title: Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice.
abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. IPF is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition (EMT). However, there is still a lack of strategies to target EMT for the treatment of IPF. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin (BLM). Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells (HBEs) and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-β, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-β in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University.
authors.forename: Xiang
authors.initials: X
authors.lastname: Huang
authors.forename: Weicheng
authors.initials: W
authors.lastname: Wang
authors.forename: Huaqin
authors.initials: H
authors.lastname: Yuan
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Lele
authors.initials: L
authors.lastname: Li
authors.forename: Xingxin
authors.initials: X
authors.lastname: Wu
authors.forename: Jinhua
authors.initials: J
authors.lastname: Luo
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000818:Animals; D001761:Bleomycin; D001980:Bronchi / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D007211:Indoles; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D051785:Smad Proteins; D054852:Small Molecule Libraries; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D001761:Bleomycin; D000077210:Sunitinib