Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AIM:To investigate effect of losartan, an AT1 receptor antagonist, on hepatic fibrosis induced by CCl(4); and to determine whether or not AT1 receptors are expressed on hepatic stellate cells. METHODS AND RESULTS:Fifty male Sprague-Dawley rats, weighing (180 plus minus20)g, were randomized into five groups (control group, model group, and three losartan treated groups), in which all rats were given the subcutaneous injection of 40% CCl(4)(every 3 days for 6 weeks) except for rats of control group. Rats of losartan-treated groups were treated with losartan (20 mg/kg, 10 mg/kg, 5 mg/kg, daily gavage). After 6 weeks liver tissue and serum samples of all rats were examined. Serum hyaluronic acid (HA), procollagen type III (PC III) were detected by radioimmunoassays. van Giesion collagen staining was used to evaluate the extracellular matrix of rats with liver fibrosis. The expression of AT1 receptors, transforming growth factor-beta (TGF-beta), and alpha-smooth muscle actinalpha-SMA) in liver tissue were determined by immunohistochemical techniques. Compared with model group, serum ALT and AST of losartan-treated groups were significantly reduced (italic>t = 4.20,P < 0.01 and italic>t = 4.57,P < 0.01). Serum HA and PC III also had significant differences (italic>t = 3.53,P<0.01 and t=2.20, P<0.05). The degree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors, TGF-beta, and alpha-SMA in liver tissue.CONCLUSION:AT1 receptor antagonist, losartan, could limit the progression of the hepatic fibrosis induced by CCl(4). The mechanism may be related to the decrease in the expression of AT1 receptors and TGF-beta, ameliorating the injury of hepatocytes; activation of local renin-angiotensin system might relate to hepatic fibrosis; and during progression of fibrosis, activated hepatic stellate cells might express AT1 receptors.
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PMID:Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl(4). 1181 43

Hepatic stellate cells are the primary cell type responsible for matrix deposition in liver fibrosis, undergoing a process of transdifferentiation into fibrogenic myofibroblasts. These cells, which undergo a similar transdifferentiation process when cultured in vitro, are a major target of the profibrogenic agent transforming growth factor-beta (TGF-beta). We have studied activation of the TGF-beta downstream signaling molecules Smads 2, 3, and 4 in hepatic stellate cells (HSC) cultured in vitro for 1, 4, and 7 days, with quiescent, intermediate, and fully transdifferentiated phenotypes, respectively. Total levels of Smad4, common to multiple TGF-beta superfamily signaling pathways, do not change as HSC transdifferentiate, and the protein is found in both nucleus and cytoplasm, independent of treatment with TGF-beta or the nuclear export inhibitor leptomycin B. TGF-beta mediates activation of Smad2 primarily in early cultured cells and that of Smad3 primarily in transdifferentiated cells. The linker protein SARA, which is required for Smad2 signaling, disappears with transdifferentiation. Additionally, day 7 cells demonstrate constitutive phosphorylation and nuclear localization of Smad 2, which is not affected by pretreatment with TGF-beta-neutralizing antibodies, a type I TGF-beta receptor kinase inhibitor, or activin-neutralizing antibodies. These results demonstrate essential differences between TGF-beta-mediated signaling pathways in quiescent and in vitro transdifferentiated hepatic stellate cells.
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PMID:Smads 2 and 3 are differentially activated by transforming growth factor-beta (TGF-beta ) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent. 1254 35

Accumulation of hydrophobic bile acids during cholestasis leads to generation of oxygen free radicals in the liver. Accordingly, this study investigated whether polyphenols from green tea Camellia sinenesis, which are potent free radical scavengers, decrease hepatic injury caused by experimental cholestasis. Rats were fed a standard chow or a diet containing 0.1% polyphenolic extracts from C. sinenesis starting 3 days before bile duct ligation. After bile duct ligation, serum alanine transaminase increased to 760 U/l after 1 day in rats fed a control diet. Focal necrosis and bile duct proliferation were also observed after 1-2 days, and fibrosis developed 2-3 wk after bile duct ligation. Additionally, procollagen-alpha1(I) mRNA increased 30-fold 3 wk after bile duct ligation, accompanied by increased expression of alpha-smooth muscle actin and transforming growth factor-beta and the accumulation of 4-hydroxynenonal, an end product of lipid peroxidation. Polyphenol feeding blocked or blunted all of these bile duct ligation-dependent changes by 45-73%. Together, the results indicate that cholestasis due to bile duct ligation causes liver injury by mechanisms involving oxidative stress. Polyphenols from C. sinenesis scavenge oxygen radicals and prevent activation of stellate cells, thereby minimizing liver fibrosis.
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PMID:Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats. 1279 96

Previous studies have showed that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of liver cirrhosis. The localization of angiotensin II receptor in hepatic stellate cells opens up a new research direction of RAS in the regulation of liver fibrosis. However, the potential role of angiotensin II on Kupffer cells remains unexplored. As Kupffer cells are actively involved in the fibrotic process, the present study aimed, specifically, to demonstrate the presence of key RAS components, with particular reference to the AT(1) receptor, and its potential role in hepatic Kupffer cells. The expression of key RAS components in rat liver and isolated hepatic Kupffer cells was analyzed by RT-PCR. The expression and precise localization of AT(1) receptors in hepatic Kupffer cells were investigated by Western blot analysis and immunofluorescent double staining, respectively. The effect of angiotensin-stimulated Kupffer cells on the expression of the fibrogenic factors, i.e. transforming growth factor-beta (TGF-beta) and fibronectin, was examined by semi-quantitative RT-PCR. RT-PCR analysis showed that mRNA of several key RAS components-angiotensin II receptors, angiotensinogen, renin and angiotensin-converting enzyme, particularly the AT(1) receptors, was expressed in the liver and isolated hepatic Kupffer cells. The AT(1) receptor protein was consistently expressed in hepatic Kupffer cells as evidenced by Western blot analysis. Double immunostaining confirmed that the AT(1) receptors were specifically localized to the Kupffer cells from the liver and isolated hepatic Kupffer cells. On the other hand, angiotensin II stimulated mRNA expression of TGF-beta and fibronectin, which could be inhibitable by saralasin and losartan, the nonselective and specific antagonists for AT(1) receptors, respectively. The present findings clearly demonstrated the expression, localization and potential role of local RAS components with particular emphasis on the AT(1) receptors in hepatic Kupffer cells. The intimate interaction of angiotensin II with its AT(1) receptor located in the Kupffer cells and its fibrogenic action may represent a regulatory mechanism in the development of liver fibrosis such as inflammation and cirrhosis.
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PMID:Expression and localization of AT1 receptors in hepatic Kupffer cells: its potential role in regulating a fibrogenic response. 1459 16

During liver fibrogenesis, quiescent HSC (hepatic stellate cells) become active, a transformation that is associated with enhanced cell proliferation and overproduction of ECM (extracellular matrix). Inhibition of cell proliferation and induction of apoptosis are potential strategies to block the activation of HSC for the prevention and treatment of liver fibrosis. Levels of PPARgamma (peroxisome proliferator-activated receptor gamma) are dramatically diminished in parallel with HSC activation. Stimulation of PPARgamma by its agonists inhibits HSC activation in vitro and in vivo. We demonstrated recently that curcumin, the yellow pigment in curry, inhibited HSC activation in vitro, reducing cell proliferation, inducing apoptosis and inhibiting ECM gene expression. Further studies indicated that curcumin induced the gene expression of PPARgamma and stimulated its activity in activated HSC in vitro, which was required for curcumin to inhibit HSC proliferation. The aims of the present study were to evaluate the roles of PPARgamma activation in the induction of apoptosis and suppression of ECM gene expression by curcumin in activated HSC, and to elucidate the underlying mechanisms. Our results demonstrated that blocking PPARgamma activation abrogated the effects of curcumin on the induction of apoptosis and inhibition of the expression of ECM genes in activated HSC in vitro. Further experiments demonstrated that curcumin suppressed the gene expression of TGF-beta (transforming growth factor-beta) receptors and interrupted the TGF-beta signalling pathway in activated HSC, which was mediated by PPARgamma activation. Taken together, our results demonstrate that curcumin stimulated PPARgamma activity in activated HSC in vitro, which was required for curcumin to reduce cell proliferation, induce apoptosis and suppress ECM gene expression. These results provide novel insight into the mechanisms responsible for the inhibition of HSC activation by curcumin. The characteristics of curcumin, which has no adverse health effects, make it a potential candidate for prevention and treatment of hepatic fibrosis.
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PMID:Activation of PPARgamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro. 1532 Aug 68

Using a cDNA microarray, we identified osteopontin (OPN) as one of the genes upregulated in cultured activated hepatic stellate cells (HSCs). Northern and western blot analyses showed that OPN was increasingly expressed during the progressive activation of cultured rat HSCs, and a significant increase in OPN was observed in carbon tetrachloride-induced rat liver fibrosis. In biliary atresia, OPN protein was predominantly expressed in Kupffer cells and HSCs in the necrotic areas. Incubation of HSCs with recombinant OPN-induced significant proliferative and migratory effects, and induced matrix metalloproteinase 2 production and activation. Moreover, OPN increased type I collagen production and type II transforming growth factor-beta receptor mRNA and protein. In conclusion, this study shows that OPN is expressed in activated HSCs and suggests that the upregulation of OPN might be a central pathway of HSC activation.
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PMID:Effects and regulation of osteopontin in rat hepatic stellate cells. 1554 83

It is widely recognized that activated hepatic stellate cells (HSC) play a pivotal role in development of liver fibrosis. A platelet-derived growth factor (PDGF) is the most potent mitogen for HSC. The aim of this study was to examine the effect of imatinib mesylate (STI-571, Gleevec), a clinically used PDGF receptor (PDGFR) tyrosine kinase inhibitor, on development of experimental liver fibrosis. The rat model of pig serum-induced hepatic fibrosis was used to assess the effect of daily oral administration of STI-571 on the indexes of fibrosis. STI-571 markedly attenuated development of liver fibrosis and hepatic hydroxyproline and serum fibrosis markers. The number of alpha-smooth muscle actin-positive cells and mRNA expression of alpha2-(I)-procollagen, tissue inhibitor of metalloproteinases-1, and transforming growth factor-beta were also significantly suppressed by STI-571. Our in vitro study showed that STI-571 markedly attenuated PDGF-BB-induced proliferation and migration and alpha-SMA and alpha2-(I)-procollagen mRNA of activated HSC in a dose-dependent manner. STI-571 also significantly attenuated PDGF-BB-induced phosphorylation of PDGFR-beta, MEK1/2, and Akt in activated HSC. Because STI-571 is widely used in clinical practice, it may provide an effective new strategy for antifibrosis therapy.
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PMID:Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. 1561 80

The hepatic stellate cell (HSC) is the predominant cell type responsible for excess collagen deposition during liver fibrosis. Both transforming growth factor-beta (TGF-beta), the most potent fibrogenic cytokine for HSCs, which classically activates Smad signaling, and p38 MAPK signaling have been shown to influence collagen gene expression; however, the relative contribution and mechanisms that these two signaling pathways have in regulating collagen gene expression have not been investigated. The aim of this study was to investigate the relative roles and mechanisms of both Smad and p38 MAPK signaling in alpha1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad signaling reduced alpha1(I) collagen mRNA expression in untreated or TGF-beta-treated HSCs, and when both signaling pathways were simultaneously inhibited, alpha1(I) collagen gene expression was essentially blocked. Both signaling pathways were found to independently and additively increase alpha1(I) collagen gene expression by transcriptional mechanisms. TGF-beta treatment increased alpha1(I) collagen mRNA half-life, mediated by increased stability of alpha1(I) collagen mRNA through p38 MAPK signaling but not through Smad signaling. In conclusion, both p38 MAPK and Smad signaling independently and additively regulate alpha1(I) collagen gene expression by transcriptional activation, whereas p38 MAPK and not Smad signaling increased alpha1(I) collagen mRNA stability.
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PMID:SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor-beta-stimulated hepatic stellate cells. 1564 78

To study the anti-fibrogenic mechanisms of S-adenosylmethionine (AdoMet), transgenic mice harboring the -17 kb to +54 bp of the collagen alpha2 (I) promoter (COL1A2) cloned upstream from the beta-gal reporter gene were injected with carbon tetrachloride (CCl4) to induce fibrosis and coadministered either AdoMet or saline. Control groups received AdoMet or mineral oil. AdoMet lowered the pathology in CCl4-treated mice as shown by transaminase levels, hematoxylin and eosin, Masson's trichrome staining, and collagen I expression. beta-Galactosidase activity indicated activation of the COL1A2 promoter in stellate cells from CCl4-treated mice and repression of such activation by AdoMet. Lipid peroxidation, transforming growth factor-beta (TGFbeta) expression, and decreases in glutathione levels were prevented by AdoMet. Incubation of primary stellate cells with AdoMet down-regulated basal and TGFbeta-induced collagen I and alpha-smooth muscle actin proteins. AdoMet metabolites down-regulated collagen I protein and mRNA levels. AdoMet repressed basal and TGFbeta-induced reporter activity in stellate cells transfected with COL1A2 promoter deletion constructs. AdoMet blocked TGFbeta induction of the -378 bp region of the COL1A2 promoter and prevented the phosphorylation of extracellular signal-regulated kinase 1/2 and the binding of Sp1 to the TGFbeta-responsive element. These observations unveil a novel mechanism by which AdoMet could ameliorate liver fibrosis.
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PMID:S-adenosylmethionine blocks collagen I production by preventing transforming growth factor-beta induction of the COL1A2 promoter. 1598 38

Liver fibrosis and cirrhosis involve multiple cellular and molecular events that lead to deposition of an excess of extracellular matrix proteins and increase the distortion of normal liver architecture. Etiologies include chronic viral hepatitis, alcohol abuse and drug toxicity. Degradation of these matrix proteins occurs predominantly as a result of a family of enzymes called metalloproteases (MMPs) that specifically degrade collagenous and non-collagenous substrates. Matrix degradation in the liver is due to the action of at least four of these enzymes: MMP-1, MMP-2, MMP-3 and MMP-9. In the fibrinolytic system, MMPs can be activated through proteolytic cleavage by the action of urokinase plasminogen activator; a second mechanism includes the same metalloproteases. This activity is regulated at many levels in the fibrinolytic system. The main regulator is the PAI-1. This molecule blocks the conversion of plasminogen into plasmin, and the MMP cannot be activated. At a second level, the inhibition is possible by binding to inhibitors called TIMP that can inhibit the proteolitic activity even when the MMPs had been previously activated by plasmin. During abnormal conditions, overexpression of these inhibitors is directed by the transforming growth factor-beta that in a fibrotic disease acts as an extremely important adverse factor.
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PMID:[Hepatic fibrosis: role of matrix metalloproteases and TGFbeta]. 1616 29


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