title: Ponatinib ameliorates pulmonary fibrosis by suppressing TGF-β1/Smad3 pathway.
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.
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, PR China.
authors.forename: Yubei
authors.initials: Y
authors.lastname: Qu
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, PR China.
authors.forename: Zechun
authors.initials: Z
authors.lastname: Kang
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, PR China. Electronic address: jwl518@163.com.
authors.forename: Wanglin
authors.initials: W
authors.lastname: Jiang
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, PR China. Electronic address: Lucky_lcj@sina.com.
authors.forename: Changjun
authors.initials: C
authors.lastname: Lv
mesh_terms: D000199:Actins; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D001761:Bleomycin / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis; D011658:Pulmonary Fibrosis / Q000473:pathology; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D007093:Imidazoles; D020574:Proto-Oncogene Proteins c-sis; D011724:Pyridazines; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D016222:Fibroblast Growth Factor 2; D001761:Bleomycin; D000077214:Becaplermin; C545373:ponatinib
keywords: Apoptosis; EMT; PDGF-BB/FGF-2; Ponatinib; Pulmonary fibrosis; TGF-β1/Smad3