Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Canine chronic hepatitis (CCH) is a progressive inflammatory disease of unknown etiology. To characterize the inflammatory infiltrate, 16 dogs with CCH were selected and classified into three groups based on the stage of fibrosis, as evaluated with Masson's trichrome stain. The inflammatory infiltrate in each liver section was immunohistochemically characterized and evaluated using CD3, lysozyme, lamba and kappa light chain, and alpha-smooth muscle actin antibodies. Numerous breeds were affected, and middle-aged females predominated in this select group. Necroinflammatory activity progressively increased and then waned as the hepatitis progressed to cirrhosis. CD3+ lymphocytes were the most numerous lymphoid cells in dogs with CCH. Degenerate hepatocytes were occasionally surrounded by CD3+ lymphocytes. Necrosis was positively correlated with the number of CD3+ lymphocytes. The lamba and kappa light chain-positive cell infiltrate was variable but generally mild. A positive correlation between the lambda and kappa light chain-positive cells and the portal alpha-smooth muscle actin was found. The number of alpha-smooth muscle actin-positive cells (myofibroblasts) in portal triads and fibrous septa was positively correlated with the stage of fibrosis. In contrast, no correlation was found between the number of lysozyme-positive cells (Kupffer cells) and the stage of fibrosis. These results further support the idea of an immune-mediated process in CCH and suggest that periductular myofibroblasts play an important role in canine liver fibrogenesis.
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PMID:Characterization of the inflammatory infiltrate in canine chronic hepatitis. 1173 95

Liver disease causes significant morbidity and mortality from multilobular cirrhosis in patients with cystic fibrosis. Abnormal bile transport and biliary fibrosis implicate abnormal biliary physiology in the pathogenesis of cystic fibrosis-associated liver disease (CFLD), yet the mediators linking biliary events to fibrosis remain unknown. Activated hepatic stellate cells (HSCs) are the pre-eminent mediators of fibrosis in a range of hepatic disorders. The dominant stimulus for matrix production by HSCs is the cytokine transforming growth factor (TGF)-beta(1). In CFLD, the role of HSCs and the source of TGF-beta(1) have not been evaluated. Liver biopsy tissue obtained from 38 children with CFLD was analyzed. Activated HSCs, identified by co-localization of procollagen alpha(1)(I) mRNA and alpha-smooth muscle actin, were demonstrated as the cellular source of excess collagen production in the fibrosis surrounding the bile ducts and the advancing edge of scar tissue. TGF-beta protein and TGF-beta(1) mRNA expression were shown to be predominantly expressed by bile duct epithelial cells. TGF-beta(1) expression was significantly correlated with both hepatic fibrosis and the percentage of portal tracts showing histological abnormalities associated with CFLD. This study demonstrates a definitive role for HSCs in fibrogenesis associated with CFLD and establishes a potential mechanism for the induction of HSC collagen gene expression through the production of TGF-beta(1) by bile duct epithelial cells.
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PMID:The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. 1200 Jul 22

Secreted protein, acidic and rich in cysteine (SPARC), which functions in tissue remodeling, has been reported to be expressed by myofibroblasts in liver cirrhosis and hepatocellular carcinoma. This study aimed to reveal its expression in chronic hepatitis. Immuno-light and electron microscopy demonstrated that SPARC was expressed by nerve fibers and hepatic stellate cells (HSCs) in the liver parenchyma and myofibroblasts in the fibrous septa. Reaction products were localized in the rough endoplasmic reticulum and nuclear envelope. Serial section analysis demonstrated that SPARC, platelet-derived growth factor receptor-beta, and alpha-smooth muscle actin were co-expressed by HSCs. Quantitative analysis demonstrated that, while SPARC-positive HSCs were sparse in control livers, they significantly increased in number in the livers with chronic hepatitis. There were, however, no significant differences in number among the grades of activity, the stages of fibrosis, or etiology (virus-infected or autoimmune, hepatitis B virus or hepatitis C virus). In liver cirrhosis, however, they significantly decreased in number. The present results indicate that SPARC is expressed by activated HSCs in chronic hepatitis, suggesting the involvement of SPARC in hepatic fibrogenesis after chronic injuries.
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PMID:Expression of SPARC by activated hepatic stellate cells and its correlation with the stages of fibrogenesis in human chronic hepatitis. 1244 77

Hyaluronic acid (HA) plays prominent role in the pathogenesis of liver fibrosis. The mechanism of increased serum and liver HA during hepatic fibrosis was studied in rats. Liver injury was induced by intraperitoneal injections of N-nitrosodimethylamine (NDMA) for 7 consecutive days. A group of animals were sacrificed on everyday during injection and also on days 14 and 21 after the start of NDMA administration. The alpha-smooth muscle actin (alpha-SMA) was stained as a marker for activated stellate cells. Liver HA was studied by histochemical methods and serum HA was monitored by HA binding protein assay. CD44 was stained immunohistochemically. After the start of NDMA administration, necrosis was initiated on day 3 and massive necrosis was observed on days 5 and 7. Fibrosis was developed on day 14 and early cirrhosis was present on day 21. Staining of alpha-SMA demonstrated activated stellate cells from day 3 onwards. Serum HA peaked on day 7 and reduced afterwards. Serial liver sections stained for HA revealed excessive accumulation of HA during NDMA administration. On days 14 and 21, alpha-SMA and HA staining was remarkable in fibrotic and cirrhotic areas. CD44 staining was negative except during necrosis. It is concluded that the early elevation of serum HA is due to the increased synthesis and simultaneous release from the necrotic liver. In latter stages the increase of both serum and liver HA is contributed by the increased synthesis by the activated stellate cells and reduced clearance by the impaired sinusoidal endothelial cells.
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PMID:Expression of hyaluronic acid in N-nitrosodimethylamine induced hepatic fibrosis in rats. 1464 95

Liver cirrhosis (LC) is a chronic disease with high mortality rate and its pathophysiology includes hepatic parenchymal cell destruction, connective tissue formation, and nodular regeneration. Colchicine has been used in liver diseases as an anti-inflammatory and anti-fibrotic drug. However, there is controversy over the beneficial effects of colchicine in LC treatment. In the present study, we injected rats with multiple doses of dimethylnitrosamine for 4 weeks and used rats with severe LC to determine whether colchicine treatment improved liver functions and resolved cirrhotic nodules. Colchicine (30-150microg/kg per day, i.p., for 4 weeks) failed to significantly increase the survival rate of LC rats. Animals were subjected to blood biochemical, liver histopathological and immunochemical analyses. The plasma albumin level, decreased in cirrhotic rats, was restored by colchicine treatment along with reduction of ascites. Colchicine decreased the accumulated extracellular matrix and the multiple fibrotic nodules formed in cirrhotic liver, and eliminated alpha-smooth muscle actin (alpha-SMA)-positive cells. In activated stellate cells, colchicine inhibited alpha-SMA and transforming growth factor-beta1 (TGFbeta1) expression. The results of the present study showed that colchicine resolves cirrhotic nodules and accumulated fibers in the liver of LC rats, but failed to significantly improve the survival rate of LC animals, and that the beneficial effects of colchicine in cirrhotic animals result from stellate cell inactivation and inhibition of TGFbeta1 expression.
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PMID:Effects of colchicine on liver functions of cirrhotic rats: beneficial effects result from stellate cell inactivation and inhibition of TGF beta1 expression. 1472 49

Nerve growth factor (NGF) is suggested to have a role in tumor progression in addition to its role in differentiation and survival of neuronal cells. We investigated expression of NGF and its receptors, TrkA and p75NTR, in hepatocellular carcinomas (HCCs). Although hepatocytes and hepatic stellate cells (HSCs) showed respectively weak and intense NGF immunostaining in the background livers of patients suffering from liver cirrhosis (LC) or chronic hepatitis (CH), intense staining was demonstrated in HCC cells of 33 of 54 (61.1%) tumors. RT-PCR detected NGF mRNA in 7 freshly-isolated HCC samples, and in 2 of 4 cases, in which both background livers and tumors could be analyzed, NGF mRNA was more abundant in the tumors than the background livers. TrkA was detected in the smooth muscle cells of hepatic arteries, but it was negative in tumor cells as well as non-neoplastic hepatocytes. p75NTR and alpha-smooth muscle actin (alphaSMA) was expressed in HSCs in the background liver and fibroblast-like cells in stromal septa, whereas HSCs within the HCC tissues were mostly negative for p75NTR but positive for alphaSMA. This suggests that HSCs in HCC have a different property from those in background livers. Furthermore, the stromal septa contained abundant nerve fibers, which may be related to the increased NGF expression in HCC cells. NGF and its receptors are then thought to have a role in cellular interactions involving HCC cells, HSCs, arterial cells and nerve cells in HCC tissues.
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PMID:Expression of NGF in hepatocellular carcinoma cells with its receptors in non-tumor cell components. 1552 89

As part of an investigation on the role of estrogen in liver disease, we tested the effects of estradiol-3-benzoate (EB) in the thioacetamide (TAA)-induced rat liver cirrhosis model. Male F344 rats (n = 100) were divided into six groups. Animals of groups 1-4 received TAA (0.03% in drinking water) for 12 weeks, and groups 5 and 6 served as controls without TAA. For the exposure period, EB pellets were implanted subcutaneously to give doses of 0 (groups 1 and 5), 1 (group 2), 10 (group 3), and 100 mug (groups 4 and 6) simultaneously. All animals were sacrificed at week 12. Significant increase of liver cirrhosis, liver weight, collagen content, and lipid peroxidation in the livers was evident in groups 3 and 4 (p < 0.05) compared with group 1. Formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was significantly elevated in group 4 (p < 0.01), along with expression of alpha-smooth muscle actin (alpha-SMA) and stellate cell activation-associated protein (STAP), as determined by RT-PCR analysis (p < 0.01). However, there were no differences in liver weight, collagen content, lipid peroxidation, 8-OHdG formation, and alpha-SMA and STAP mRNA expression between groups 5 and 6. We conclude that EB treatment enhances TAA-induced cirrhosis, associated with increase of oxidative stress and activation of hepatic stellate cells.
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PMID:Enhancement by estradiol 3-benzoate in thioacetamide-induced liver cirrhosis of rats. 1571 88

Hepatic stellate cells have been considered the most important cell-type involved in hepatic fibrogenesis. Proliferation and differentiation of hepatic stellate cells into myofibroblast-like cells has been related to the development of liver fibrosis. The alpha-actin expressed by hepatic stellate cells was considered a marker of their activation to myofibroblast-like cell. The aim of this study is to evaluate the changes in morphology, distribution, percentage and alpha-smooth muscle actin expression of hepatic stellate cells in normal and cirrhotic livers, and to correlate activated hepatic stellate cells with the progression of fibrosis. Human liver biopsies (n=121) were divided in five groups: 1) normal livers (controls); 2) cirrhosis post-HCV hepatitis; 3) cirrhosis post-HBV hepatitis; 4) non viral related cirrhosis; 5) recurrent HCV hepatitis after orthotopic liver transplantation. Samples immunostained with anti alpha-smooth muscle actin antibody by immunoperoxidase method were semi-quantitatively evaluated. Liver fibrosis was quantified by computer image analysis on specimens stained with Masson's trichrome. In normal adult livers stellate cells were very rarely stained for alpha-smooth muscle actin. In cirrhotic livers, a strongly enhanced percentage of stellate cells expressing alpha-smooth muscle actin was detected in cirrhotic fragments with respect to the control group, with a significant correlation between alpha-smooth muscle actin positive stellate cells and the volume fraction of fibrosis. Moreover, liver biopsies of recurrent hepatitis revealed an increased number of activated stellate cells compared to normal livers, and intermediate volume fraction of fibrosis. These results confirmed that a direct correlation existed between activated stellate cells and the progression of fibrosis. Alpha-smooth muscle actin confirmed to be a reliable marker of hepatic stellate cells activation also in precocious stages of the disease.
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PMID:Activated hepatic stellate cells in liver cirrhosis. A morphologic and morphometrical study. 1571 57

Liver cirrhosis is characterized by hepatic dysfunction with extensive accumulation of fibrous tissue in the liver. In response to chronic hepatic injury, hepatic portal myofibroblasts and activated hepatic stellate cells (HSCs) play a role in liver fibrosis. Although administration or gene expression of hepatocyte growth factor (HGF) leads to improvement in hepatic fibrosis/cirrhosis, the related mechanisms are not fully understood. We investigated mechanisms involved in resolution from liver cirrhosis by HGF, focusing on growth regulation and apoptosis in portal myofibroblasts. Cultured rat HSCs could not proliferate, were withdrawn after passage, and were replaced by proliferating portal myofibroblasts during the passages. In quiescent HSCs, c-Met receptor expression was undetected whereas c-Met receptor expression was detected in activated HSCs and liver myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA), suggesting that activated HSCs and portal myofibroblasts are targets of HGF. For cultured rat portal myofibroblasts, HGF counteracted phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and mitogenic stimulus induced by platelet-derived growth factor, induced c-jun N-terminal kinase (JNK) 1 phosphorylation, and promoted apoptotic cell death. In the dimethylnitrosamine rat model of liver cirrhosis, administration of HGF suppressed proliferation while promoting apoptosis of alpha-SMA-positive cells in the liver, events that were associated with reduced hepatic expressions of alpha-SMA and histological resolution from liver cirrhosis. Growth inhibition and enhanced apoptosis in portal myofibroblasts by HGF are newly identified mechanisms aiding resolution from liver fibrosis/cirrhosis by HGF.
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PMID:Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis. 1579 83

Liver cirrhosis is one of the major complications of hepatitis C virus (HCV) infection, but the mechanisms underlying HCV-related fibrogenesis are still not clear. Although the roles of HCV core protein remain poorly understood, it is supposed to play an important role in the regulation of cellular growth and hepatocarcinogenesis. The aim of this study was to examine the role of HCV core protein on the hepatic fibrogenesis. We established an in vitro co-culture system with primary hepatic stellate cell (HSC) isolated from rats, and a stable HepG2-HCV core cell line which had been transfected with HCV core gene. The expressions of fibrosis-related molecules transforming growth factor beta1 (TGF-beta1), transforming growth factor beta receptor II (TGFbetaRII), alpha-smooth muscle actin (alpha-SMA) and connective tissue growth factor (CTGF) were analyzed via histological or molecular methods. In addition, the expression levels of matrix metaloprotinase-2 (MMP-2) and collagen type I (Col I) from the co-cultured media were measured by zymogram and ELISA, respectively. The expressions of alpha-SMA, TGF-beta1, Col I, TGFbetaRII and MMP-2 were significantly increased in the co-culture of stable HepG2-HCV core with HSC. Moreover, the significant increases of CTGF and TGF-beta1 in the HCV core-expressing cells were observed by either Northern or Western blot analysis. These results suggest that HCV core protein may contribute to the hepatic fibrogenesis via up-regulation of CTGF and TGF-beta1.
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PMID:HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-beta1. 1588 28


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