering indicated that factors beyond Muc5b influence bleomycin-induced lung injury.
Conclusions:
- Muc5b expression alone does not fully determine bleomycin-induced lung fibrosis.
- Additional genetic and transcriptomic factors likely interact with MUC5B in the pathogenesis of lung fibrosis.
- DO strains and their crosses are valuable models for dissecting the genetic architecture of lung fibrosis.
