Cabozantinib ameliorates lipopolysaccharide-induced lung inflammation and bleomycin--induced early pulmonary fibrosis in mice

Abstract

The lung, as the primary organ for gas exchange in mammals, is the main target organ for many pathogens and allergens, which may cause acute lung injury. A certain proportion of acute lung injury may progress into irreversible pulmonary fibrosis. Both acute lung injury and pulmonary fibrosis have high mortality rates and few effective treatments. Cabozantinib is a multi-target small molecule tyrosine kinase inhibitor and has been approved for the treatment of multiple malignant solid tumors. In this study, we explored the role of cabozantinib in acute lung injury and pulmonary fibrosis in vivo and in vitro. In the lipopolysaccharide and bleomycin induced mouse lung injury models, cabozantinib significantly improved the pathological state and reduced the infiltration of inflammatory cells in the lung tissues. In the bleomycin induced pulmonary fibrosis model, cabozantinib significantly reduced the area of pulmonary fibrosis and improved lung function in mice. The results of in vitro studies showed that cabozantinib could inhibit the inflammatory response and apoptosis of alveolar epithelial cells by inhibiting the activation of TLR4/NF-κB and NLRP3 inflammasome pathways. At the same time, cabozantinib could inhibit the activation of lung fibroblasts through suppressing the TGF-β1/Smad pathway, and promote the apoptosis of fibroblasts. In summary, cabozantinib could alleviate lung injury through regulating the TLR4 /NF-κB/NLRP3 inflammasome pathway, and alleviate pulmonary fibrosis by inhibiting the TGF-β1/Smad3 signaling pathway.