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)

Paraffin-embedded liver tissue from 60 biopsied or autopsied cases, including 20 cases each of acute mild hepatitis, chronic active hepatitis and active cirrhosis were studied with immunohistochemical double labelling technique by using polyclonal anti-Fas and anti-Fas ligand. The detection rates for Fas and Fas ligand were 76.7% (46/60) and 70.0% (42/60), respectively. Fas antigen was located in cytoplasm of hepatocytes. Fas ligand was expressed mainly in infiltrating lymphocytes in portal or periportal areas (34/42, 80.9%) and also in the cytoplasm of some hepatocytes (25/42, 59.5%). The distribution of Fas ligand-positive hepatocytes was similar to that of Fas-positive hepatocytes in liver tissue. The positive cells were scattered in the intralobular areas in acute mild hepatitis, but they were more commonly aggregated in periportal areas, especially near the edges of the piecemeal necrosis region or in infiltrating mononucleocytes in chronic active hepatitis and active cirrhosis, Double labelling studies showed that both Fas and Fas ligand might be expressed in the same or different hepatocytes of the same area. Our results suggest that Fas-Fas ligand system may play an important role in liver cell injury due to hepatitis B virus infection.
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PMID:[Expression of Fas and Fas ligand in liver tissue infected with hepatitis B virus]. 1043 77

The release of soluble circulating molecules represents a prominent feature during the course of immune-mediated clinical conditions. To further assess the relationship between serum concentrations of adhesion or apoptotic-related soluble structures and liver diseases, we evaluated the levels of intercellular adhesion molecule-1 (sICAM-1), Fas receptor (CD95) and Fas ligand (sCD95L) in a group of patients affected by Hepatitis C Virus (HCV)-induced chronic hepatitis (CH-C), HCV-positive liver cirrhosis with superimposed hepatocellular carcinoma (HCC), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and alcoholic liver cirrhosis (ALC). Results show that sICAM-1 values were in all instances significantly elevated when compared to those seen in healthy donors. Similar findings were noted in subjects with liver diseases in terms of sCD95 concentrations, even if to a different degree of statistical significance. Finally, sCD95L amounts were augmented in AIH, PBC, ALC and CH-C in comparison to controls, while in the HCC counterpart sCD95L levels fell within normal range. All together, these findings emphasize the occurrence of circulating soluble molecules in patients with various chronic liver diseases, likely reflecting the involvement of several pathogenetic mechanisms.
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PMID:sICAM-1, sCD95 and sCD95L levels in chronic liver diseases of different etiology. 1073 54

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

Apoptosis plays an important role in the progression of alcohol-induced liver disease to cirrhosis. Oxidative stress is an early event in the development of apoptosis. The major aim of this study was to study the conditions in which oxidative stress occurs in chronic alcoholism and its relationship with apoptosis of hepatocytes. We have found that oxidative stress is associated with chronic ethanol consumption in humans and in rats, in the former independently of the existence of alcohol-induced liver disease. Ethanol or acetaldehyde induces apoptosis in hepatocytes isolated from alcoholic rats, but not in those from control rats. Inhibition of aldehyde dehydrogenase, but not of cytochrome P450 2E1, prevents ethanol-induced cell death. Ethanol-induced apoptosis is caused by increased reactive oxygen species (ROS) driven by increased availability of the reduced form of nicotinamide-adenine dinucleotide (NADH) owing to mitochondrial acetaldehyde metabolism and it is prevented by blocking the opening of mitochondrial permeability transition (MPT) pores with cyclosporine A. Inhibition of nitric oxide (NO) synthase or addition of antioxidant vitamins C and E completely prevented ethanol-induced apoptosis. Mitochondrial oxidative stress, which occurs during chronic alcoholism, renders hepatocytes susceptible to apoptosis. On the other hand, the CD95 ligand expression was up-regulated by acetaldehyde. In conclusion, ethanol induces apoptosis via 2 different pathways: MPT and up-regulation of the expression of CD95-Fas ligand. The overproduction of ROS by mitochondria, driven by acetaldehyde metabolism, is a common trigger of both mechanisms.
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PMID:Mitochondrial oxidative stress and CD95 ligand: a dual mechanism for hepatocyte apoptosis in chronic alcoholism. 1198 71

Fas ligand (FasL) plays an important role in the regulation of apoptosis. Soluble FasL (sFasL) is produced by a cleavage of FasL from the cell surface by metalloproteinase. Whether or not sFasL exists or is elevated in the pleural effusion of different etiologies is unknown. The present study is designed to determine pleural effusion and serum sFasL levels under different clinical conditions, and ascertain if there exists a significant difference in the levels found in different clinical conditions, and whether this difference can be used as a tool for differential diagnosis. Soluble FasL levels in the pleural effusion and serum of 103 patients, including 37 with malignant pleural effusion, 24 with uncomplicated parapneumonic effusion, 8 with bacterial empyema, 16 with tuberculous pleurisy, and 18 with transudate effusion (8 with congestive heart failure and 10 with viral liver cirrhosis), were analyzed with ELISA assays. Pleural effusion from patients with bacterial empyema (median 79.4 pg/ml) and TB pleurisy (median 31.9 pg/ml) contained significantly higher amounts of sFasL than the pleural effusion from all other conditions studied (p <0.001). Viral liver cirrhosis had a significantly higher serum sFasL level (median 53.6 pg/ml, p = 0.025, when compared with other patients). Patients with congestive heart failure had the lowest serum sFasL levels when compared with other patients (p = 0.014). There was no significant correlation between pleural effusion sFasL levels and other parameters, such as effusion LDH, cell count, neutrophil, and lymphocyte percentage. In conclusion, soluble FasL is a useful marker for the differentiation of bacterial empyema and TB pleurisy from other disease entities. In addition, the elevation of serum sFasL levels in viral liver cirrhosis can also be used to differentiate cirrhosis from congestive heart failure, in which both effusions are transudate.
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PMID:Pleural effusion and serum soluble fas-ligand levels are elevated in different clinical conditions. 1210 54

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

IL-18 is a pleiotropic cytokine and is produced by various types of cells including activated macrophages, particularly Kupffer cells. IL-18 has potential to activate inflammatory responses through induction of IFN-gamma production in collaboration with IL-12. Somewhat paradoxically, IL-18 also has the capacity to induce allergic responses via induction of IL-4 production by T helper cells and to activate mast cells and basophils to release atopic effector molecules such as histamine. Indeed, IL-18 is involved in inflammatory tissue injuries, such as Crohn's disease and atherosclerosis, and also in hyper IgE and atopic dermatitis. IL-18 is particularly important for induction of experimental liver diseases. Endotoxin-induced liver injury or Fas ligand-induced hepatitis is caused by endogenous IL-18 in mice. Moreover, patients with liver diseases such as fulminant hepatitis, liver cirrhosis due to hepatitis virus infection and primary biliary cirrhosis show elevation of serum levels of IL-18, that correlates with the corresponding disease severity. Therefore, endogenous IL-18 plays a major role in induction of some types of liver injuries in mice and human. NKT cells that express both T cell receptor and NK cell marker are abundant in the liver of mice and human. Recent studies have revealed that NKT cells participate in some types of liver injuries, such as concanavalin A-induced T cell-mediated hepatitis and malaria hepatitis. In this review article, we focus on IL-18-involving liver damages and NKT-cell-mediated liver injuries.
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PMID:Cytokine-induced inflammatory liver injuries. 1452 86

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

Hepatitis C virus (HCV) is a major human pathogen causing chronic liver disease, which leads to cirrhosis of liver and hepatocellular carcinoma. The HCV core protein, a viral nucleocapsid, has been shown to affect various intracellular events, including cell proliferation and apoptosis. However, the precise mechanisms of the effects are not fully understood. In this study, we show that HCV core protein sensitizes human hepatocellular carcinoma cell line, Huh7, conferred sensitivity to TRAIL-, but not Fas ligand-mediated apoptosis. Huh7 cells are resistant to TRAIL, despite the induction of caspase-8 after TRAIL engagement. However, HCV core protein induces TRAIL apoptosis signaling via sequential induction of caspase-8, Bid cleavage, activation of mitochondrial pathway, and effector caspase-3. HCV core protein also induces activation of caspase-9 after TRAIL engagement, and the induction of TRAIL sensitivity by HCV core protein could be reversed by caspase-9 inhibitor. Therefore, the HCV core protein-induced TRAIL-mediated apoptosis is dependent upon activation of caspase-8 downstream pathway to convey the death signal to mitochondria, leading to activation of mitochondrial signaling pathway and breaking the apoptosis resistance. These results combined indicate that the HCV core protein enhances TRAIL-, but not Fas ligand-mediated apoptotic cell death in Huh7 cells via a mechanism dependent on the activation of mitochondria apoptosis signaling pathway. These results suggest that HCV core protein may have a role in immune-mediated liver cell injury by modulation of TRAIL-induced apoptosis.
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PMID:Hepatitis C virus core protein modulates TRAIL-mediated apoptosis by enhancing Bid cleavage and activation of mitochondria apoptosis signaling pathway. 1569 47


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