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.

Insulin-like growth factor binding protein-4 exerts antifibrotic activity by reducing levels of connective tissue growth factor and the C-X-C chemokine receptor 4

“…45 TGF-ß interacts with its type I (TßRI) and type II (TßRII) receptors, resulting in the downstream phosphorylation of SMAD2 and SMAD3. 51 Our findings suggest that the antifibrotic activity of IGFBP-4 is independent of IGF-I since mutating the IGF binding domain of IGFBP-4 did not abrogate the protein's antifibrotic effects in our models. 48 C-terminal domain phosphorylation of SMAD2/3 by TßRI kinase defines the TGF-ß canonical signaling pathway, 49 whereas phosphorylation of SMAD2 and SMAD3 linker domain by kinases such as MAPKs, ERK, and P38 is characteristic of the noncanonical TGF-ß signaling pathway.…”

“…For example, sunitinib, a small molecule kinase inhibitor, reduced phosphorylation of serine residues on SMAD2/3 and attenuated bleomycininduced pulmonary fibrosis in mice. 51 Our findings suggest that the antifibrotic activity of IGFBP-4 is independent of IGF-I since mutating the IGF binding domain of IGFBP-4 did not abrogate the protein's antifibrotic effects in our models. The antifibrotic activity of IGFBP-4 can be added to a growing list of other activities attributed to the IGF-independent function of IGFBP-4, such as its ability to reduce postoperative peritoneal adhesions in rats, 13 its antiangiogenic and antitumorigenic effects, as well as its Wnt signaling inhibitory function, 11,29 some of which have been attributed to the carboxy-terminal region of IGFBP-4.…”

Identification of biomarkers in common chronic lung diseases by co-expression networks and drug-target interactions analysis

“…Tyrosine kinases play an essential role in the pathogenesis of the IPF. Furthermore, this drug can block the process of Epithelial to Mesenchymal Transition (EMT) by TGF-β, and EMT plays a vital role in the development of IPF (Huang et al 2016). Sunitinib also reduces mucus and inflammation and repairs remodeling in asthmatic patients (Huang et al 2009).…”

Repurposing of Kinase Inhibitors for Treatment of COVID-19

“…Alvocidib also shows anti-inflammatory activity by blocking leukocyte-endothelial association by inhibiting CDK9 (134). Pazopanib exhibits antifibrotic activity through modulating inflammatory cytokines, and sunitinib inhibited bleomycin-induced pulmonary fibrosis in mice (135) (136). Sunitinib, believed to primarily work through PDGFR-mediated signaling, was also shown to suppress cytokine storm in a mouse model (137).…”