Translational Research, 2015, vol. 165, n. 2
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 mL/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 CCl4 administration. Treatment with CCl4 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, CCl4 induced an increase in the
messenger RNA levels of collagens I and III, transforming growth factor (TGF)-b,
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-b,
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 CCl4-induced liver fibrosis
