Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells

Murata, Tōru; Arii, Shigeki; Nakamura, Toshio; Mori, Akira; Kaido, Toshimi; Furuyama, Hiroaki; Furumoto, Katsuyoshi; Nakao, Teizo; Isobe, Naoki; Imamura, Masayuki

doi:10.1016/s0168-8278(01)00169-6

Cited by 77 publications

(64 citation statements)

References 41 publications

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“…Serum hyaluronate has been suggested to be used in prediction of hepatic fibrosis and the evaluation of treatment response of various antifibrotic drugs in human studies [36] and in rat [37,38] models of hepatic fibrosis. Several influencing factors such as hepatic inflammatory activity and the indicators of this activity (i.e.…”

Section: Discussionmentioning

confidence: 99%

Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats

Soylu

Aydoğdu²,

Başaran³

et al. 2006

WJG

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AIM:To investigate whether antioxidants vitamin E and C can retard development of hepatic fibrosis in the biliary-obstructed rats. METHODS:Fifty Wistar albino rats were randomly assigned to 5 groups (10 rats in each). Bile duct was ligated in 40 rats and they were treated as follows: group vitC, vitamin C 10 mg/kg sc daily; group vitE, vitamin E 15 mg/kg sc daily; group vitEC, both of the vitamins; bile duct-ligated (BDL, control) group, physiological saline sc. The fifth group was assigned to sham operation. At the end of fourth week, the rats were decapitated, and hepatic tissue biochemical collagen content and collagen surface area were measured. Hepatic tissue specimens were histopathologically evaluated according to Scheuer system. Serum hyaluronate levels were measured by ELISA method. RESULTS:Despite being higher than sham group, hepatic collagen level was significantly decreased in each of the vitC, vitE and vitEC groups (32.7 ± 1.2, 33.8 ± 2.9, 36.7 ± 0.5 μg collagen/mg protein, respectively) compared to BDL (48.3 ± 0.6 mg collagen/g protein) (P < 0.001 for each vitamin group). Each isolated vitamin C, isolated vitamin E and combined vitamin E/C supplementation prevented the increase in hepatic collagen surface density (7.0% ± 1.1%, 6.2% ± 1.7%, 12.3% ± 2.0%, respectively) compared to BDL (17.4% ± 5.6%) (P < 0.05 for each). The same beneficial effect of vitamin C, vitamin E and combined vitamin E/C treatment was also observed on the decrease of serum hyaluronate levels compared to BDL group (P < 0.001). The relative liver and spleen weights, serum transaminases, cholestatic enzymes, bilirubins and histopathological inflammation scores were not different between the antioxidant treatment groups and the control. However, fibrosis staging scores were obviously reduced only in the vitamin E/C combination group (vit EC: 2.4 ± 0.8 vs BDL: 3.1 ± 0.7; P < 0.05). CONCLUSION:Each antioxidant vitamin E, vitamin C and their combination retard hepatic fibrosis in biliary-obstructed rats. Oxidative stress may play a role in the pathogenesis of hepatic fibrosis in secondary biliary cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats

Soylu

Aydoğdu²,

Başaran³

et al. 2006

WJG

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“…28 The only effective approach to treating advanced liver fibrosis is transplantation. 29 However, several potential anti-fibrotic therapies have been investigated, including interferon ␣ and ␥, 30,31 hepatocyte growth factor gene therapy, 32 and inhibitors of transforming growth factor-␤-1, 33 Rho GTPase-associated kinase, 34 and the renin-angiotensin system. 35 Two approaches to removing the fibrotic scar involve increasing the levels of ECM-degrading MMPs or decreasing the levels of their natural inhibitors, the TIMPs.…”

Section: Discussionmentioning

confidence: 99%

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats

et al. 2004

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F ibrosis is associated with many liver diseases, including hepatitis C virus infection, iron deposition, alcohol consumption, and nonalcoholic fatty liver disease. Hepatic fibrosis results from a net increased synthesis and decreased degradation of extracellular matrix (ECM) proteins. Type I collagen is the most prevalent ECM protein deposited, 1 with activated hepatic stellate cells (HSCs) serving as the primary source. Following a fibrogenic stimulus, HSCs activate from their normal quiescent state, whereby they increase synthesis of procollagen type I messenger RNA (mRNA) and protein, 1,2 and increase cellular proliferation, migration, and contractility. 3,4 Excess ECM accumulation results in scarring within the tissue. Our understanding of ECM degradation during hepatic fibrosis is still very limited. ECM degradation is mediated by matrix metalloproteinases (MMPs), a family of zinc-dependent enzymes grouped into collagenases, gelatinases, stromelysins, and membrane-type MMPs, 5 based upon their substrates. Interstitial collagenases (MMP-1 and MMP-13 in humans,

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“…11,12 Moreover, activation of Rho induces a myofibroblast, aSMAexpressing differentiation program in several cell types. 27,28 Activation of Rho is followed by activation of ROCK, which phosphorylates non-muscle myosin II, inducing translocation of transcription factors serum response factor and myocardin-related transcriptional activator from the cytoplasm to the nucleus and transcription of aSMA.…”

Section: Thyroid Hormones Induce Hsc Activation I Zvibel Et Almentioning

confidence: 99%

Thyroid hormones induce activation of rat hepatic stellate cells through increased expression of p75 neurotrophin receptor and direct activation of Rho

Zvibel

Atias

Phillips

et al. 2010

Laboratory Investigation

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We have previously shown that hyperthyroidism is detrimental for liver fibrosis and in this study we have investigated the mechanisms regulating triiodothyronine (T3) and L-thyroxine (T4) activation of hepatic stellate cells (HSC). Expression of a-smooth muscle actin (aSMA) and p75 neurotrophin receptor (p75NTR) was determined by western blot analyses and transient transfection of the promoters. Rho activation was assayed using a pull-down assay and by ELISA. Expression of thyroid hormone receptor a1 decreases, whereas T4 receptor integrin aVb3 increases, with transdifferentiation of HSC to myofibroblasts. T3 and T4 enhance HSC activation, without affecting proliferation or phosphorylation of mitogen-activated protein kinase, signal transducer and activator of transcription 3 or Akt. Addition of 10 À7 M T3 or T4 to thyroid hormone-depleted serum induces a twofold increase in activation marker aSMA, as well as upregulation of p75NTR protein levels. Both hormones enhance transcription of aSMA and p75NTR. We report a novel signaling pathway for thyroid hormones, activation of Rho. T4 induces activation of Rho acting through avb3 integrin, and the activation is abolished by the T4 antagonist, tetraiodothyroacetic acid, by peptide RGD and by a function-blocking antibody to integrin b3. T3 and T4 increase phosphorylation of non-muscle myosin light chain II, a downstream signal to Rho/Rho-kinase activation. T3 also induces expression of tumor necrosis factor-a. In vivo, administration of T3 or T4 together with thioacetamide (TAA) enhances fibrosis after 3 weeks, compared with the TAA-treated group, accompanied by increased aSMA in T3-and T4-treated groups, and of p75NTR in T4-treated rats. Thyroid hormones enhance activation of HSC through increased p75NTR and aSMA expression and activation of Rho, therefore accelerating development of liver fibrosis.

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Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells

Abstract: These findings indicate that Y-27632 may be useful for the clinical management of liver fibrosis.

Cited by 77 publications

References 41 publications

Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats

Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats

Thyroid hormones induce activation of rat hepatic stellate cells through increased expression of p75 neurotrophin receptor and direct activation of Rho

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