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Updated: Sep 7, 2025
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
Nintedanib induces gene expression changes in the lung of induced-rheumatoid arthritis-associated interstitial lung
Shintaro Mikami1, Yoko Miura2, Shinji Kondo3
1Department of Pulmonary Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan.
Abstract:
Nintedanib is a multi-tyrosine kinase inhibitor widely used to treat progressive fibrosing interstitial lung diseases because it slows the reduction in forced vital capacity. However, the prognosis for patients treated with nintedanib remains poor. To improve nintedanib treatment, we examined the effects of nintedanib on gene expression in the lungs of induced-rheumatoid arthritis-associated interstitial lung disease model mice, which develop rheumatoid arthritis and subsequent pulmonary fibrosis. Using next-generation sequencing, we identified 27 upregulated and 130 downregulated genes in the lungs of these mice after treatment with nintedanib. The differentially expressed genes included mucin 5B and heat shock protein 70 family genes, which are related to interstitial lung diseases, as well as genes associated with extracellular components, particularly the myocardial architecture, suggesting unanticipated effects of nintedanib. Of the genes upregulated in the nintedanib-treated lung, expression of regulatory factor X2, which is suspected to be involved in cilia movement, and bone morphogenetic protein receptor type 2, which is involved in the pathology of pulmonary hypertension, was detected by immunohistochemistry and RNA in situ hybridization in peripheral airway epithelium and alveolar cells. Thus, the present findings indicate a set of genes whose expression alteration potentially underlies the effects of nintedanib on pulmonary fibrosis. It is expected that these findings will contribute to the development of improved nintedanib strategies for the treatment of progressive fibrosing interstitial lung diseases.
Insights
Nintedanib treatment for fibrosing lung diseases alters gene expression, revealing new targets. This study identifies specific genes affected by nintedanib, potentially improving future treatment strategies for interstitial lung diseases.
Area of Science:
- Pulmonary Medicine
- Pharmacogenomics
- Molecular Biology
Background:
- Nintedanib is a tyrosine kinase inhibitor used for progressive fibrosing interstitial lung diseases, but patient prognosis remains poor.
- Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) models offer insights into pulmonary fibrosis.
- Understanding nintedanib's molecular effects is crucial for enhancing treatment efficacy.
Purpose of the Study:
- To investigate the impact of nintedanib on lung gene expression in a mouse model of RA-ILD.
- To identify novel molecular targets and pathways affected by nintedanib treatment.
- To explore potential mechanisms underlying nintedanib's therapeutic effects and limitations.
Main Methods:
- Utilized a mouse model of induced rheumatoid arthritis-associated interstitial lung disease.
- Administered nintedanib to model mice and analyzed lung tissue.
- Employed next-generation sequencing to identify differentially expressed genes.
- Validated key gene expression changes using immunohistochemistry and RNA in situ hybridization.
Main Results:
- Nintedanib treatment resulted in 27 upregulated and 130 downregulated genes in the lungs.
- Affected genes included Mucin 5B, Heat Shock Protein 70 family, and those related to extracellular components and myocardial architecture.
- Upregulated genes like regulatory factor X2 (cilia movement) and bone morphogenetic protein receptor type 2 (pulmonary hypertension) were localized in airway and alveolar cells.
Conclusions:
- Nintedanib significantly alters lung gene expression in RA-ILD models, impacting pathways beyond fibrosis.
- Identified specific genes, including RFX2 and BMPR2, whose altered expression may mediate nintedanib's effects.
- Findings provide a basis for developing improved nintedanib-based therapeutic strategies for progressive fibrosing interstitial lung diseases.
