Nintedanib inhibits the development and progression of peritoneal fibrosis

Abstract

Background Nintedanib, an FDA approved triple tyrosine kinase inhibitor, exhibits an antifibrotic effect in idiopathic pulmonary and renal fibrosis. Its effect on peritoneal fibrosis remains unexplored. Methods The present study investigated the effect of nintedanib on the development and progression of peritoneal fibrosis by administration fo nintedanib immediately after peritoneal injury or starting at day 21 of the injury in a in a mouse model of chlorhexidine gluconate-induced peritoneal fibrosis. Peritoneal fibrosis and associated mechanisms were examined by immunohistochemistry and immunoblot analysis. Results Administration of nintedanib immediately after peritoneal injury attenuated peritoneal fibrosis, whereas delayed administration of nintedanib not only halted the progression of peritoneal fibrosis, but also in part reversed the established fibrosis. Mechanistically studies showed that nintedanib inhibited injury-induced mesothelial-to-mesenchymal transition, expression of several cytokines/chemokines, vascularization and infiltration of macrophages to the injured peritoneum. Nintedanib also blocked phosphorylation of platelet derived growth factor receptor, fibroblast growth factor receptor, vascular endothelial growth factor receptor, and Src, downregulated expression of Snail and Twist, two transcription factors and inactivated several signaling pathways associated with peritoneal fibrosis, including Smad3, signal transducer and Activator of transcription 3, and nuclear factor-κB. Moreover, late treatment with nintedanib promoted expression of matrix metallopeptidase 2 and reduced expression of tissue inhibitor of metalloproteinases 2 in the injured peritoneum. Finally, nintedanib abrogated transforming growth factor β1–induced mesothelial-to-mesenchymal transition and phosphorylation of aforementioned signaling molecules in cultured human peritoneal mesothelial cells. Conclusions These results suggest that nintedanib may inhibit peritoneal fibrosis development and progression by blocking mesothelial-to-mesenchymal transition, inflammation, and angiogenesis, and partially reversed established peritoneal fibrosis through metalloproteinases-mediated extracellular matrix degradation. Therefore, nintedanib holds therapeutic potential for the prevention and treatment of peritoneal fibrosis.