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Updated: Jun 26, 2025
A Mouse Model of Pulmonary Fibrosis Induced by Nasal Bleomycin Nebulization
Published on: January 20, 2023
Selpercatinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-β1 signaling pathway
Shimeng Li1, Zhichao Liu1, Xiaodan Jiao2
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, China.
Abstract:
IPF is a chronic, progressive, interstitial lung disease with high mortality. Current drugs have limited efficacy in curbing disease progression and improving quality of life. Selpercatinib, a highly selective inhibitor of receptor tyrosine kinase RET (rearranged during transfection), was approved in 2020 for the treatment of a variety of solid tumors with RET mutations. In this study, the action and mechanism of Selpercatinib in pulmonary fibrosis were evaluated in vivo and in vitro. In vivo experiments demonstrated that Selpercatinib significantly ameliorated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro, Selpercatinib inhibited the proliferation, migration, activation and extracellular matrix deposition of fibroblasts by inhibiting TGF-β1/Smad and TGF-β1/non-Smad pathway, and suppressed epithelial-mesenchymal transition (EMT) like process of lung epithelial cells via inhibiting TGF-β1/Smad pathway. The results of in vivo pharmacological tests corroborated the results obtained from the in vitro experiments. Further studies revealed that Selpercatinib inhibited abnormal phenotypes of lung fibroblasts and epithelial cells in part by regulating its target RET. In short, Selpercatinib inhibited the activation of fibroblasts and EMT-like process of lung epithelial cells by inhibiting TGF-β1/Smad and TGF-β1/non-Smad pathways, thus alleviating BLM-induced pulmonary fibrosis in mice.
Insights
Selpercatinib effectively treats pulmonary fibrosis by inhibiting fibroblast activation and epithelial-mesenchymal transition. This novel therapeutic approach shows promise for idiopathic pulmonary fibrosis (IPF) patients.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Cell Biology
Background:
- Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with limited treatment options and high mortality.
- Current therapies offer minimal efficacy in slowing disease progression or improving patient quality of life.
Purpose of the Study:
- To evaluate the efficacy and mechanism of Selpercatinib, a RET inhibitor, in treating pulmonary fibrosis.
- To investigate Selpercatinib's effects on fibroblast activation and epithelial-mesenchymal transition (EMT) in vitro and in vivo.
Main Methods:
- In vivo studies using bleomycin (BLM)-induced pulmonary fibrosis model in mice.
- In vitro experiments assessing fibroblast proliferation, migration, activation, and extracellular matrix deposition.
- Analysis of TGF-β1/Smad and TGF-β1/non-Smad pathways and epithelial-mesenchymal transition (EMT) in lung epithelial cells.
Main Results:
- Selpercatinib significantly ameliorated BLM-induced pulmonary fibrosis in mice.
- In vitro, Selpercatinib inhibited fibroblast activation and extracellular matrix deposition by targeting TGF-β1 pathways.
- Selpercatinib suppressed EMT-like processes in lung epithelial cells via the TGF-β1/Smad pathway, partly by regulating RET.
Conclusions:
- Selpercatinib demonstrates therapeutic potential for pulmonary fibrosis by inhibiting key fibrotic pathways.
- The drug alleviates pulmonary fibrosis by reducing fibroblast activation and suppressing EMT.
- Selpercatinib's mechanism involves targeting the RET pathway and TGF-β1 signaling cascades.
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