Tohoku J. Exp. Med., 2016 August, 239(4)

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

XIANG HUANG,¹ WEICHENG WANG,¹ HUAQIN YUAN,² JING SUN,¹ LELE LI,¹ XINGXIN WU,³ JINHUA LUO⁴ and YANHONG GU¹

¹Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
²Department of Medical Oncology, GaoChun People's Hospital, Gaochun, Nanjing, Jiangsu, China
³School of Life Sciences, Nanjing University, Nanjing, China
⁴Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

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.

keywords —— epithelial-mesenchymal transition; pulmonary fibrosis; Smad2/3; sunitinib; transforming growth factor-β

© 2016 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2016, 239, 251-261

Correspondence: Yanhong Gu, Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.

e-mail: guyhphd@163.com

Jinhua Luo, Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.

e-mail: ljhua1966@126.com

Xingxin Wu, School of Life Sciences, Nanjing University, 163 Xianlin Ave, Nanjing, Jiangsu 210023, China.

e-mail: xingxin.wu@nju.edu.cn