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

To date, there have been no reports of the involvement of the Fas system in recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT). In 25 patients who underwent OLT for HCV-related liver cirrhosis, we evaluated the expression of the Fas antigen (FasAg) on hepatocytes, apoptic hepatocytes, and serum levels of soluble Fas (sFas). The level of HCV viremia and HCV genotype were determined by polymerase chain reaction. Serum sFas levels were determined by an enzyme immunoassay procedure. DNA fragmentation was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) technique on deparaffinized liver samples. FasAg expression was evaluated by an immunoperoxidase method. Sixteen patients had evidence of recurrent HCV disease. The number of hepatocytes expressing FasAg and the percentage of apoptotic hepatocytes was greater among patients who developed recurrent hepatitis than among those who did not (P <.01 and P <.0001, respectively). There was a correlation between hepatic expression of FasAg, intensity of lobular inflammation (P =.007), and TUNEL index (P <.001). The levels of sFas were greater among the patients with recurrent HCV hepatitis than those without recurrent hepatitis (P <.04). We conclude that (1) Fas expression is up-regulated in recurrent HCV after OLT and is related to the grading of liver disease; likewise, levels of sFas were greater in the patients with recurrent HCV hepatitis; and (2) the demonstration of hepatocytes with FasAg expression and the labeling of the nuclei by TUNEL assay suggest that hepatic apoptosis mediated by the Fas system may have a role in the pathogenesis of recurrent HCV hepatitis after OLT.
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PMID:Involvement of the fas system in hepatitis C virus recurrence after liver transplantation. 1098 54

Molsidomine is effective in reducing portal hypertension in cirrhosis, but its effect on hepatitis is not known. In the present study, the effect of molsidomine on hepatitis was examined using mouse concanavalin A (Con A)-induced hepatitis and mouse anti-Fas antibody-induced hepatitis. Treatment of mice with Con A caused elevation of plasma alanine aminotransferase (ALT) at 8 and 24 h (n=4). Pretreatment of mice with molsidomine (3, 10, 30 and 100 mg/kg, i.p.) prevented Con A-induced hepatitis. Treatment of mice with anti-Fas antibody (150 microg/kg, i.v.) caused elevation of plasma ALT at 3.5 h. Pretreatment mice with molsidomine (10 mg/kg, i.p.) showed only 47% inhibition of anti-Fas antibody caused elevation of plasma ALT. The present results showed effectiveness of molsidomine in preventing Con A-induced mice hepatitis.
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PMID:Prevention of concanavalin A-induced mice hepatitis by molsidomine. 1117 12

Persistent hepatitis C virus (HCV) infection often progresses to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Numerous viruses have been reported to escape from apoptotic mechanism to maintain persistent infection. In the present study, we characterized the effect of HCV proteins on the Fas signal using HCV transgenic mice, which expressed core, E1, E2, and NS2 proteins, regulated by the Cre/loxP switching system. The transgene expression of HCV transgenic mice caused resistance to Fas antibody stimulated lethality. Apoptotic cell death in the liver of HCV protein expressing mice was significantly reduced compared with nonexpressing mice. Histopathological analysis and DNA fragmentation analysis revealed that the HCV proteins suppressed Fas-mediated apoptotic cell death. To identify the target pathway of HCV proteins, we characterized caspase activity. The activation of caspase-9 and -3/7 but not caspase-8 was inhibited by HCV proteins. Cytochrome c release from mitochondria was inhibited in HCV protein expressing mice. These results indicated that the expression of HCV proteins may directly or indirectly inhibit Fas-mediated apoptosis and death in mice by repressing the release of cytochrome c from mitochondria, thereby suppressing caspase-9 and -3/7 activation. These results suggest that HCV may cause persistent infection, as a result of suppression of Fas-mediated cell death.
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PMID:Inhibition of cytochrome c release in Fas-mediated signaling pathway in transgenic mice induced to express hepatitis C viral proteins. 1127 24

To investigate the roles of apoptosis and the Fas system (Fas, Fas ligand, soluble Fas) in the process of liver cirrhosis (LC) converting into hepatocellular carcinoma (HCC), expression of Fas and Fas ligand (FasL) in 49 LC and 36 HCC samples was detected by immunohistochemical method. Apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method. Serum soluble Fas (sFas) levels in 28 cases of LC and 27 cases of HCC were measured by enzyme-linked immunosorbent assay (ELISA) method. Compared with LC, apoptotic indices (AI) in HCC tissues were significantly reduced (P < 0.001), expression of Fas was decreased (P < 0.05), and that of FasL was increased (P < 0.05). Serum sFas levels in HCC patients were significantly higher than those in normal controls. Down-regulation of Fas expression, up-regulation of FasL expression in hepatocytes and elevation of sFas level in serum might contribute to tumor escape from immune surveillance of the body. Apoptosis and the Fas system are significantly involved in the process of liver cirrhosis converting into hepatocellular carcinoma.
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PMID:Apoptosis and Fas system are significantly involved in the process of liver cirrhosis converting into hepatocellular carcinoma. 1152 16

Epidemiological studies have established that heavy alcohol consumption in persons with chronic hepatitis C virus (HCV) infection is associated with advanced liver disease, including cirrhosis. The aims of this study were to evaluate the relationship between alcohol consumption and hepatocyte apoptosis in HCV-infected patients and to determine the role of Fas in HCV-mediated apoptosis. Liver tissue from 44 HCV-infected patients with variable alcohol consumption, and 10 normal control subjects who did not consume alcohol was examined for hepatocyte apoptosis, proliferation and Fas expression. Alcohol consumption was assessed using the 'Lifetime Drinking History' alcohol questionnaire. HCV RNA, alanine aminotransferase (ALT) and ferritin were also assessed in addition to demographic data. Hepatocyte apoptosis was significantly greater in HCV-infected patients compared to controls. Expression of Fas (CD95) was found in HCV patients but not in controls. The degree of Fas expression correlated with hepatocyte apoptosis as detected by terminal UTP nick end labelling (TUNEL). Active ethanol consumption led to a significant increase in hepatocyte apoptosis. Fas expression correlated with fibrosis in HCV-infected patients who were not actively drinking ethanol. In summary, HCV leads to increased apoptotic cell death in hepatocytes. Programmed cell death can be further up-regulated by active ethanol consumption. The correlation between Fas expression and TUNEL supports the hypothesis that the Fas-Fas ligand interaction is the major mechanism for HCV-induced hepatocyte apoptosis.
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PMID:Fas-mediated hepatocyte apoptosis is increased by hepatitis C virus infection and alcohol consumption, and may be associated with hepatic fibrosis: mechanisms of liver cell injury in chronic hepatitis C virus infection. 1170 71

The case of a variant of hepatocellular carcinoma is described, which, based on its unique histology, we propose to term, medullary-like hepatocellular carcinoma. It developed in a 56-year-old male patient with liver cirrhosis, and consisted of large, amphophilic cells with a solid growth pattern. The tumour was densely infiltrated with lymphocytes and plasma cells. Lymphocytes formed a mixture of B and T cells, and plasma cells were polytypic. In addition, numerous S-100 protein-reactive stellate cells were observed at the tumour border, where marked apoptosis of hepatocellular carcinoma cells was evident. In areas of dense lymphoplasmacytic infiltration, part of the tumour cells had lost their intercellular connections and their beta-catenin reactivity. Some tumour cells expressed FasL, but not Fas. The tumour exhibited several foci of regression, showing small remnants of damaged tumour cells within dense infiltrations. The patient is alive without evidence of disease 25 months after resection. Medullary-like hepatocellular carcinoma is a lesion which mimics several features known for other medullary carcinomas, including a marked immune response which may be responsible for partial regression of this tumour.
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PMID:Hepatocellular carcinoma with an unusual medullary-like histology and signs of regression ("medullary-like hepatocellular carcinoma"). 1246 3

In viral hepatitis, binding of Fas ligand (FasL) with Fas expressed on the surfaces of infected hepatocytes induces apoptosis, removing hepatitis virus along with infected hepatocytes. We measured serum concentrations of soluble Fas (sFas) and FasL (sFasL), expression of membrane-bound FasL, and expression of FasL-mRNA in patients with chronic hepatitis C without cirrhosis (CH-C) and chronic hepatitis C with liver cirrhosis (LC-C). In CH-C, sFasL concentrations were lower and FasL-mRNA expression was significantly less than in volunteers. In LC-C, sFas concentrations were significantly greater than in healthy volunteers, while sFasL, membrane-bound FasL expression, and FasL-mRNA expression did not show significant differences. We also examined these variables over 24 h following the first interferon (IFN) treatment in patients with CH-C. Serum concentrations of sFas and sFasL, and FasL-mRNA expression increased markedly beyond amounts present before IFN injection until 12 h after IFN injection. However, membrane-bound FasL expression decreased until 6 h, followed by an increase until 24 h. Our findings suggest that the ratio of membrane-bound FasL to sFasL may be regulated to remove virally infected cells in CH-C. In addition, apoptosis mediated by the Fas/FasL system may be influenced by IFN injection for treatment of CH-C.
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PMID:The expression of Fas and Fas ligand, and the effects of interferon in chronic liver diseases with hepatitis C virus. 1247 30

Hepatocytes express keratins 8 and 18 (K8/18) as their only cytoskeletal intermediate filament (IF) proteins, and K8/18 mutations predispose their carriers to liver cirrhosis. Transgenic mice that overexpress mutant human K18 (Arg89-->Cys [R89C]) develop mild chronic hepatitis, hepatocyte fragility, keratin filament disruption, and increased susceptibility to drug-induced liver injury. K18 is a major caspase substrate during apoptosis, and K8- or K18-null mice are significantly predisposed to Fas- and possibly tumor necrosis factor (TNF)-mediated apoptosis in the liver. Here we tested the potential role of the K18 R89C mutation on Fas- or TNF-mediated apoptotic liver injury by injecting Fas antibody (Ab) or TNF-alpha plus actinomycin D into mice that overexpress wild-type (WT) human K18 (with intact filament network, termed TG2 mice) or into K18 R89C mice (with disrupted filament network). K18 R89C mice are significantly more susceptible to Fas-mediated liver injury compared with nontransgenic and TG2 mice. This included differences in lethality, histology, apoptosis, and serum transaminase levels. In contrast, K18 WT and R89C mice manifest similar sensitivity to TNF-induced injury. Both Fas- and TNF-induced apoptosis in liver tissues are associated with caspase-mediated K18 degradation and increased keratin phosphorylation on several but not all sites. In conclusion, transgenic mouse K18 mutation and its consequent keratin filament disruption predispose hepatocytes to Fas- but not TNF-mediated apoptotic injury. This supports the association of keratin mutations with cirrhosis in patients with liver disease and suggests that keratins modulate apoptosis induced by Fas but not TNF.
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PMID:Keratin mutation in transgenic mice predisposes to Fas but not TNF-induced apoptosis and massive liver injury. 1271 81

We investigated the immune responses of patients with cholestatic and hepatitis C virus-positive (HCV-positive) liver cirrhosis by analysing T-cell subsets and cytokine levels in the portal and peripheral veins, using flow cytometry and enzyme-linked immunosorbent assay. In cholestatic liver cirrhosis, the proportion of natural-killer (NK) T cells and interleukin (IL) 6 and IL-18 levels in the portal venous blood were significantly higher than those in the peripheral venous blood. In HCV-positive liver cirrhosis, the proportions of NK T cells and Fas+ T cells and IL-6 and soluble Fas levels in the portal venous blood were significantly higher than those in the peripheral venous blood. These results suggest that in these diseases, activated T cells and soluble molecules in portal venous blood may promote Fas/FasL-mediated apoptosis of the bile-duct cells and hepatocytes, and contribute to the deterioration in liver function as an inevitable result of positive feedback.
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PMID:Activated T cells and soluble molecules in the portal venous blood of patients with cholestatic and hepatitis C virus-positive liver cirrhosis. Possible promotion of Fas/FasL-mediated apoptosis in the bile-duct cells and hepatocyte injury. 1287 Mar 69

Liver homeostasis is achieved by the removal of diseased and damaged hepatocytes and their coordinated replacement to maintain a constant liver cell mass. Cirrhosis, viral hepatitis, and toxic drug effects can all trigger apoptosis in the liver as a means of removing the unwanted cells, and the Fas "death receptor" pathway comprises a major physiological mechanism by which this occurs. The susceptibility to Fas-mediated apoptosis is, in part, a function of the hepatocyte's proteome. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known to influence apoptosis, conceivably by regulating the expression of genes involved in apoptotic signaling. In this article, we present evidence demonstrating that AhR expression and function promote apoptosis in liver cells in response to Fas stimulation. Reintroduction of the AhR into the AhR-negative BP8 hepatoma cells as well as into primary hepatocytes from AhR knockout mice increases the magnitude of cell death in response to Fas ligand. Enhanced apoptosis correlates with increased caspase activity and mitochondrial cytochrome c release but not with the expression of several Bcl-2 family proteins. In vivo studies showed that in contrast to wild-type mice, AhR knockout mice are protected from the lethal effects of the anti-Fas Jo2 antibody. Moreover, down-regulation of the aryl hydrocarbon receptor nuclear translocator protein in vivo by adenovirus-mediated RNA interference to suppress AhR activity provided wild-type mice partial protection from Jo2-induced lethality.
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PMID:The aryl hydrocarbon receptor predisposes hepatocytes to Fas-mediated apoptosis. 1555 Jun 80


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