Cocktail therapy with a combination of interferon, ribavirin and angiotensin-II type 1 receptor blocker attenuates murine liver fibrosis development

Abstract

Abstract. 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 ccl 4 -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 CCl 4 , 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.

Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis

“…We previously demonstrated that blockade of angiotensin-II (AT-II) signal transduction through AT-II type 1 receptor (AT1R) inhibited hepatic fibrogenesis in rats [11,12]. The inhibitory effects of ARB mostly coincided with the suppression of activated hepatic stellate cells (Ac-HSC) [13]. Moreover, we demonstrated AT-II augmented LPS-TLR4 signaling through AT1R and ARB improved hepatic fibrogenesis and reduced TLR4-mediated innate immune signaling in Ac-HSC [14].…”

Alteration of the ERK5 pathway by hydroxysafflor yellow A blocks expression of MEF2C in activated hepatic stellate cellsin vitro: Potential treatment for hepatic fibrogenesis

“…HSYA interrupted ERK5 signaling in culture-activated HSC by reducing the phosphorylation of ERK5 and its downstream MEF2C gene, leading to the inhibition of HSC activation. An effective therapeutic strategy for suppressing liver fibrosis should improve the overall prognosis of patients with chronic liver diseases (Yoshiji et al, 2011). At this time, there is no ideal drug therapy for hepatic fibrosis (Pradeep Kumar et al, 2011).…”

Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on hepatic fibrosis

“…(14,15) This inhibitory effect of AT1R blocker (ARB) mostly coincided with the suppression of activated-HSCs (Ac-HSCs). (16) Accordingly, combined INT747 and ARB treatment might be useful in NASH. Here, we evaluated the effect and possible underlying mechanisms of combined INT747 and ARB administration on hepatic fibrogenesis in two different NASH rat models.…”