Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bcl-2 protein blocks apoptosis and is involved in human intrahepatic bile-duct development. Formalin-fixed, paraffin-embedded archival tissue from 42 HBV and HCV hepatitis [20 acute AH, 22 chronic hepatitis (CH)], 12 active cirrhosis (CR) and 20 hepatocellular carcinoma (HCC) was immunostained for bcl-2 protein. In all cases, bcl-2 protein was detected in portal and intralobular lymphocytes but not in hepatocytes or Kupffer cells. Bcl-2 was positive in the cytoplasm of small portal bile ducts of chronic hepatitis, while it was strongly expressed in newly formed bile-ductules of the limiting plate, mainly in CH with marked activity and CR. Bcl-2 was detected in small bile ducts in only one case of acute hepatitis and was not detected in any case of HCC. Bcl-2 seems to be involved in the regulation of growth and apoptosis of cholangiolar cells. Its expression in small bile ducts and in newly-formed ductules especially in CH with marked activity and CR, implies that the embryonic model of intrahepatic bile duct development may be recapitulated in chronic hepatic disease. Moreover, it supports evidence for the existence of the controversial long-lived stem population in the liver. Bcl-2 does not seem to be involved in hepatocarcinogenesis.
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PMID:Bcl-2 protein expression in acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. 1004 90

The proto-oncogene product bcl-2 is known to inhibit apoptotic cell death, and its dysregulation might play a critical role in the development of autoimmune disease. To elucidate the role of bcl-2 in autoimmune hepatitis (AIH), its expression in peripheral blood mononuclear cells (PBMC) and in liver-infiltrating lymphocytes (LIL) was investigated. Increased bcl-2 expression in PBMC was found in AIH patients compared with that in chronic hepatitis C (CHC) patients and in healthy controls. The level of bcl-2 expression significantly correlated with serum ALT level. Further analysis showed that CD4+ T cells are enriched in bcl-2-expressing PBMC. To characterize the Th1/Th2 profile of bcl-2-expressing CD4+ T cells, intracellular interferon-gamma (IFN-gamma) and IL-4 were analysed. The results revealed that most of the bcl-2-expressing cells were found to be IFN-gamma-secreting Th1 cells. In three patients for whom their clinical courses could be followed, bcl-2 expression was decreased after the initiation of immunosuppressive therapy with corticosteroids. However, the level of IFN-gamma + cells was not altered. Immunohistochemical analysis also showed that large amounts of bcl-2+ cells were observed in periportal area in the liver. In conclusion, bcl-2-expressing cells were shown to be increased in peripheral blood and liver in AIH and the bcl-2 product was expressed mainly in CD4+ Th1-type cells, suggesting that these cells might promote the cellular immune response and contribute to the development of hepatitis and hepatocellular damage in AIH.
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PMID:Increased bcl-2 expression in lymphocytes and its association with hepatocellular damage in patients with autoimmune hepatitis. 1020 18

In primary biliary cirrhosis, biliary epithelial cell death by apoptosis results in progressive bile duct loss. We examined immunohistochemically 4 apoptosis-regulating bcl-2 familial proteins (bcl-2, mcl-1, bcl-X, and bax) in the biliary epithelium in 19 cases of primary biliary cirrhosis. Ten cases of chronic hepatitis C, 9 cases of extrahepatic biliary obstruction, and 10 cases of normal liver were used as a control. Bcl-2 and mcl-1 are inhibitors of apoptosis, bcl-X, probably bcl-XL in biliary epithelial cells, an inhibitor, and bax, a promoter of apoptosis. First, we clarified the distribution of bcl-2 familial proteins on the intrahepatic biliary tree in normal livers. Bcl-2 was detected in the interlobular bile ducts and bile ductules, but not in the large and septal bile ducts in all cases examined. Mcl-1, bcl-X, and bax were diffusely detectable at the any level of the intrahepatic biliary tree, with a staining pattern that was diffuse and cytoplasmic. This distribution pattern was preserved in extrahepatic biliary obstruction. Bcl-2 expression was lost or markedly reduced in the damaged interlobular bile ducts in primary biliary cirrhosis, whereas the reduction was only focal or mild in the bile ducts with hepatitis-associated damage in chronic hepatitis C. Expression levels of mcl-1, bcl-X, and bax were similarly reduced to that of bcl-2 in these 2 diseases. These findings suggest that bax is not important as a proapoptotic factor in the damaged bile ducts and that downregulation of bcl-2 and mcl-1, and probably that of bcl-XL, leads to a decrease in the threshold of apoptosis and increase in the vulnerability to apoptotic stimuli in these bile ducts, followed by the progressive apoptotic loss of interlobular bile ducts, in primary biliary cirrhosis.
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PMID:Expression of Bcl-2 familial proteins is reduced in small bile duct lesions of primary biliary cirrhosis. 1068 31

We used the terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) method to detect apoptosis, and immunohistochemical staining for molecules related to apoptosis, a marker of cell proliferation, and surface markers of lymphocytes to examine 20 patients with autoimmune hepatitis (AIH). Confluent hepatic necrosis was frequently found, in which rosette formation of hepatocytes and ductular proliferation were common. TUNEL staining and staining for Lewis Y antigen, Bax protein, and Fas antigen were found in biliary epithelial cells in bile ducts and proliferating atypical bile ductules in regions of confluent necrosis with severe lymphocytic infiltration. TUNEL staining and staining for Lewis Y antigen and Bax protein were found in rosette-forming hepatocytes. Many hepatocytes in lobules without injury were stained for proliferating cell nuclear antigen (PCNA). bcl-2 oncoprotein was found in many lymphocytes surrounding proliferating atypical bile ductules and rosette-forming hepatocytes in regions of confluent necrosis, in which CD20 and OPD 4 were found. Apoptosis of both hepatocytes in rosette arrangement and biliary epithelial cells in bile ducts and proliferating atypical bile ductules may play a role in progression of AIH as well as confluent hepatic necrosis.
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PMID:Significant role of apoptosis in type-1 autoimmune hepatitis. 1072 2

Hepatocyte damage in autoimmune hepatitis (AIH) and chronic viral hepatitis C (CVH) is attributed to an immune response. We analysed liver biopsy specimens from 4 children with AIH type I, 3 children with AIH type II and 2 children with CVH, using ApopDetek in situ hybridisation method and Mabs anti CD95, Ki67, bcl-2 by means of APAAP technique. The histological appearance of apoptotic bodies in both conditions was similar. The proliferation activity of the hepatocytes was elevated in cases of CVH and less extensive in AIH. Immunohistochemical analysis suggested that the liver damage in AIH and CVH could be mediated by CD95 system as a mechanism of T-cell mediated cytotoxicity.
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PMID:[Apoptosis and hepatic cell proliferation in autoimmune hepatitis and chronic viral hepatitis C in children: analysis of APO-1/Fas (CD95), bcl-2 and Ki67 expression]. 1091 Jun 54

Chronic hepatitis C virus (HCV) infection is frequently associated with a variety of autoimmune phenomenons. Mixed cryoglobulinemia (MC) appears in up to 50% of chronic HCV-infected patients. Cryoglobulins consist of immunoglobulin complexes precipitating in vitro when cooled below body temperature. In most cases IgM with rheumatoid factor activity is found in cryoprecipitates which could lead to vasculitis induced by the deposition of immnuocomplexes in small vessels. This vasculitis is thought to cause clinical symptoms called Meltzer's triad. This triad is represented by purpura, arthralgia and weakness. One third of patients suffering from HCV-associated mixed cryoglobulinemia are developing typical symptoms during their course of disease. The striking association between HCV infection and MC has conduced to the hypothesis that HCV is of major importance in the production of MC with followed vasculitis. Both hepatrophism and lymphotrophism have been reported for the hepatitis C virus. Infection of B-cells by HCV could probably lead to a bcl-2 translocation and immunoglobulin gene rearrangement which results in clonal lymphoproliferation and in synthesis of monoclonal IgM with rheumatoid factor activity. These IgM form immunocomplexes with IgG in the cold, which are finally responsible for the described vasculitis. Histopathological changes of the liver are dominated by chronic HCV infection. The majority of times mild activity of hepatitis or mild fibrosis could be found. Nevertheless, cirrhosis is more often found in HCV-infected patients suffering from MC compared to patients without MC. Conventional treatment of MC is aimed to reduce circulating immune complexes by immunosupression and plasmapheresis. With the emerging concept of a viral pathogenesis the therapeutic approach has changed during the last decade. Interferon treatment of MC, particularly of HCV-associated MC is well established nowadays.
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PMID:Hepatitis C virus-associated mixed cryoglobulinemia. Clinical manifestations, histopathological changes, mechanisms of cryoprecipitation and options of treatment. 1164 46

The bcl-2 gene is involved in the regulation of programmed cell death by providing a survival advantage to rapidly proliferating cells. This study investigates bcl-2 protein expression in liver biopsies with acute or chronic viral hepatitis B (HBV) or C(HCV). The study comprised 60 liver biopsies with hepatitis B or C. These included 10 biopsies from cases with acute lobular hepatitis (ALH), and 50 with chronic hepatitis (CH). In addition, 10 liver biopsies were used as controls. In CH cases, HAI grade ranged from 3/18 to 15/18, and stage from 1 to 6 (6HBV/8HCV). Immunohistochemical bcl-2 expression was assessed using the streptavidin-biotin method and the presence of apoptotic cells was evaluated by TUNEL method. Immunohistochemical and in situ hybridization (TUNEL) results were expressed following morphometric analysis. In CH cases, bcl-2 was detected in portal and intralobular lymphocytes, and in cholangiolar epithelial cells of the interface area. In ALH and control cases, bcl-2 was expressed only in lymphocytes. Lymphocytic bcl-2 expression was correlated directly with categories A, C and D of HAI (P < 0.001), whereas the degree of fibrosis was reversibly correlated to bcl-2 expression. In conclusion, in cases of chronic hepatitis, bcl-2 expression in cholangioles of interface area suggests that this oncoprotein may be involved in regulation of growth of these epithelial cells.
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PMID:Expresssion of bcl-2 oncoprotein in cases of acute and chronic viral hepatitis type B and type C: a clinicopathologic study. 1214 25

We compared the biological mechanism of cell death during hepatotoxicity induced by ligation of the Fas receptor in wild-type and liver-specific bcl-2 transgenic mice. Transgenic overexpression of Bcl-2 in mouse hepatocytes can prevent lethal hepatitis induced by agonistic anti-Fas antibodies. In contrast, Fas ligand (FasL)-induced death cannot be overcome in bcl-2 transgenic mice, indicating that anti-Fas antibodies do not reliably mimic the more physiological ligand. Different apoptotic parameters, viz. caspase activation, cytochrome c release and nuclear DNA degradation were analysed. No differences, however, could be observed between wild-type and bcl-2 transgenic mice after injection with a lethal dose of soluble FasL, indicating that apoptosis by FasL-dependent ligation is not modulated by Bcl-2 in vivo. These results demonstrate that the stimulus determines the outcome between type I mitochondria-independent apoptosis, in the case of FasL, or type II mitochondria-dependent and Bcl-2-inhibitable apoptosis, in the case of anti-Fas antibodies.
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PMID:A Bcl-2 transgene expressed in hepatocytes does not protect mice from fulminant liver destruction induced by Fas ligand. 1284 4

Inhibition of NFkappaB enhances the susceptibility of cancer to TRAIL-mediated apoptosis and is suggested as a strategy for cancer therapy. Because the role of NFkappaB in TRAIL-mediated apoptosis of hepatocytes is unknown, we investigated the influence of NFkappaB-inhibition in death ligand-mediated apoptosis in hepatitis. Adenoviral hepatitis resulted in upregulation of NFkappaB-activity, which could be inhibited by expression of IkappaBalpha-superrepressor. We treated mice after the onset of adenoviral hepatitis with adenoviruses expressing FasL (AdFasL), TRAIL (AdTRAIL), or GFP (AdGFP). In contrast to apoptosis induced by AdFasL, NFkappaB inhibition strongly enhanced AdTRAIL-mediated apoptosis of hepatocytes. Expression of IkappaBalpha inhibits adenoviral infection-mediated overexpression of bcl-xl, providing a molecular mechanism for TRAIL sensitization. In agreement with this hypothesis, downregulation of bcl-xl by siRNA enhanced susceptibility of hepatocytes to TRAIL, but not to FasL-mediated apoptosis, resulting in TRAIL-mediated severe liver damage after AdTRAIL application. Our data demonstrate that inhibition of NFkappaB in adenoviral hepatitis strongly sensitizes hepatocytes to TRAIL-mediated apoptosis. Bcl-xl, in contrast to bcl-2 and c-FLIP, is strongly upregulated after viral infection and represents an essential NFkappaB-dependent survival factor against TRAIL-mediated apoptosis. In conclusion, inhibition of NFkappaB or bcl-xl during TRAIL therapy may harbor a risk of liver damage in patients with viral hepatitis.
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PMID:NFkappaB-mediated upregulation of bcl-xl restrains TRAIL-mediated apoptosis in murine viral hepatitis. 1566 Mar 91

Because the underlying mechanism of hepatocellular damages in autoimmune hepatitis (AIH) still remains unclear, analysis of CD28 and bcl-2 molecules, which are critical for T cell activation and survival, was performed in patients with AIH. The number of CD28(+)CD4(+) peripheral blood mononuclear cells (PBMC) in corticosteroid (CS)-treated patients was comparable to normal control individuals but decreased in untreated AIH patients. In contrast, the number of CD28(+)CD8(+) PBMC was decreased in both CS-treated and untreated AIH patients. Analysis of liver-infiltrating mononuclear cells (LIMC) showed that the number of CD28(+)CD4(+) and CD28(-)CD8(+) LIMC were positively correlated with the histology activity index score. Bcl-2(+)CD4(+) LIMC were observed in the portal area of the liver and the numbers fluctuated with disease activity during the time course after CS administration. By contrast, CD8(+) LIMC were shown not to express bcl-2. Taken collectively, these results suggest that bcl-2(+)CD28(+)CD4(+) and bcl-2(-)CD28(-)CD8(+) cells may play critical and distinct roles in hepatocellular damage in AIH.
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PMID:Analysis of CD28 and bcl-2 expression on peripheral blood and liver-infiltrating mononuclear cells in patients with autoimmune hepatitis. 1677 79


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