Blockade of type β transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat

Abstract

We eliminated type ␤ transforming growth factor (TGF-␤) signaling by adenovirus-mediated local expression of a dominant-negative type II TGF-␤ receptor (AdCAT␤-TR) in the liver of rats treated with dimethylnitrosamine, a model of persistent liver fibrosis. In rats that received a single application of AdCAT␤-TR via the portal vein, liver fibrosis as assessed by histology and hydroxyproline content was markedly attenuated. All AdCAT␤-TRtreated rats remained alive, and their serum levels of hyaluronic acid and transaminases remained at low levels, whereas all the AdCAT␤-TR-untreated rats died of liver dysfunction. The results demonstrate that TGF-␤ does play a central role in liver fibrogenesis and indicate clearly in a persistent fibrosis model that prevention of fibrosis by anti-TGF-␤ intervention could be therapeutically useful.

Sorafenib inhibits transforming growth factor β1-Mediated Epithelial-Mesenchymal Transition and apoptosis in mouse hepatocytes

“…Given the prominent role of TGFb in EMT and fibrogenesis, a number of strategies for blocking TGF-b signaling have been proposed. [22][23][24] Small molecules targeting this signaling cascade have great therapeutic potential. To identify such candidates, a drug library screen was performed using (CAGA) 12 -Lux, a luciferase reporter that is activated in response to a wide range of TGF-b1 concentrations (Supporting Fig.…”

“…Several gene therapy approaches using dominant-negative TGF-b receptors and BMP-7 have been developed to prevent fibrosis in different tissues. 22,23 Similarly, ectopic overexpression of Smad7 in the hepatocytes of transgenic mice was shown to attenuate TGF-b signaling and thereby improve CCl 4 -induced liver fibrosis. 24 In addition to these protein-based therapies, small molecules and biological agents that act on this signaling cascade have shown strong therapeutic potential in clinical settings.…”

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

“…Among the numerous profibrogenic mediators, TGF-β is regarded as the most potent in liver fibrosis. Overexpression of TGF-β in the liver has been shown to induce severe liver fibrosis [22], whereas disrupting its synthesis or signaling pathway markedly decreased fibrosis in experimental models [23]. In HSC, TGF-β promotes the activation process, stimulates the synthesis of ECM proteins and inhibits their degradation [24].…”

Current concepts in radiation enteritis and implications for future clinical trials

“…However, if the rats were transfected with an adenoviral vector carrying a truncated TGF-␤ receptor (AdCAT␤-TR) prior to DMN induction, then liver fibrosis was reduced significantly. 104 Furthermore, all of the DMN-treated rats that were infused with saline or with the adenoviral vector died, whereas the rats that were infused with AdCAT␤-TR survived. In a similar experiment using an adenovirus that carried a soluble receptor for TGF-␤, liver fibrosis also was decreased after DMN treatment, because the soluble receptor bound to TGF-␤ and prevented its biologic action.…”

“…Ramos et al 69 Human IPF ELISA, RT-PCR Increased Ziesche et al 70 Human IPF ELISA, RT-PCR Increased, inhibited by IFN-␥ Gauldie et al 72 Rat EPF IH, CGT Increased Querfeld et al 74 Human SS IH, ISH Increased Ihn et al 75 Human SS ELISA, IB Increased, inhibited by TGF-␤ Ab Oh et al 83 Rat DN NB, MLEC Increased, inhibited by TGF-␤ Ab Hong et al 86 Mouse DN IH, ISH, SH Increased Sharma et al 87 Human DN ELISA Increased, inhibited by, captopril Helmich et al 88 Human DN SEI Increased Mezzano et al 90 Human MN IH, ISH Increased Honkanen et al 91 Human MN EIA Increased Diamond et al 92 Rat ON NB, IL Increased Isaka et al 96 Rat ON IH, NB, ISH, AODN transfer Increased, inhibited by TGF-␤ AODN Kaneto et al 97 Human ON IH, RT-PCR Increased Sharma et al 100 Human CAN RT-PCR Increased Cuhaci et al 101 Human CAN IH Increased Qi et al 104 Rat LC NB, AdCAT␤-TR transfection Inhibited by AdCAT␤-TR transfection Ueno et al 105 Rat LC IF, ELISA, AdT␤-ExR Inhibited by AdT␤-ExR injection Zhang et al 106 Rat LC ELISA Increased, inhibited by IFN-␥ gene transfer Bacr et al 107 Human LC NB, IH Increased …”