Ponatinib ameliorates pulmonary fibrosis by suppressing TGF-β1/Smad3 pathway

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Pharmacology

Background:

• Idiopathic pulmonary fibrosis involves the TGF-β1/Smad3 pathway, driving lung fibroblast proliferation and epithelial cell activation.
• The anti-fibrotic potential of Ponatinib, a multi-targeted tyrosine-kinase inhibitor, remains unexplored.

Purpose of the Study:

• To investigate Ponatinib's effects on TGF-β1-mediated epithelial-mesenchymal transition (EMT), lung fibroblast proliferation, and alveolar epithelial cell apoptosis in vitro.
• To evaluate Ponatinib's efficacy in a bleomycin-induced pulmonary fibrosis model in vivo.

Main Methods:

• Assessed Ponatinib's impact on EMT in A549 cells, human lung fibroblast (HLF-1) proliferation, and type I alveolar epithelial cell (AT I) apoptosis.
• Utilized a bleomycin (BLM)-induced pulmonary fibrosis rat model to assess Ponatinib's in vivo therapeutic effects.

Main Results:

• Ponatinib reduced EMT markers (vimentin, p-Smad3) and increased E-cadherin in A549 cells.
• Ponatinib attenuated AT I apoptosis by increasing the Bcl-2/Bax ratio and inhibited HLF-1 proliferation by decreasing PDGF-BB and FGF-2.
• In vivo, Ponatinib ameliorated BLM-induced pulmonary fibrosis, reducing pathological scores, collagen deposition, and key fibrotic markers (p-Smad3, α-SMA, PDGF-BB, FGF-2).

Conclusions:

• Ponatinib effectively reverses EMT, inhibits apoptosis and proliferation, and prevents pulmonary fibrosis.
• These effects are mediated through the suppression of the TGF-β1/Smad3 signaling pathway.