Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

作者：Crespo Irene; San Miguel Beatriz; Fernandez Ana; De Urbina Juan Ortiz; Gonzalez Gallego Javier; Tunon Maria J^*

来源：Translational Research, 2015, 165(2): 346-357.

DOI：10.1016/j.trsl.2014.10.003

We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl4). Mice in treatment groups received CCl4 5,a/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCI4 administration. Treatment with CCI4 resulted in fibrosis evidenced by the staining of Van Gieson and a-smooth muscle actin (a-SMA) positive cells in the liver. At both 4 and 6 weeks, CCU induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-0, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of a-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-0, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCI4-induced liver fibrosis.

• 出版日期2015-2