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. 2015 Oct:34:1-7.
doi: 10.1016/j.pupt.2015.07.004. Epub 2015 Aug 5.

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

Yubei Qu  1 , Liang Zhang  1 , Zechun Kang  1 , Wanglin Jiang  2 , Changjun Lv  3
Affiliations

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

Yubei Qu et al. Pulm Pharmacol Ther. 2015 Oct.

Abstract

TGF-β1/Smad3 pathway plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, including lung fibroblasts proliferation and epithelial cell aberrant activation. Ponatinib is a multi-targeted tyrosine-kinase inhibitor. However, whether Ponatinib has anti-fibrotic functions is unknown. In this study, the effects of Ponatinib on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1), on the apoptosis of human type I alveolar epithelial cells (AT I) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis was investigated in vivo. Treatment with Ponatinib resulted in a reduction of EMT in A549 cells with a decrease in vimentin and p-Smad3, whereas an increase in E-cadherin. Apoptosis of AT I was attenuated with an increase in the Bcl-2/Bax ratio. HLF-1 proliferation was reduced with a decrease in PDGF-BB and FGF-2 expressions. Treatment with Ponatinib resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with reductions of the pathological score, collagen deposition, p-Smad3, α-SMA, PDGF-BB and FGF-2 expression. In summary, Ponatinib reversed the EMT, inhibited the apoptosis of AT I, as well as HLF-1 proliferation and prevented pulmonary fibrosis by suppressing the TGF-β1/Smad3 pathway.

Keywords: Apoptosis; EMT; PDGF-BB/FGF-2; Ponatinib; Pulmonary fibrosis; TGF-β1/Smad3.

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