UMLS:C0239946 - FACTA Search

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Query: UMLS:C0239946 (liver fibrosis)
8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibrillin-1, together with elastin, is the main component of elastic fibers found throughout the extracellular space and responsible for the biomechanical properties of most tissues and organs. In this work, fibrillin-1 expression and modulation were explored in experimental rat liver fibrosis and in vitro; furthermore, the role of fibrillin-1 fragments on cell adhesion was analyzed. Fibrosis was induced by subjecting rats to common bile duct ligation for 72 h and 7 days or carbon tetrachloride (CCl(4)) treatment for 2 and 6 weeks. Immunohistochemistry showed that, after bile duct ligation, fibrillin-1, elastin, and alpha-smooth muscle actin colocalized in the developing portal connective tissue. In CCl(4)-treated animals, a similar colocalization was observed in septa; however, elastin deposition was not observed around activated alpha-smooth muscle actin-positive stellate cells of the parenchyma. Treatment with the profibrogenic mediator transforming growth factor-beta1 (TGF-beta1) greatly increased the fibrillin-1 expression of cultured liver fibroblasts. The level of fibrillin-1 expression was significantly higher in cells grown in restrained (stressed) collagen lattices compared with those grown in unrestrained collagen lattices. Cell adhesion on the C-terminal fragment of fibrillin-1 containing the RGD sequence (rF6H) slightly increased (between 0.3 and 2.5 microg/ml) and decreased at higher concentrations, while adhesion on the N-terminal fragment of fibrillin-1 (rF16) was dose-dependently decreased. In addition, the rF16 fragment decreased cell adhesion to fibronectin. In conclusion, our study illustrates the important deposition of fibrillin-1 that occurs in two mechanistically distinct settings of liver fibrogenesis. Furthermore, the induction of fibrillin-1 expression by TGF-beta1 and mechanical stress, and the antiadhesive properties of fibrillin-1 fragments suggest important implications for physiological and pathological fibrillin-1 catabolism during tissue remodeling.
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PMID:Fibrillin-1 expression in normal and fibrotic rat liver and in cultured hepatic fibroblastic cells: modulation by mechanical stress and role in cell adhesion. 1466 Oct 32

The extracellular matrix (ECM) expression is subject to distinct changes during ontogeny, and the natural course of liver fibrosis in neonates is thought to differ from that in adults. We compared the expression and distribution of main ECM components between neonatal and adult liver fibrosis. Liver biopsies from infants with neonatal cholestasis and fibrosis were compared to adult biopsies exhibiting an equivalent stage of fibrosis. All biopsies were examined by immunohistochemistry (indirect ABC method) for the ECM proteins, collagens I, III, IV, and VI, laminin, and fibronectin. Infants (aged 1-8 months) with neonatal hepatitis (n = 3), extrahepatic biliary atresia (EHBA) (n = 5), and normal histology (n = 2) were compared with 9 adults (aged 17-70 years) with chronic hepatitis (n = 3), primary biliary cirrhosis (PBC) (n = 4), and normal histology (n = 2). Collagens I, III, and IV and fibronectin were significantly increased in neonatal hepatitis with mild fibrosis (score < or = 4) compared to adults with an equivalent fibrosis stage. This increase was particularly notable in perisinusoidal spaces. Laminin expression was increased in portal and perisinusoidal spaces both in neonatal hepatitis and extrahepatic biliary atresia with mild fibrosis. In infants with moderate to severe fibrosis (score > or = 6), only collagen I was increased in comparison to adults, whereas collagen VI expression was identical in all groups, irrespective of the degree of fibrosis. Expression of matrix proteins was not different in infants and adults without fibrosis. The increased perisinusoidal deposition of certain ECM components in infants with active hepatitis and mild fibrosis may point to an underlying difference in the mechanism or stimulus of fibrogenesis in neonates as compared to adults.
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PMID:Divergent patterns of extracellular matrix protein expression in neonatal versus adult liver fibrosis. 1469 30

Activation of hepatic stellate cells (HSC) is a central event in the pathogenesis of liver fibrosis during chronic liver injury. We examined the expression of retinoic acid (RAR) and retinoid X receptors (RXR) during HSC activation and evaluated the influence of natural and synthetic retinoic acids (RA) on the phenotype of culture-activated HSC. The expression of the major RAR/RXR subtypes and isoforms was analyzed by Northern hybridization. Presence of functional receptor proteins was established by gel shift analysis. Retinoic acids, RAR, and RXR selective agonists and an RAR antagonist were used to evaluate the effects of retinoid signalling on matrix synthesis by Northern blotting and immunoprecipitation, and on cell proliferation by BrdU incorporation. The 9-cisRA and synthetic RXR agonists reduced HSC proliferation and synthesis of collagen I and fibronectin. All-trans RA and RAR agonists both reduced the synthesis of collagen I, collagen III, and fibronectin, but showed a different effect on cell proliferation. Synthetic RAR agonists did not affect HSC proliferation, indicating that ATRA inhibits cell growth independent of its interaction with RARs. In contrast, RAR specific antagonists enhance HSC proliferation and demonstrate that RARs control proliferation in a negative way. In conclusion, natural RAs and synthetic RAR or RXR specific ligands exert differential effects on activated HSC. Our observations may explain prior divergent results obtained following retinoid administration to cultured stellate cells or to animals subjected to fibrogenic stimuli.
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PMID:Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids. 1475 28

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is accompanied by inflammation and fibrosis eventually leading to cirrhosis. The chemokine CXCL12 is involved in chronic inflammatory conditions. The role of the CXCL12/CXCR4 pathway in HCV- and HBV-associated liver inflammation and fibrosis was therefore studied. The levels and tissue localization of CXCL12 in liver and plasma of HCV and HBV patients were tested using immunohistochemistry and ELISA. The expression and function of CXCR4 on liver-infiltrating lymphocytes (LIL) were tested by FACS and transwell migration assays. We found that CXCL12 is expressed by bile duct epithelial cells in normal liver tissue. Bile duct proliferation and liver fibrosis in chronic HCV and HBV infection result in the anatomical re-distribution of CXCL12 in the liver. Moreover, CXCL12 is up-regulated in the endothelium of neo-blood-vessels formed in active inflammatory foci and is significantly elevated, compared with controls, in the plasma of patients with advanced liver fibrosis. Complementing these observations were others indicating that over 50% of LIL express CXCR4 and, in response to CXCL12, migrated and adhered to fibronectin. These observations suggest an important role for the CXCL12/CXCR4 pathway in recruitment and retention of immune cells in the liver during chronic HCV and HBV infection.
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PMID:Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus. 1504 28

Hepatic fibrosis, is a wound healing process characterized by accumulation of extracellular matrix proteins (ECM) especially collagen types I and III, as well as an increase in other extracellular matrix constituents such as proteoglycans, fibronectin and laminin in response to liver injury. Recruitment of leukocytes takes place after the insult and requires several adhesion molecules. Monocytes and macrophages are involved in inflammatory actions by producing nitric oxide and inflammatory cytokines. As a consequence of chronic tissue damage stellate cells (SC) as well as extracellular matrix producting cells, undergo a process of activation characterized by proliferation, motility, contractility, and synthesis of extracellular matrix. Activation of SC is regulated by several soluble factors, including cytokines, chemokines, growth factors, and products of oxidative stress. TGF - b and IL- 6 are the two main fibrogenic cytokines. Potential regulatory factors of the activation of SC are important targets for future antifibrogenic treatments.
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PMID:Liver fibrosis and inflammation. A review. 1511 54

Rat Kupffer cells (KC), hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC) all express the C5a receptor (C5aR) constitutively in contrast to hepatocytes (HC). HSC showed an unexpectedly high level of expression of the C5aR. As these cells are known to play a key role in the induction of liver fibrosis we hypothesized that C5a may possibly induce fibrogenetic proteins in these cells. HSC are known to express the extracellular matrix (ECM) proteins collagen IV, fibronectin, entactin and the structure protein smooth muscle actin (SMA) which is regarded as a marker for the fibrotic conversion of HSC to myofibroblast-like cells. We investigated the effect of recombinant rat C5a (rrC5a) on the upregulation of these ECM-proteins and of SMA, all of which are known to be expressed by HSC. The profibrotic cytokine TGF-beta1 (2 ng/ml), which was used as a control, clearly upregulated the three matrix proteins but not SMA. In the absence of any stimulus HSC upregulated the three ECM-proteins as well as SMA during their conversion into myofibroblast-like cells. This resulted in a high stimulus-independent plateau of the mRNA expressions for all four proteins after four to five days of culture. Readouts were therefore taken at 72 h after the isolation of the HSC when the investigated mRNA levels had not yet reached their maxima due to the conversion of the cells. The first 24 h of culture were performed without stimulus and the following 48 h in the presence of 100 nM rrC5a (1 micro g/ml) or TGF-beta1 (2 ng/ml). Only fibronectin-specific mRNA was clearly upregulated by C5a whereas entactin, collagen IV and SMA were not affected by C5a. By competitive-quantitative PCR the upregulation of fibronectin-specific mRNA was determined to be about five-fold. As TGF-beta1 upregulated all of the three investigated ECM-proteins but not SMA it was checked as to whether C5a might act indirectly by upregulating the expression of TGF-beta1 in KC and HSC, as both cell types are known to be sources of this profibrotic cytokine. However, using RT-PCR, such an effect was not detectable in either cell type after 3, 10 or 24 h.
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PMID:Upregulation of fibronectin but not of entactin, collagen IV and smooth muscle actin by anaphylatoxin C5a in rat hepatic stellate cells. 1537 59

Mice lacking aryl hydrocarbon (dioxin) receptor (AhR) had variable degree of hepatic fibrosis and altered liver architecture. Transforming growth factor-beta (TGF-beta), a major profibrogenic molecule in the liver, is localized to the extracellular matrix by its association to the latent TGF-beta-binding protein-1 (LTBP-1). Very recently, LTBP-1 has been shown to be negatively regulated by the AhR. Embryonic fibroblasts from AhR-null (AhR(-/-)) mice overexpress LTBP-1 and secrete four times more active TGF-beta than wild-type fibroblasts. To test whether TGF-beta and LTBP-1 overexpression colocalize within the fibrotic nodule of AhR(-/-) liver, we have characterized this hepatic portal fibrosis using collagen protein staining, immunohistochemistry and in situ hybridization. LTBP-1 mRNA and protein were overexpressed in the fibrotic region and colocalized with other indicators of fibrosis such as collagen and fibronectin and the fibroblast marker proteins alpha-actin and vimentin. TGF-beta protein also colocalized with fibrosis, although in contrast, TGF-beta mRNA expression, rather than restricted to the fibrotic compartment, was present throughout the hepatic parenchyma and exhibited similar levels in wild-type and AhR(-/-) mice. These results suggest that LTBP-1 targets TGF-beta to specific areas of the liver and that the AhR could be a negative regulator of liver fibrosis, possibly through the control of LTBP-1 and TGF-beta activities.
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PMID:Liver portal fibrosis in dioxin receptor-null mice that overexpress the latent transforming growth factor-beta-binding protein-1. 1537 62

Liver cirrhosis is caused by a relative imbalance between synthesis and degradation of collagens. Arg-Gly-Asp (RGD) peptide is a major adhesive domain of several extracellular matrix (ECM) components, such as that involved in the binding of fibronectin to the alpha5beta1 integrin receptor. We previously reported that RGD peptide increased the expression of matrix metalloproteinase in hepatic stellate cells (HSCs) which play a major role in hepatic fibrosis. We evaluated whether RGD-peptides inhibit the progression of liver fibrosis in an animal model of carbon tetrachloride-induced hepatotoxicity. RGD peptide (GRGDS) (1 mg/kg body weight) was injected intraperitoneally (i.p.) 3 times a week for one month. The group treated with control peptide (GRGES) showed pathologically typical hepatic fibrosis, while the RGD-treated group showed minimal fibrotic changes. The liver contents of collagen and hydroxyproline in the RGD-treated group was significantly lower than that of the control group. Collagenase activity measured in liver homogenates was significantly higher in the treated group than in the control group. In an in vitro study using TWNT-4 cells derived from human HSCs, RGD peptide (100 mug/ml) reduced the expression of type I collagen and tissue inhibitor of matrix metalloproteinase-1, and increased that of matrix metalloproteinase-1. These results indicated that RGD peptides inhibited liver fibrosis associated with both decreased collagen production and increased collagenase acitivity, and suggested that RGD peptide might be useful for the therapy of hepatic fibrosis.
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PMID:Arg-Gly-Asp (RGD) peptide ameliorates carbon tetrachloride-induced liver fibrosis via inhibition of collagen production and acceleration of collagenase activity. 1554 72

Excessive production of extracellular matrix is responsible for clinical manifestations of fibroproliferative disorders and drugs which can inhibit excessive synthesis of type I collagen are needed for the therapy. Several dicationic diphenylfurans were synthesized and were found to bind RNA. Two of these type compounds were able to reduce synthesis of type I collagen by human fibroblasts and human activated hepatic stellate cells (HSCs). Activated HSCs are responsible for collagen production in liver fibrosis. When added at 40 microM compound 588 reduced intracellular level and secretion of procollagen alpha1(I) by 50%, while compound 654 reduced these parameters by more than 80% at 20 microM. 654 also significantly reduced secretion of fibronectin. Toxic effects were observed at 80 microM for 588 and 40 microM for 654. 654 reduced expression of a reporter gene with collagen signal peptide, while expression of the same gene without signal peptide was unaffected. Also, expression of intracellular proteins tubulin and calnexin was unchanged. 654 accumulated inside the cell in the cytoplasm and did not change the steady-state level of collagen mRNAs. Treatment of cells with proteosome inhibitor MG132 did not change the inhibitory effect of 654, suggesting that 654 acts as suppressor of translation of proteins containing a signal peptide. Most secreted proteins of fibroblasts and activated HSCs are components of extracellular matrix. Therefore inhibition of their production, as shown here for procollagen alpha1(I) and fibronectin, may be a useful property of some of diphenylfurans, making these compounds a basis for development of antifibrotic drugs.
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PMID:Inhibitory effect of dicationic diphenylfurans on production of type I collagen by human fibroblasts and activated hepatic stellate cells. 1570 83

The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)gamma exert counter-regulatory effects on hepatic stellate cells (HSCs) and protect against liver fibrosis development in rodents. Here, we investigated whether FXR ligands regulate PPARgamma expression in HSCs and models of liver fibrosis induced in rats by porcine serum and carbon tetrachloride administration and bile duct ligation. Our results demonstrate that HSCs trans-differentiation associated with suppression of PPARgamma mRNA expression, whereas FXR mRNA was unchanged. Exposure of cells to natural and synthetic ligands of FXR, including 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic derivative of chenodeoxycholic acid, reversed this effect and increased PPARgamma mRNA by approximately 40-fold. Submaximally effective concentrations of FXR and PPARgamma ligands were additive in inhibiting alpha1(I) collagen mRNA accumulation induced by transforming growth factor (TGF)beta1. Administration of 6-ECDCA in rats rendered cirrhotic by porcine serum and carbon tetrachloride administration or bile duct ligation reverted down-regulation of PPARgamma mRNA expression in HSCs. Cotreatment with 6-ECDCA potentiates the antifibrotic activity of rosiglitazone, a PPARgamma ligand, in the porcine serum model as measured by morphometric analysis of liver collagen content, hydroxyproline, and liver expression of alpha1(I) collagen mRNA, alpha-smooth muscle actin, fibronectin, TGFbeta1, and tissue inhibitor of metalloprotease 1 and 2, whereas it enhanced the expression of PPARgamma and uncoupling protein 2, a PPARgamma-regulated gene, by 2-fold. In conclusion, by using an in vitro and in vivo approach, we demonstrated that FXR ligands up-regulate PPARgamma mRNA in HSCs and in rodent models of liver fibrosis. A FXR-PPARgamma cascade exerts counter-regulatory effects in HSCs activation.
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PMID:Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. 1938 39

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