TNFα is required for cholestasis-induced liver fibrosis in the mouse

Abstract

TNFα, a mediator of hepatotoxicity in several animal models, is elevated in acute and chronic liver diseases. Therefore, we investigated whether hepatic injury and fibrosis due to bile duct ligation (BDL) would be reduced in TNFα knockout mice (TNFα−/−). Survival after BDL was 60% in wild-type mice (TNFα+/+) and 90% in TNFα−/− mice. Body weight loss and liver to body weight ratios were reduced in TNFα−/− mice compared to TNFα+/+ mice. Following BDL, serum alanine transaminases (ALT) levels were elevated in TNFα+/+ mice (268.6 ± 28.2 U/L) compared to TNFα−/− mice (105.9 U/L ± 24.4). TNFα −/− mice revealed lower hepatic collagen expression and less liver fibrosis in the histology. Further, α-smooth muscle actin, an indicator for activated myofibroblasts, and TGF-β mRNA, a profibrogenic cytokine, were markedly reduced in TNFα−/− mice compared to TNFα+/+ mice. Thus, our data indicate that TNFα induces hepatotoxicity and promotes fibrogenesis in the BDL model.

Olive oil and its phenolic compounds (hydroxytyrosol and tyrosol) ameliorated TCDD-induced heptotoxicity in rats via inhibition of oxidative stress and apoptosis

“…It offers protection to cells from oxidative damages induced by hydrogen peroxides and hydroperoxides (Gabele et al, 2009). In TCDD-intoxicated rats, there was an elevation in GSH level (p50.05) (Figure 3) in liver homogenates compared with vehicle control rats.…”

Protective effect of the aqueous extract from the root ofPlatycodon grandiflorumon cholestasis-induced hepatic injury in mice

“…BC703 may reduce oxidative stress by recovery of antioxidative enzymes, together with decrease in lipid peroxidation and oxidative stress. However, TNF-α in BDL-induced cholestasis mediates acute and chronic liver injury and plays an important role in hepatic fibrosis and cirrhosis (Gäbele et al, 2009). Khanal et al (2009) reported that saponins isolated from the root of P. grandiflorum decreased the TNF-α level on acute ethanol-induced hepatic injury in mice.…”

The Role of PI3K p110gamma in chronic liver injury

“…Thus, we first assessed PI3K p110γ mRNA expression in different murine models of chronic liver injury by quantitative PCR. We observed a significantly increased expression in the BDL model, which is a well established liver fibrosis model (Ezure et al, 2000,Gabele et al, 2009,Isayama et al, 2006 ( Fig. 4a), as well as in two dietary NASH models, namely the MCD model (Weltman et al, 1996) (Fig 4b) and a high fat diet (HFD) model (Fig 4c), which are also well established (Gabele et al, 2011b,Gabele et al, 2011a,Matsuzawa et al, 2007,Paigen et al, 1985.…”

“…The bile duct ligation model has already widely been used to evaluate genetic factors, which are associated with hepatic fibrogenesis. Experimental liver fibrogenesis is for example increased in IL-6 knockout mice, but decreased in TNF-and CD14 knockout mice (Ezure et al, 2000,Gabele et al, 2009,Isayama et al, 2006.…”