Tracking anti-fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: An insight

The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl4 for 12weeks. During the last 8weeks of treatment, rats were also injected daily intraperitoneally with 20mg/kg imatinib or 20, 10 or 5mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti-inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of -smooth muscle actin, transforming growth factor (TGF)-1 antibodies and platelet-derived growth factor receptor (PDGFR) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10mg/kg) significantly (P<0.05) decreased all serum fibrotic markers measured, but 20mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P<0.05) decreased the CCl4-induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10mg/kg nilotinib significantly decreased TGF-1 levels and tissue expression of its antibody, as well expression of PDGFR. In conclusion, low doses (5 and 10 but not 20mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)-1 and IL-6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF-1 levels and decreasing expression of PDGFR.