An effective therapeutic strategy for suppressing
liver fibrosis development should improve the overall prognosis of patients with chronic
liver diseases. Despite efforts to develop
anti-fibrotic agents, no drugs have yet been approved as anti-fibrotic treatments for humans. An alternative strategy may be to employ a clinically available agent that also exhibits anti-fibrotic activities, for which the safety of long-term administration has been proven. The aim of the current study was to elucidate the combined effect of clinically used
interferon (IFN),
ribavirin (Rib) and
angiotensin-II receptor blocker (ARB) on
liver fibrosis development in mice. A model of CCl4-induced hepatic
fibrosis was used to assess the effect of IFN, Rib and ARB. IFN, Rib and ARB were administered after a two-week treatment with CCl4, and the hepatic indices of
fibrosis were assessed at eight weeks. Single treatment with IFN, Rib or ARB at the clinically available comparable doses significantly attenuated the liver fibrogenesis associated with the suppression of the number of α-smooth muscle actin positive cells, and the hepatic
transforming growth factor-β (TGF-β)
mRNA. Hepatic neovascularization, which is also known to play a pivotal role in liver fibrogenesis, and
vascular endothelial growth factor (
VEGF), a potent
angiogenic factor, were also markedly inhibited. Combination treatment with any two agents exerted a more potent inhibitory effect than any single treatment. Moreover, the triple cocktail treatment revealed further suppressive effects than any two agent combination. Furthermore, in vitro studies showed that similar combined effects were observed on the proliferation and TGF-β
mRNA expression of activated hepatic stellate cells and endothelial cell tube formation. These results indicate that the cocktail combination treatment of clinically used IFN, Rib and ARB may provide a new strategy for anti-
liver fibrosis therapy.