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)

In some cases of ascitic fluid due to cirrhosis, benign mesothelial clusters may be observed, accompanied by markedly atypical cells that have been proposed to be abnormal macrophages, mesothelial cells or necrotic cells of hepatic origin. The aim of this study was to determine the origin of these cells with the use of a panel of monoclonal antibodies (MAbs) against cell surface antigens. Furthermore, the lymphocyte subpopulations were analyzed for a possible correlation with the presence of abnormal cells. Markedly atypical cells were found in 4 of 12 cases. They showed no phagocytosis of latex particles and were negative for MAbs My4 (CD14), HLE-1 (CD45), Leu M1 (CD15), CEA 3-13 and HEA-125. They reacted positively with BMA-120 and HLA-1. This staining pattern demonstrated the mesothelial origin of the markedly atypical cells. The profile of the lymphocyte subpopulations in the cases with markedly atypical cells was not different from the other cases. We propose that these cells are abortive cluster formations of mesothelial cells.
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PMID:Immunocytochemical analysis of ascitic fluid due to cirrhosis. A contribution to understanding the origin of markedly atypical cells. 154 8

Elevated concentrations of lipopolysaccharide have been found in serum of patients with severe parenchymal liver disease and its toxic effect is thought to involved in hemodynamic disturbances seen in cirrhosis. A soluble form of the receptor (sCD14) for lipopolysaccharide is present in serum and is released by stimulated macrophages, indicating macrophage activation. We investigated sCD14 serum levels and in vitro production by lipopolysaccharide stimulated peripheral blood monocytes in patients with various liver diseases. In acute viral hepatitis serum sCD14 levels were significantly higher during the first 2 weeks after onset of jaundice (n=11; 3.6 +/- 0.9 microg /ml (mean +/- SD)) than in healthy control individuals (n=52; 2.5 +/- 0.7 microg/ml; p<0.001). These elevated serum levels corresponded to enhanced in vitro production of sCD14 by lipopolysaccharide-stimulated peripheral blood monocytes (n=11; 365 +/- 262 ng/ml) as compared to control monocytes (n=52; 228 +/- 74 ng/ml; p=0.02). Similarly, patients with alcoholic cirrhosis had significantly increased sCD14 serum levels (n=31; 4.5 +/- 3.2 microg/ml; p<0.001) and in vitro sCD14 production by lipopolysaccharide-stimulated monocytes (291 +/- 153 ng/ml; p=0.014). Serum sCD14 levles correlated with the severity of disease (Child A: 2.6 +/- 1.0 microg/ml; Child B: 4.4 +/- 2.1 microg/ml; Child C: 7.8 +/- 5.1 micro/ml; Anova: p=0.001). Patients with chronic viral hepatitis had only slightly elevated serum sCD14 levels (n=17; 2.9 +/- 0.7 microg/ml; p=0.01) and increased in vitro production of sCD14 by peripheral blood monocytes (320 +/- 128 ng/ml; p<0.001). The elevated serum concentration of sCD14 in alcoholic cirrhosis and acute and chronic viral hepatitis points to an incrased macrophage activation in these diseases. sCD14 from serum is able to associate with cells not expressing membrane CD14, such as endothelial cells, allowing those cells to bind and respond to lipopolysaccharide. Elevated levels of sCD14 could in this way contribute to the toxic effects of lipopolysaccharide in severe liver disease.
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PMID:Increased in vitro production and serum levels of the soluble lipopolysaccharide receptor sCD14 in liver disease. 865 56

Intestinal bacterial overgrowth and translocation, both common in cirrhosis with ascites, may lead to the activation of monocytes and lymphocytes, increased levels of proinflammatory cytokines, and enhanced synthesis of nitric oxide present in cirrhosis. Bacterial endotoxin promotes the synthesis of lipopolysaccharide (LPS)-binding protein (LBP), and forms a LPS-LBP complex that binds to CD14. This study was designed to evaluate LBP levels and their correlation to the immune response and the hemodynamic status in cirrhotic patients. Plasma LBP, endotoxin, soluble CD14 (sCD14), cytokines, renin, nitrites, and systemic vascular resistance were determined before and 4 weeks after norfloxacin or placebo in 102 cirrhotic patients and 30 controls. LBP was elevated in 42% of ascitic cirrhotic patients (15.7 +/- 0.7 versus 6.06 +/- 0.5 microg/mL, P <.01). In 60% of high LBP patients, endotoxin was within normal range. Among ascitic patients, those with high LBP showed greater (P <.05) levels of sCD14, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), nitrites + nitrates (NOx)/creatinine, and renin, and lower vascular resistance. In the cirrhotic patients with high LBP, norfloxacin normalized (P <.01) LBP (from 16.6 +/- 0.5 to 5.82 +/- 0.8 microg/mL) and sCD14; reduced the level of cytokines, NOx/creatinine, and renin; and increased vascular resistance; but lacked effect in patients with normal LBP. Portal pressure was unchanged after norfloxacin in another group of 18 cirrhotic patients with high and 19 with normal LBP. In conclusion, the subset of ascitic cirrhotic patients with marked immune and hemodynamic derangement is identified by increased LBP levels. Amelioration of these abnormalities by norfloxacin suggests the involvement of enteric bacteria or their products in the triggering of the process.
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PMID:Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. 1250 Feb 6

Bacterial lipopolysaccharide (LPS) stimulates Kupffer cells and participates in the pathogenesis of alcohol-induced liver injury. However, it is unknown whether LPS directly affects hepatic stellate cells (HSCs), the main fibrogenic cell type in the injured liver. This study characterizes LPS-induced signal transduction and proinflammatory gene expression in activated human HSCs. Culture-activated HSCs and HSCs isolated from patients with hepatitis C virus-induced cirrhosis express LPS-associated signaling molecules, including CD14, toll-like receptor (TLR) 4, and MD2. Stimulation of culture-activated HSCs with LPS results in a rapid and marked activation of NF-kappaB, as assessed by in vitro kinase assays for IkappaB kinase (IKK), IkappaBalpha steady-state levels, p65 nuclear translocation, NF-kappaB-dependent luciferase reporter gene assays, and electrophoretic mobility shift assays. Lipid A induces NF-kappaB activation in a similar manner. Both LPS- and lipid A-induced NF-kappaB activation is blocked by preincubation with either anti-TLR4 blocking antibody (HTA125) or Polymyxin B. Lipid A induces NF-kappaB activation in HSCs from TLR4-sufficient (C3H/OuJ) mice but not from TLR4-deficient (C3H/HeJ) mice. LPS also activates c-Jun N-terminal kinase (JNK), as assessed by in vitro kinase assays. LPS up-regulates IL-8 and MCP-1 gene expression and secretion. LPS-induced IL-8 secretion is completely inhibited by the IkappaB super repressor (Ad5IkappaB) and partially inhibited by a specific JNK inhibitor, SP600125. LPS also up-regulates cell surface expression of ICAM-1 and VCAM-1. In conclusion, human activated HSCs utilize components of TLR4 signal transduction cascade to stimulate NF-kappaB and JNK and up-regulate chemokines and adhesion molecules. Thus, HSCs are a potential mediator of LPS-induced liver injury.
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PMID:Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. 1271 78

It has been suggested that oxidative stress participates in the pathogenesis of hepatitis C virus infection. It also has been made clear that redox status in T cell and macrophage relates to the activity of virus infectious disease such as HIV infection. With such background we evaluated the relationship between the intracellular redox status of T cell and macrophage and the activity of HCV positive chronic liver disease. Intracellular GSH and GSSG levels of T cell and macrophage were determined in twenty-five HCV positive asymptomatic carriers (C-ASC), sixty-three chronic hepatitis patients (C-CH), ten HCV positive liver cirrhosis patients (C-LC) and twenty-nine healthy controls. The intracellular GSH levels of T cell (T-GSH) significantly decreased in both C-CH and C-LC compared with healthy controls. No significant differences in the T-GSH levels were found between healthy controls and C-ASC. T-GSH levels of C-CH and C-LC were significantly lower compared with C-ASC. The intracellular GSH levels of macrophage (CD14-GSH) of C-LC were significantly decreased compared with healthy controls. The CD14-GSH levels of C-CH and C-LC were significantly lower compared with C-ASC. There was no correlation between intracellular GSH, GSSG levels and the serum levels of iron-related markers, fibrogenesis markers and other clinical parameters. These results suggest that the intracellular redox status of T cell and macrophage relates to the progression of HCV related chronic liver disease.
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PMID:[The relationship between the intracellular redox status of immune cells and progression of hepatitis C virus related chronic liver disease]. 1555 20

While the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome will have steatosis, only a minority will ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity are the most important environmental factors determining disease risk. For NAFLD, dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the alcohol dehydrogenases and aldehyde dehydrogenase alcohol metabolising genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, TNF-alpha, transforming growth factor-beta, and angiotensinogen may be associated with steatohepatitis and/or fibrosis.
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PMID:Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease. 1703 1

Although the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome have steatosis, only a minority ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of liver fibrosis. For ALD, the dose and pattern of alcohol intake, coffee intake, and dietary and other lifestyle factors leading to obesity are the most important environmental determinants of disease risk. For NAFLD, dietary saturated fat and antioxidant intake, small bowel bacterial overgrowth, and obstructive sleep apnea syndrome may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the ADH and ALDH alcohol metabolizing genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, tumor necrosis factor alpha, transforming growth factor beta, and angiotensinogen may be associated with steatohepatitis or hepatic fibrosis or both.
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PMID:Genetics of alcoholic liver disease and nonalcoholic fatty liver disease. 1729 76

The functions of dendritic cells (DCs) are impaired in patients with liver cirrhosis. It is well-known that cirrhotic patients show decreased levels of plasma branched-chain amino acids (BCAA). Although amino acids are associated with maintaining the cell structure and function in many organs, limited data are available regarding the role of amino acids including BCAA in the immune system. We aimed to investigate the roles of BCAA in the function of human monocyte-derived DCs (MoDC). CD14-positive monocytes (CD14 (+)) were isolated from PBMC from healthy volunteers and hepatitis C virus (HCV) cirrhotic patients. In medium deprived of BCAA or valine, monocytes were able to differentiate into immature, but not into mature, DCs and showed weak expression of CD83. The deprivation of leucine or isoleucine did not affect this process. The MoDC allostimulatory capacity was significantly decreased in medium deprived of BCAA or valine (p = 0.017, p = 0.012, Bonferroni's analysis, respectively). Annexin V(FITC)/propidium iodide staining showed that the DC yield and viability were not significantly different under any medium. Immunoblotting demonstrated that depletion of valine or leucine decreased phospho-S6 kinase expression. Valine increased dose-dependently the allostimulatory capacity and IL-12 production of MoDC from both healthy volunteers and HCV cirrhotic patients. An elevated extracellular concentration of valine could improve the DC function in cirrhotic patients. These data provide a rationale for nutrition therapy that could be beneficial to patients with cirrhosis.
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PMID:Extracellular branched-chain amino acids, especially valine, regulate maturation and function of monocyte-derived dendritic cells. 1798 6

Tissue factor (TF) is one of the proteins that participate in hemostatic and inflammatory processes. Activated monocytes present in the liver increase expression of TF, and while accumulating in the organ they can intensify inflammation. The aim of the present study was to evaluate the expression of TF on monocytes in advanced liver cirrhosis with regard to other activation markers. The flow cytometric analysis of TF (CD142), CD14, adhesive molecules CD11b and CD11c, costimulatory molecules CD40, CD80 and CD86, and HLA-DR on monocytes was carried out in 45 patients with postalcoholic liver cirrhosis (Child Pugh B, 20 patients; Child Pugh C, 25 patients) and in 25 healthy persons. The positive correlation between monocytic TF expression and monocyte [soluble CD14 (sCD14), CD11b, monocyte aggregates] activation, the expression of costimulatory molecules on monocytes (CD40, CD80), blood platelet (soluble P-selectin, microplatelets) activation, the level of tumor necrosis factor-alpha, biochemical parameters of liver damage (alanine aminotransferase, aspartate aminotransferase, alkaline phosphate, gamma-glutamyltransferase, and bilirubin) as well as coagulation disorders were observed in the study. In conclusion, the study revealed that the activation of monocytes and blood platelets is accompanied by the elevation of monocytic TF expression in advanced liver cirrhosis. The monocytic TF is a significant link connecting clotting processes and inflammatory and immunological phenomena in liver cirrhosis.
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PMID:Increase in expression of monocytic tissue factor (CD142) with monocytes and blood platelet activation in liver cirrhosis. 1798 14

The present study aimed to investigate the association between TLR4 mutations (Asp299Gly and Thr399Ile) and CD14 polymorphisms (base pair -159 and -260) with HBV-related cirrhosis in Chinese Han patients. By use of a polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis technique, we genotyped Toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile and CD14-159 and -260 polymorphisms in 110 HBV-related cirrhotic patients and 110 healthy controls from the Chinese Han population. We found significant differences in the genotypes and allele frequencies of CD14-159 (but not -260) between healthy controls and liver cirrhotic patients, and both the CD14-159 and -260 genotypes were significantly different among Child-Pugh grades in cirrhotic patients. No TLR4 Asp299Gly and Thr399Ile mutations were detected in any cirrhotic patients or healthy controls in the Chinese Han population. These findings indicated that the polymorphisms of CD14, but not TLR4 Asp299Gly and Thr399Ile mutations, may be an important genetic factor for HBV-related cirrhotic injury in the Chinese Han population.
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PMID:CD14-159 and -260 gene polymorphisms are associated with HBV-related cirrhotic injury in Chinese Han patients. 1866 12


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