Abstract
Liver fibrosis is the excessive extracellular matrix accumulation of proteins, such as collagen, which follows the chronic liver diseases. Advanced liver fibrosis leads to cirrhosis and liver failure. Nilotinib is a second-generation tyrosine kinase inhibitor, which showed antifibrotic efficacy. Stem cell therapy still has some limitations such as oncogenesis, unexpected differentiation, and ethical consideration. Stem cells secrete cytokines and growth factors that showed paracrine-mediated antifibrotic and anti-inflammatory effects in vivo and in vitro. Thus, stem cell-conditioned medium (SC-CM), which contains the secretory proteins of stem cells, may have an antifibrotic role. This study was carried out to examine the antifibrotic effect of Nilotinib and stem cell exosomes on CCl4-induced liver fibrosis in rats. Male Wistar rats were injected intraperitoneally with CCl4 twice a week for 9 weeks and given daily treatments of Nilotinib (20 mg/kg), stem cell exosomes (0.5 ml/rat), and the combination treatment of Nilotinib and stem cell exosomes during the last 5 weeks of CCl4 intoxication. Liver fibrosis and also antifibrotic efficacy of the treatments were estimated with liver function tests, oxidative stress parameters, apoptotic parameters, histopathological examination, and hydroxyproline contents. Results showed that the combination of Nilotinib and stem cell-conditioned media had more antifibrotic effects than each one alone (P value < 0.001).
Highlights
Fibrosis is a common pathological process for the majority of liver diseases which leads to liver cirrhosis and/or hepatocellular carcinoma
We compared Nilotinib, Imatinib, and silymarin in their effect as antifibrotic agents [4]; we found that Nilotinib is better than silymarin and less toxic than Imatinib, and we found that Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases [7]
We studied the therapeutic effect of stem cells in liver fibrosis and found that they are comparable to Nilotinib as an antifibrotic agent [8]
Summary
Fibrosis is a common pathological process for the majority of liver diseases which leads to liver cirrhosis and/or hepatocellular carcinoma. It is a consequence of almost all chronic liver diseases predominantly arising from viral, alcohol-induced, autoimmune, and metabolic etiologies [1]. Tyrosine kinase activation has been involved in fibrogenesis. Tyrosine kinases are implicated in various cellular activities, including differentiation, apoptosis, metabolism, and growth [3]. Besides the tyrosine kinases’ physiological roles, recent studies have shown their activation role in carcinogenesis pathophysiology, fibrogenesis, Stem Cells International rheumatoid arthritis, and vascular remodeling. Inhibitors that block tyrosine kinase activity may be helpful for the treatment of these diseases [4]
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