Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-β soluble receptor: Implications for antifibrotic therapy

Yata, Yutaka; Gotwals, Philip J.; Koteliansky, Victor; Rockey, Don C.

doi:10.1053/jhep.2002.32673

Cited by 151 publications

(107 citation statements)

References 37 publications

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“…Soluble TGF-b receptors and soluble Tb-RII antibodies block hepatic fibrosis in animal models. [32][33][34] In this study, we demonstrated that EGCG dose dependently blocked TGF-b signaling in passaged HSC (Figure 1a). Further experiments revealed that EGCG had no effect on the secretion or activation of latent TGF-b1 (Figure 2a).…”

Section: Discussionsupporting

confidence: 53%

The antifibrogenic effect of (−)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells

Zhou

Zheng

et al. 2006

Laboratory Investigation

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Hepatic stellate cells (HSC) are the major players during hepatic fibrogenesis. Overproduction of extracellular matrix (ECM) is a characteristic of activated HSC. Transforming growth factor-beta (TGF-b) is the most potent fibrogenic cytokine while connective tissue growth factor (CTGF) mediates the production of TGF-b-induced ECM in activated HSC. HSC activation and hepatic fibrogenesis are stimulated by oxidative stress. Glutathione (GSH) is the most important intracellular antioxidant. The aim of this study is to explore the mechanisms of (À)-epigallocatechin-3-gallate (EGCG), the major and most active component in green tea extracts, in the inhibition of ECM gene expression in activated HSC. It is hypothesized that EGCG inhibits ECM gene expression in activated HSC by interrupting TGF-b signaling through attenuating oxidative stress. It is found that EGCG interrupts TGF-b signaling in activated HSC by suppressing gene expression of type I and II TGF-b receptors. EGCG inhibits CTGF gene expression, leading to the reduction in the abundance of ECM, including aI(I) procollagen. Exogenous CTGF dose dependently eliminates the antifibrogenic effect. EGCG attenuates oxidative stress in passaged HSC by scavenging reactive oxygen species and reducing lipid peroxidation. De novo synthesis of GSH is a prerequisite for EGCG to interrupt TGF-b signaling and to reduce the abundance of aI(I) procollagen in activated HSC in vitro. Taken together, our results demonstrate that the interruption of TGF-b signaling by EGCG results in the suppression of gene expression of CTGF and ECM in activated HSC in vitro. In addition, our results, for the first time, demonstrate that the antioxidant property of EGCG derived from de novo synthesis of intracellular GSH plays a critical role in its antifibrogenic effect. These results provide novel insights into the mechanisms of EGCG as an antifibrogenic candidate in the prevention and treatment of liver fibrosis.

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Section: Discussionsupporting

confidence: 53%

The antifibrogenic effect of (−)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells

Zhou

Zheng

et al. 2006

Laboratory Investigation

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“…Further, the comparison of absolute expression of type I collagen mRNA and respective protein amount as assessed by Sirius red staining suggests a relatively greater reduction of collagen at the protein level after administration of sPDGFRb. This discrepancy was previously described in experiments investigating the inhibition of hepatic sPDGFRb inhibits hepatic fibrogenesis E Borkham-Kamphorst et al fibrosis by sTbRII 30 and might be due to the posttranscriptional regulation of collagen expression in cultured HSC. 44 We have not yet analyzed the impact of sPDGFRb with regard to chemotaxis of HSC towards BD structures that were shown to contribute to the development of periductular fibrosis in cholestatic disorders.…”

Section: Discussionmentioning

confidence: 70%

“…For application of purified soluble receptor proteins (sTbRII, sPDGFRb), 25 mg/animal (0.1 mg/kg sPDGFRb inhibits hepatic fibrogenesis E Borkham-Kamphorst et al body weight) was administered intravenously upon bile duct ligature (BDL) according to established protocols. 30 Injections into the peritoneum were repeated twice a week until the animals were killed 14 days after surgery.…”

Section: Experimental In Vivo Model Of Liver Fibrogenesismentioning

confidence: 99%

Dominant-negative soluble PDGF-β receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis

Borkham-Kamphorst

Herrmann

Stoll

et al. 2004

Laboratory Investigation

140

103

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Hepatic fibrogenesis is a consequence of hepatic stellate cells that become activated and transdifferentiate into a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. In this process, platelet-derived growth factor (PDGF) is the most potent stimulus for hepatic stellate cell proliferation and migration, and is overexpressed during active hepatic fibrogenesis. This cytokine binds to the PDGF receptor type b, activates Ras and sequentially propagates the stimulatory signal sequentially via phosphorylation of Raf-1, MEK and the extracellular-signal regulated kinases ERK1/ERK2. Hepatic injury is associated with both increased autocrine PDGF signaling and upregulation of PDGF receptor. In this study, we report that a dominant-negative soluble PDGF-b receptor consisting of a chimeric IgG containing the extracellular portion of the PDGF receptor type b blocks HSC activation and attenuates fibrogenesis induced by ligation of the common bile duct in rats. In culture-activated hepatic stellate cells, the soluble receptor blocks phosphorylation of endogenous PDGF receptor, phosphorylation of the ERK1/EKR2 signal and reduces proliferative activities of HSC. In vivo, both the delivery of the purified soluble PDGF antagonist and the administration of adenoviruses expressing the artificial transgene were able to reduce significantly the expression of collagen and a-smooth muscle actin. Our results demonstrate that PDGF plays a critical role in the progression and initiation of experimental liver fibrogenesis, and suggest that early anti-PDGF intervention should have a therapeutical impact on the treatment of liver fibrogenesis.

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“…13 Moreover, anti-TGF-β2 antibody and a TGF-β1 antisense oligonucleotide attenuate kidney fibrosis in the diabetic rat and in unilateral ureteral obstructions, respectively. 88,93 Hepatic fibrosis in rodents can be inhibited by soluble TβRII administered intraperitoneally 94 or by intramuscular injections of an adenovirus expressing the ectodomain of TβRII fused to the Fc portion of IgG. 95 Adenoviral soluble TβRII can also inhibit constrictive remodeling after coronary angioplasty in pigs.…”

Section: Antagonists Of Tgf-β For Disease Treatmentmentioning

confidence: 99%

Medical Applications of Transforming Growth Factor-

Flanders¹,

Burmester²

2003

Clinical Medicine & Research

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Transforming growth factor-β (TGF-β) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-βs useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-β has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-β have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-β activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.

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Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-β soluble receptor: Implications for antifibrotic therapy

Abstract: Transforming growth factor (TGF)␤

Cited by 151 publications

References 37 publications

The antifibrogenic effect of (−)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells

The antifibrogenic effect of (−)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells

Dominant-negative soluble PDGF-β receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis

Medical Applications of Transforming Growth Factor-

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