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[The effect of trofopar, AICA phosphate and Essentiale on the detoxifying function and blood circulation of the liver in lesions in man].

The comparative clinicopharmacological studies established the ability of hepatotropic agents with the membrane stabilizing properties and metabolic activity--trophopar, aika-phosphate and essential to stimulate to various degrees the processes of microsomal oxidation of antipyrine in hepatocytes at their insufficiency in patients with lesions of the hepatobiliary system of the alcohol and viral etiology. The studied drugs improve also the condition of the intrahepatic hemodynamics according to the findings of rheohepatography. The correlations between the positive dynamics of the values of antipyrine clearance, the degree of arterial blood filling (the rheographic index) and the increase of serum albumin content were found that confirms the ability of trophopar, aika-phosphate and essential to exert the complex influence on the systems and mechanisms of the realization of the liver antitoxic function.

Adolescent↗

Hepatocyte membrane-bound IgG and circulating liver-specific autoantibodies in chronic liver disease: relation to hepatitis B virus serum markers and liver histology.

Hepatocytes isolated from 101 biopsies were examined for membrane-bound IgG. The sera of the patients were tested for anti-liver-specific lipoprotein by radioimmunoassay and for liver membrane autoantibody (by indirect immunofluorescence on isolated rabbit hepatocytes. The seven patients with normal liver or minor nonspecific alterations were negative for membrane IgG and serum antibodies. Membrane IgG with granular distribution was found in 41 patients [21 hepatitis B virus-related chronic active hepatitis (CAH), 3 cryptogenic CAH, 3 chronic persistent hepatitis, 6 prolonged viral hepatitis, 1 alcoholic cirrhosis, and 6 primary biliary cirrhosis]. Membrane IgG with linear fluorescence pattern was detected in 12 cases (4 autoimmune CAH, 3 HBsAg-positive CAH, 2 alcoholic cirrhosis, 1 anti-HBc positive CAH, 1 cryptogenic CAH, and 1 prolonged viral hepatitis). A strong association between granular IgG and serum HBsAg was found. Nuclear localization of IgG was found in 34 patients and correlated with the positivity of granular membrane IgG. The highest prevalence of anti-liver-specific lipoprotein was found in primary biliary cirrhosis and autoimmune CAH cases which were also positive for liver membrane autoantibody. No relationship was found between the presence of membrane IgG and circulating liver-specific autoantibodies. Membrane IgG and anti-liver-specific lipoprotein correlated with the presence of moderate and severe portal inflammatory infiltration but not with piecemeal necrosis or transaminase levels. Eleven of the twelve patients with linear membrane IgG presented chronic active liver disease with moderate to severe signs of liver damage. Therefore, it is suggested that, while granular membrane IgGs are related to hepatitis B virus, antigenic expression on the hepatocyte surface and/or the presence of immune complexes, linear membrane IgG could play a role in the immunopathogenesis of liver cell damage particularly in "autoimmune" cases which present high percentages of positive cells liver-specific autoantibodies.

Adult↗

Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B.

CD4+CD25+ regulatory T cells (Treg) have been shown to maintain immune tolerance against self and foreign Ags, but their role in persistent viral infection has not been well-defined. In this study, we investigated whether and where CD4+CD25+ Treg contribute to the development of chronic hepatitis B (CHB). One hundred twenty-one patients were enrolled, including 16 patients with acute hepatitis B, 76 with CHB, and 29 with chronic severe hepatitis B. We demonstrated that in chronic severe hepatitis B patients, the frequencies of CD4+CD25+ Treg in both PBMC and liver-infiltrating lymphocytes were significantly increased and there was a dramatic increase of FoxP3(+)-cell and inflammatory cell infiltration in the liver compared with healthy controls. In CHB patients, circulating CD4+CD25+ Treg frequency significantly correlates with serum viral load. In acute hepatitis B patients, circulating CD4+CD25+ Treg frequency was initially low and with time, the profile reversed to exhibit an increased number of circulating Treg in the convalescent phase and restored to normal levels upon resolution. In PBMC taken from infected patients, depletion of CD4+CD25+ Treg led to an increase of IFN-gamma production by HBV-Ag-stimulated PBMC. In addition, CD4+CD25+ Treg were capable of suppressing proliferation of autologous PBMC mediated by HBV Ags, which probably reflects the generation of HBV-Ag-specific Treg in circulation and in the liver of HBV-infected patients. Together, our findings suggest that CD4+CD25+ Treg play an active role not only in modulating effectors of immune response to HBV infection, but also in influencing the disease prognosis in patients with hepatitis B.

Acute Disease↗

[Induction and pathogenesis of chronic hepatitis experimentally induced in rabbits (author's transl)].

Studies of recent years have focussed on the immunopathogenesis of chronic liver diseases. Long-term immunization of rabbits with human liver proteins leads to liver lesions typical for human CAH. Delayed hypersensitivity against rabbit liver proteins, tested by skintest, correlated with the morphological changes of the liver. Circulating autoantibodies to liver specific protein, circulating immune complexes and IgG fixed in vivo to isolated hepatocytes could be observed before the liver lesions had developed histologically. The main target antigen in experimentally induced CAH seems to be an organ-specific but species-crossreacting macrolipoprotein with a molecular weight above 1 million, which is localized on the outer surface of the hepatocyte membrane. The liver specific protein (LSP) contains species-specific and non-species-specific determinants. Autoantibodies to non-species-specific determinants of LSP could only be detected in animals which had already developed CAH. Thus experimentally CAH in rabbits may be induced by the loss of tolerance to non-species-specific determinants of the LSP complex. Cell mediated and humoral immunity to LSP in man is found in HBsAg positive and HBsAg negative inflammatory liver diseases. Thus experimental CAH in rabbits seems to be a model for virus-induced and non-virus-induced chronic inflammatory liver diseases.

Animals↗

Effects of homologous plasma cross-circulation on liver function in galactosamine-induced hepatic necrosis in rats.

Plasma cross-circulation that resembles clinical plasma exchange was carried out in rats with galactosamine (GalN)-treated hepatic failure to investigate its effect on the damaged liver function. Twenty-four hours after the injection of GalN, plasma cross-circulation was performed at a plasma flow rate of 0.1 ml/min for 6 h. At 48 h after the injection of GalN, survival was obtained in 6 of 8 GalN-injected rats treated with plasma cross-circulation as compared with 4 of 10 GalN-injected rats treated with sham circulation. State 3 oxygen consumption and ATP synthesis (mitochondrial respiratory function) and ATP, ADP, and total adenine nucleotide contents in the liver were significantly higher in the former group than in the latter group at that period, as determined by sacrificing the surviving animals. Although the survival rate was not significantly improved, evidence suggests that plasma cross-circulation enhanced mitochondrial phosphorylative activity and produced an augmented high-energy state of the liver, which had been markedly reduced by GalN administration. An efficient removal of toxic metabolites as well as an influx of a large amount of fresh plasma by plasma cross-circulation would be beneficial for the regenerative process of the necrosing liver tissues.

Adenine Nucleotides↗

Irradiation effects upon ischemic regenerating rat liver cells.

Starch particles injected into the arterial and portal systems of the liver of the rat caused a temporary blockage of the liver circulation and consequent hypoxia in the liver cells. In the regenerating liver this resulted in a 30-40% decrease of thymidine incorporation into DNA, when analysed 1.5 hours after injection. Irradiation-induced cell damage, evaluated by thymidine incorporation 1.5 hours after irradiation with a single dose of X-rays, was not ameliorated by the ischemic condition. It is suggested that this depends on an inhibited nucleotide metabolism and DNA synthesis leading to an additive metabolic hypoxic effect of the starch particles on radiation damage. An equal level of thymidine incorporation, however, was found in an ischemic and a non-ischemic group of animals 16 hours after irradiation. In this case the liver cells in the ischemic group had overcome the additional inhibition of DNA synthesis caused by temporary hypoxia.

Animals↗

Eliminating metabolic abnormalities of portacaval shunting by restoring normal liver blood flow.

Portacaval shunting causes a variety of anatomic, metabolic, and physiological changes. However, it has not been determined whether, and to what degree, these changes are permanent after a sustained period of shunting. We prepared three groups of rats for study of the recovery process. One group had side-to-side shunts for 3 wk, one group had side-to-side shunts for 2 wk followed by the restoration of normal liver circulation for 1 wk, and one group (control) had sham operations. Side-to-side shunting causes liver atrophy, increased plasma ammonia, altered plasma and brain amino acid spectra, decreased plasma glucose, and increased transport of neutral amino acids across the blood-brain barrier. After restoration of the normal pattern of liver circulation by shunt repair, the liver regained its normal size within 1 day. All abnormalities associated with liver dysfunction disappeared with the exception of plasma glucose, which remained approximately 15% lower than control values.

Amino Acids↗

Liver and circulating NK1.1(+)CD3(-) cells are increased in infection with attenuated Salmonella typhimurium and are associated with reduced tumor in murine liver cancer.

An attenuated (DeltacyA, Deltacrp) strain of Salmonella typhimurium (chi4550) containing a gene for human IL-2 (chi4550pIL2) reduces hepatic tumor burden when orally inoculated into mice with liver cancer; however, wild-type S. typhimurium is also associated with cancer regression. Therefore, experiments were designed to clarify the invasiveness and the anti-tumor properties of three strains of S. typhimurium. S. typhimurium chi4550pIL2, chi4550, or wild type (WT) was incubated with mature Caco-2 and HT-29 enterocytes, and S. typhimurium internalization was assessed. For infectivity experiments, mice were orally inoculated with saline or 10(9)S. typhimurium chi4550pIL2, chi4550, or WT; 48 h later mice were sacrificed for analysis of cecal bacteria and S. typhimurium translocation to mesenteric lymph nodes. For experiments involving tumor implantation, four groups were studied: saline control, tumor alone, chi4550pIL2+tumor, and chi4550+tumor. Mice were orally inoculated with saline or S. typhimurium and underwent laparotomy 24 h later with 5 x 10(4) MCA38 murine adenocarcinoma cells injected into the spleen. On day 14, liver tumors were counted and peripheral blood and hepatic lymphocyte populations were analyzed by FACScan. Attenuated S. typhimurium exhibited decreased internalization by cultured enterocytes and decreased infectivity after oral inoculation. Mice treated with chi4550pIL2 or chi4550 had fewer liver tumors and increased populations of hepatic and circulating NK1.1(+)CD3(-) lymphocytes compared to mice treated with saline (P < 0.01). These data suggest that attenuated S. typhimurium may have an application as an anti-tumor agent.

Animals↗

Infection of circulating and liver infiltrating T cells by hepatitis C virus of different subtypes.

Hepatitis C virus (HCV) infection display a very high rate of progression to chronicity and, like many other viruses causing persistent infections, it displays a tropism for the cells of the immune system. Peripheral blood mononuclear cells (PBMCs) from 21 HCV chronic carriers and long-term T cell clones derived from circulating or liver infiltrating T lymphocytes were tested by cDNA "nested" PCR for positive and negative strand HCV-RNA. The presence of HCV genomes in PBMCs is a frequent, although not constant, finding and can be accompanied by active viral replication, as suggested by the coexistence of negative strand HCV-RNA. Infected T cells are more represented in livers than in periphery, as indicated by comparing HCV-RNA detection in T cell clones isolated from both the compartments. Sequencing of viral genomes present in PBMCs and liver infiltrating lymphocytes showed that all the three major HCV genotypes present in our population of chronic carriers can infect lymphoid cells. Although each clonal population of T cells is infected by a single strain of HCV, in the same patient lymphoid cells can harbor different viral populations, different from those circulating at that moment in the serum.

Adult↗

Hyperdynamic circulation in liver cirrhosis: desensitization of vasoconstrictive receptors by G protein-coupled receptor kinases.

Liver cirrhosis is complicated by a hyperdynamic circulation characterized by a generalized arterial vasodilatation. This vasodilatation occurs despite high plasma concentration of several potent vasoconstrictive substances like angiotensin, vasopressin, endothelin and norepinephrine. The experimental evidence available shows that compensatory adrenergic and vasoconstrictive signals are not normally transmitted intracellularly. G protein-coupled receptor kinases phosporylate plasma membrane receptors and block the transmission of the signal intracellularly. We hypothesize that these kinases are responsible for the desensitization to vasoconstrictors observed in patients with liver cirrhosis. Pharmacological intervention at this level might be beneficial to treat complications like ascites and variceal bleeding.

Animals↗