An orally available small imidazolium salt ameliorates inflammation and fibrosis in a murine model of cholestasis

Abstract

Hepatic fibrosis is the result of chronic liver injuries underlined by diverse etiologies. The massive accumulation of extracellular matrix (ECM) proteins during fibrogenesis leads to structural distortion and functional disruption of the liver. There is currently no effective standard treatment for liver fibrosis. We previously identified a class of imidazolium salts (IMSs) with anti-fibrotic properties in a cell-based screen. In this report, we investigated the anti-fibrotic efficacy and mechanisms of a small IMS, 1,3-diisopropylimidazolium tetrafluoroborate (DPIM), in a hepatic fibrosis model induced by bile duct ligation (BDL) in mice. The orally available DPIM was administered to BDL mice via drinking water at three concentrations (0.5, 0.75, and 1 g/l) for 4 weeks. We observed a significant reduction in inflammation and collagen deposition in the liver, which could be mediated by a reduction in the expression of monocyte chemoattractant protein-1 (MCP-1) and by an enhancement in the matrix metalloproteinase-mediated ECM remodeling. The current findings highlight the importance for simultaneously targeting multiple pathways to more effectively attenuate and resolve liver fibrosis and warrant further studies on this compound in additional models of hepatic fibrosis.

Treatment of mouse liver slices with cholestatic hepatotoxicants results in down-regulation of Fxr and its target genes

“…It was suggested before, that changes related to ECM remodelling could lead to perturbations in intracellular signalling affecting Fxr related pathways and thereby leading to liver injuries [41]. …”

Attenuation of hepatic fibrosis by an imidazolium salt in thioacetamide‐induced mouse model

“…We did not detect changes of TIMP‐1 (Fig. a), which was downregulated by DPIM treatment in the BDL model . Overall, the enhanced MMPs activities by DPIM treatment could potentially help to restore the imbalanced ECM turnover in the TAA model.…”

“…Therefore, different mechanistically distinct hepatic fibrosis animal models are required to demonstrate the efficacy of anti‐fibrotic drug candidate to exclude model‐specific effects . In a previous report, we demonstrated DPIM treatment ameliorated fibrosis in a BDL induced fibrosis model, this prompted us to further investigate the anti‐fibrotic property of DPIM in other hepatic fibrosis animal models. Here we showed that DPIM could attenuate hepatic fibrosis in a TAA‐induced hepatic fibrosis model, which is considered to be more clinically relevant .…”

“…Some attempts have been made to investigate the potential biological application for this group of materials, for example, the anti‐oxidative function of imidazolium salt . We previously showed that an imidazolium salt, 1,3‐diisopropylimidazolium tetrafluoroborate (DPIM), could ameliorate liver fibrosis in a bile duct ligation (BDL) induced murine cholestasis . However, it is recognized that pathology in the BDL model shows little resemblance to human fibrosis (except for chronic biliary obstruction).…”

“…6 We previously showed that an imidazolium salt, 1,3diisopropylimidazolium tetrafluoroborate (DPIM), could ameliorate liver fibrosis in a bile duct ligation (BDL) induced murine cholestasis. 7 However, it is recognized that pathology in the BDL model shows little resemblance to human fibrosis (except for chronic biliary obstruction). In this study, we investigated the anti-fibrotic effect of DPIM and possible mechanism of action in another common murine model of liver fibrosis induced by thioacetamide (TAA), which may bear more similar histological patterns found in most human chronic liver diseases.…”