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

Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis, transdifferentiating in chronic liver disease from "quiescent" HSC to fibrogenic myofibroblasts. Transforming growth factor-beta (TGF-beta), acting both directly and indirectly, is a critical mediator of this process. To characterize the function of the TGF-beta signaling intermediates Smad2 and Smad3 in HSC, we infected primary rat HSC in culture with adenoviruses expressing wild-type and dominant negative Smads 2 and 3. Smad3-overexpressing cells exhibited increased deposition of fibronectin and type 1 collagen, increased chemotaxis, and decreased proliferation compared with uninfected cells and those infected with Smad2 or either dominant negative, demonstrating different biological functions for the two Smads. Additionally, coinfection experiments suggested that Smad2 and Smad3 signal via independent pathways. Smad3-overexpressing cells as well as TGF-beta-treated cells demonstrated more focal adhesions and increased alpha-smooth muscle actin (alpha-SMA) organization in stress fibers, although all cells reached the same level of alpha-SMA expression, indicating that Smad3 also regulates cytoskeletal organization in HSC. We suggest that TGF-beta, signaling via Smad3, plays an important role in the morphological and functional maturation of hepatic myofibroblasts.
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PMID:Smad2 and Smad3 play different roles in rat hepatic stellate cell function and alpha-smooth muscle actin organization. 1598 42

During cholestasis, bile acids accumulate in the liver, and induce cellular alterations. Cholestasis is a major cause of liver fibrosis. We have used precision-cut liver slices (PCLS) in culture to investigate the effects of bile acids on hepatic cells. Rat PCLS were placed on an insert in a vial containing culture medium, and gently agitated on a roller platform. PCLS were treated with 100 microM taurolithocholate (TLC), taurodeoxycholate (TDC) or taurocholate (TC) for 24 or 48 h. PCLS viability was measured, and immunohistochemistry was performed with antibodies against active caspase 3, platelet-derived growth factor (PDGF) receptor-beta and ED-A fibronectin. TDC and TLC, two hydrophobic bile acids, induced hepatocyte necrosis and apoptosis, whereas TC, an hydrophilic bile acid, improved slice viability as compared with controls. Both TDC and TC induced biliary epithelial cell proliferation, together with portal fibroblast proliferation and activation, as shown by PDGF receptor-beta and ED-A fibronectin expression. TLC induced biliary epithelial cell apoptosis. Our results indicate that individual bile acids induce cell type-specific effects in a complex liver microenvironment. The fact that PCLS support biliary epithelial cell and portal fibroblast proliferation will make this model very useful for the study of the mechanisms involved in portal fibrosis.
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PMID:Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices. 1640 30

Liver fibrosis is the end result of an imbalance between synthesis and degradation of extracellular matrix proteins of the liver. The extracellular matrix of the liver is complex. It comprises multiple components of three major types of macromolecules: proteins, glycoproteins and proteoglycans. The normal liver contains limited amounts of extracellular matrix composed of elastin, fibronectin, collagen, proteoglycans and other macromolecules. These molecules have specific structure-function properties. In the liver they provide a structural framework and modulate tissue repair. The fibrogenesis is a reaction to liver injury, it leads to marked impairment of hepatic sinusoidal blood flow and ultimately to cirrhosis associated with portal hypertension and hepatocyte dysfunction. The process of fibrosis is the result from complex interactions between extracellular matrix macromolecules, hepatic cells, cytokines and growth factors, that activate the stellate cells of the liver to induce the synthesis of extracellular matrix components that deposit into the local extracellular matrix and to produce the inhibitor of metalloproteinase. The end result of these activities is an imbalance in the synthesis/degradation homeostasis of the liver, that is, liver fibrosis.
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PMID:[The physiopathological mechanism of hepatic fibrosis]. 1649 97

Hepatic fibrosis is a common outcome of a variety of chronic liver diseases. Here we evaluated the therapeutic efficacy of hepatocyte growth factor (HGF) on liver fibrosis induced by bile duct ligation (BDL) and investigated potential mechanisms. Mice underwent BDL, followed by intravenous injections of naked HGF expression plasmid or control vector. HGF gene therapy markedly ameliorated hepatic fibrotic lesions, as demonstrated by reduced alpha-smooth muscle actin (alphaSMA) expression, attenuated deposition of type I and type III collagen, and normalized total hydroxyproline content. HGF also suppressed transforming growth factor-beta1 (TGF-beta1) expression. Interestingly, colocalization of alphaSMA and cytokeratin-19 in bile duct epithelium was observed, suggesting the possibility of biliary epithelial to myofibroblast transition after BDL. Cells that were still positive for cytokeratin-19 but actively producing type I collagen were found in the biliary epithelia and periductal region. Laminin staining revealed an impaired basement membrane of the bile duct epithelium in diseased liver. These lesions were largely prevented by HGF administration. In vitro, treatment of human biliary epithelial cells with TGF-beta1 induced alphaSMA and fibronectin expression and suppressed cytokeratin-19. HGF abolished the phenotypic conversion of biliary epithelial cells induced by TGF-beta1. These results suggest that HGF ameliorates hepatic biliary fibrosis in part by blocking bile duct epithelial to mesenchymal transition.
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PMID:Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation. 1665 17

Renal fibrosis is the final common pathway of most progressive renal diseases. C5 was recently identified as a risk factor for liver fibrosis. This study investigated the role of C5 in the development of renal tubulointerstitial fibrosis by (1) induction of renal fibrosis in wild-type and C5(-/-) mice by unilateral ureteral ligation (UUO) and (2) investigation of the effects of a C5a receptor antagonist (C5aRA) in UUO. In C5(-/-) mice, when compared with wild-type controls, markers of renal fibrosis (Sirius Red, type I collagen, fibronectin, alpha-smooth muscle actin, vimentin, and infiltrating macrophages) were significantly reduced on day 5 of UUO. On day 10, fibronectin mRNA and protein expression were still reduced in the C5(-/-) mice. Cortical mRNA of all PDGF isoforms and of TGF-beta(1) (i.e., central mediators of renal disease) were significantly reduced in C5(-/-) mice when compared with controls. Renal tubular cell expression of the C5aR was sparse in normal cortex but markedly upregulated after UUO. Treatment of wild-type UUO mice with C5aRA also led to a significant reduction of cortical Sirius Red staining, fibronectin protein expression, and PDGF-B mRNA expression on day 5. Neither genetic C5 deficiency nor C5aRA treatment caused any histologic changes in the nonobstructed kidneys. In cultured murine cortical tubular cells, C5a stimulated production of TGF-beta(1), and this was inhibited by C5aRA. Using a combined genetic and pharmacologic approach, C5, in particular C5a, is identified as a novel profibrotic factor in renal disease and as a potential new therapeutic target.
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PMID:Complement C5 mediates experimental tubulointerstitial fibrosis. 1738 34

Hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in liver fibrogenesis. The excessive synthesis of ECM proteins deteriorates hepatic architecture and results in liver fibrosis and cirrhosis. This study investigated the role of bone morphogenetic protein 7 (BMP7) as a member of the transforming growth factor (TGF)-beta superfamily in chronic liver disease. Plasma levels of BMP7 were significantly elevated in patients with chronic liver disease compared with healthy controls. Immunohistochemistry of cirrhotic human liver demonstrated upregulated BMP7 protein expression in hepatocytes as compared with normal human liver. Because gene expression for all putative BMP7 receptors was induced during the culture activation process of primary human HSCs, we studied the effects of BMP7 on hTERT immortalized human HSCs in vitro. BMP7, as expressed and secreted after infection with adenoviruses encoding BMP7 (AdBMP7), increased proliferation of HSCs. The mRNA and protein expression of type I collagen and fibronectin was increased in BMP7-stimulated HSCs. Elevated systemic and hepatic levels of BMP7 in patients with chronic liver disease may contribute to progression of liver fibrogenesis in vivo.
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PMID:Bone morphogenetic protein 7 is elevated in patients with chronic liver disease and exerts fibrogenic effects on human hepatic stellate cells. 1741 33

Liver fibrosis and cirrhosis are common sequelae to diverse liver injuries in the tropics or Nigeria. The development of hepatic fibrosis or cirrhosis is due to increased synthesis, deposition, and possibly reduced degradation of hepatic extracellular matrix components, especially collagens, such as interstitial type I and III, basement membrane type IV, microfibrillar type VI, and pericellular type V, non-collagenous proteins, such as laminin, fibronectin, undulin, etc., and various types of proteoglycans, such as hyaluronan, etc. In Nigeria, the common approach for diagnosing or assessing the activity of connective tissue in this organ is the histological examination of a biopsy, if one is performed by a specialist physician. The liver biopsy provides a static picture of the changes that have already taken place in the liver. Another possible method is (where the facilities are available) a quantitative assessment of the liver biopsy by biochemical determination of total collagen via hydroxyproline. Biopsy is an invasive method and cannot be repeated often enough in the bid to ensuring an intensive follow-up of the changes taking place during the course of antifibrotic treatment or therapy. Thus, serum or other biological fluid assays for connective tissue proteins, such as the aminoterminal propeptide of type III Procollagen PIIINP, or the dimeric carboxyterminal domain of type IV collagen known as NCl or PIVCP, laminin, and others are essentially non-invasive and can be carried out repeatedly. In addition, the measurement of certain enzymes of connective tissue proteins in serum may the reflect activity of liver fibrogenesis. They offer the potential for diagnosis and therapeutic control. However, it is very important to note that circulating biochemical markers of fibrogenesis, fibrolysis or both may not reflect hepatic fibrosis or cirrhosis, since they are not liver-specific. Thus, the best diagnostic approach would be the identification and measurement in serum of the driving force of fibrogenic process.
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PMID:Biochemical markers, extracellular components in liver fibrosis and cirrhosis. 1768 72

Serum tests measuring the dynamic processes of fibrogenesis and fibrolysis may reflect the severity of liver disease. Fibronectin plays a role in liver fibrosis. The aim of this study was to assess the diagnostic value of fibronectin in chronic HCV infection among Egyptian patients. Fibronectin was identified using specific monoclonal antibody and Western blot at 90-kDa in sera of HCV infected patients with liver fibrosis. The purified serum fibronectin showed one peak at 8 min when analyzed by capillary zone electrophoresis. Fibronectin was quantified in serum using ELISA. The mean (+/-SD) serum level of fibronectin (mg/L) in liver fibrosis patients were 450.9 (+/-170.3) and 230.5 (+/-90.3) in control individuals, respectively. There was a significant correlation between METAVIR score and serum fibronectin (r=0.401; P<0.0001). The area under the receiver operating characteristic (ROC) curve of fibronectin for discriminating patients with liver fibrosis from those with no fibrosis livers and its p value were 0.78 and P<0.0001. The efficiency of fibronectin for discriminating patients with liver fibrosis from those with non fibrosis livers was 75%. In conclusion, serum fibronectin can differentiate HCV infected patients with liver fibrosis from patients with non fibrosis.
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PMID:Immunochemical identification and detection of serum fibronectin in liver fibrosis patients with chronic hepatitis C. 1788 87

Vitamin A is an essential lipid-soluble nutrient that is crucial for morphogenesis and adult tissue maintenance. The retinoid homeostasis in the liver depends on a regular supply of vitamin A from an adequate dietary intake to preserve the normal organ structure and functions. This study focuses on the effect of vitamin A deficiency on the morphology and extracellular proteins expression of the liver in adult Wistar rats. Animals were fed with a normal (control group) or deficient vitamin A diet for 3 months. At the end of the experimental period, histological examination of the livers under light and electron microscopy revealed that vitamin A deficiency produced a loss of hepatocyte cord disposition with an irregular parenchymal organization. Abundant fat droplets were present in the cytoplasm of the hepatocytes. Elongated myofibroblastic-like cells with an irregular cytoplasmic process and without lipid droplets could be seen at the perisinusoidal space, where an elevated intensity of alpha smooth muscle actin (alpha-SMA) was observed. These results suggest that an activation of hepatic stellate cells (HSCs) occurred. Moreover, immunochemical methods revealed that vitamin A deficiency led to an increased expression of hepatic fibronectin, laminin and collagen type IV. We propose that vitamin A deprivation caused liver injury and that HSCs underwent a process of activation in which they produced alpha-SMA and synthesized extracellular components. These changes may be a factor predisposing to liver fibrosis. In consequence, vitamin A deprivation could affect human and animal health.
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PMID:Vitamin A deficiency injures liver parenchyma and alters the expression of hepatic extracellular matrix. 1898 69

A class of imidazolium salts (IMSs) is routinely used in organic synthetic chemistry as precursors to generate N-heterocyclic carbenes (NHCs) with catalytic activity. However, their biological properties are largely unknown. The current study investigates the biological activity of a typical NHC precursor DBZIM and its trimer TDBZIM in hepatic stellate cells (HSCs), which is an in vitro model for studying liver fibrosis. The results show that HSCs treated with IMSs have an enhanced GSH/GSSG ratio and a reduced level of reactive oxygen species (ROS), which may consequently contribute to the attenuation in gene expression of fibrogenic molecules such as smooth muscle actin-alpha (SMAA), transforming growth factor-beta 1 (TGF-beta1), procollagen alphaI(I) and fibronectin. Further, the in vivo experiments demonstrate that DBZIM is an anti-fibrotic agent in a mouse model of liver fibrosis. These findings suggest that the versatile IMSs could be a potential source for developing novel therapeutics to treat liver fibrosis and other fibrogenic disorders caused by oxidative stress and TGF-beta1 mal-signalling.
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PMID:A class of imidazolium salts is anti-oxidative and anti-fibrotic in hepatic stellate cells. 1967 67


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