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)

Patients with acute liver failure accumulate toxic substances in the circulation which may impair recovery of hepatic function. The aim of this study was to test an in vitro assay to detect inhibitory substances in the serum of patients with acute liver failure. Human liver-derived HepG2 cells were incubated for 24h in 96 well plates (30,000 cells/well) with sera (10%) from 24 patients with acute liver failure due to paracetamol overdose or NANB hepatitis and 11 normal controls. DNA synthesis was determined from the incorporation of 3H-thymidine and cell viability by the metabolism of the tetrazolium dye MTS. HepG2 cells exposed to acute liver failure sera incorporated significantly less 3H-thymidine (median 30% of control, range 0.2-169%) than normal sera (100%, 76-133%, p=0.002). Cell viability was also reduced (75%, 33-112% vs 100%, 96-105%, p<0.001). There was no correlation between these values and patient outcome or levels of plasma TNF-alpha or serum interferon-gamma. The assay detected inhibitory substances in sera of patients with acute liver failure and could be used to monitor the use of liver support systems.
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PMID:Assay to detect inhibitory substances in serum of patients with acute liver failure. 1021 46

Tumor necrosis factor (TNF) is considered to be deeply involved in the hepatocyte damages in severe hepatitis. To delineate which mediators are involved in the production of TNF in vivo, we examined regulatory mechanisms of the production of TNF by rat Kupffer cells using a variety of mediators. Lipopolysaccharide (LPS) markedly induced TNF production by Kupffer cells. Kinetic studies revealed a rapid release of TNF within 3-4 hrs after the addition of LPS to the culture medium. Spleen cell derived-macrophage activating factor prepared from rat spleen cells did not by itself induce the production of TNF. However, the presence of a small amount of the factor during or before exposure to LPS induced higher levels of TNF, suggesting that macrophage activating factor had a priming effect. Recombinant human interferon-gamma and recombinant human granulocyte-macrophage colony stimulating factor, the natural types of which are components of the macrophage activating factor, displayed similar effects. Prostaglandin E2 (PGE2) and dexamethasone both inhibited LPS-induced TNF production in a dose dependent manner. Indomethacin, a cyclooxygenase inhibitor, increased LPS-induced TNF production. Interestingly, a combination of PGE2 and indomethacin inhibited TNF production more strongly than PGE2 alone, suggesting that the simultaneous treatment with PGE2 and indomethacin decreases liver damage in severe hepatitis rather than PGE2 alone. In addition, PGE2 pretreatment reduced the response to the newly added PGE2, suggesting the presence of a desensitization mechanism in the PGE2 receptor system. These findings suggest that spleen cell-derived macrophage activating factor and bowel-derived LPS take important parts in TNF production through the portal blood in the liver in vivo.
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PMID:Tumor necrosis factor production by rat Kupffer cells-regulation by lipopolysaccharide, macrophage activating factor and prostaglandin E2. 1033 31

The administration of concanavalin A (Con A) to mice induces cytokine-dependent hepatitis. In the present study, the effect of glycyrrhizin on Con A-induced hepatitis was examined. Treatment of mice with Con A (0.2 mg/mouse, i.v.) induced elevation of the plasma transaminase activities at 24 h. Mice were treated with glycyrrhizin (100, 200 and 400 mg/kg, i.p.), and glycyrrhizin at the doses of 200 and 400 mg/kg inhibited the Con A-induced elevation of the plasma transaminase activities. At 1 h after Con A treatment, interferon-gamma, tumor necrosis factor-alpha, interleukin-2 and interleukin-6 proteins were released into the plasma. Although treatment with glycyrrhizin at 200 mg/kg inhibited Con A-induced hepatitis, it did not affect the release of any of these Con A-induced cytokines into the plasma. The present results clearly show that glycyrrhizin inhibited Con A-induced hepatitis without affecting cytokine expression.
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PMID:Glycyrrhizin protects mice from concanavalin A-induced hepatitis without affecting cytokine expression. 1040 81

The interferon-gamma (IFN-gamma) transgenic mouse expresses the IFN-gamma gene strongly in the liver and develops chronic hepatitis from 6-10 weeks of age. Previously we reported the detection of hepatocyte apoptosis and the expression of the Fas system in the transgenic mouse liver. The objective of the present study was to examine the possible development of favorable conditions for predisposing cells to malignancy. The connection between the cell cycle and cancer has become evident, and the relation of cyclin D1 (CD1) with hepatocellular carcinomas has been strengthened. In the liver of transgenic mice of 48 weeks of age, c-myc and CD1 gene expression was induced, indicating progression of the cell cycles. p21 gene expression in the transgenic mouse liver might counteract cell-cycle progression promoted by c-myc and CD1. In the liver of 8-week-old transgenic mice, expression of c-myc mRNA was correlated with the levels of plasma transaminase activities. In these 8-week-old transgenic mice, however, CD1 mRNA was not induced, regardless of the progression of hepatitis. Based on these results, we conclude that long lasting hepatitis may lead to favorable conditions for predisposing cells to malignancy.
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PMID:Long lasting chronic hepatitis is accompanied by cyclin D1 gene expression in the mouse. 1042 76

Acute concanavalin A (Con A)-induced hepatitis in mice is an animal model for hepatic injury induced by activated T cells. The evolution of hepatic involvement can be followed from hour to hour by measuring serum transaminase levels. We investigated the possible role of endogenous interleukin-6 (IL-6) in this model. We found serum IL-6 levels and splenic IL-6 mRNA during Con A-induced hepatitis to be significantly lower in interferon-gamma (IFN-gamma)-deficient mice, which are resistant against the Con A-induced syndrome, than in wild-type ones, suggesting that systemic IL-6 production favors development of hepatic injury. However, IL-6-deficient mice proved to be more susceptible to the disease than wild-type mice, indicating that endogenous IL-6 plays a predominantly hepatoprotective role. Experiments in which wild-type mice were treated with anti-IL-6 antibodies, before or after Con A challenge, allowed us to reconcile these contrasting observations. The antibody injections resulted in a biphasic alteration of serum IL-6 levels, initial neutralization being followed by rebound increased levels due to accumulation of IL-6 in the form of antigen-antibody complexes. The effect of antibody on disease severity differed depending on the time of injection. Antibody injection at 2.5 h post Con A resulted in delayed disease manifestation, whereas treatment initiated before Con A resulted in accelerated disease. We conclude that endogenous IL-6 plays a bimodal role. IL-6 present before Con A challenge as well as that induced in the very early phase after Con A injection triggers hepatoprotective pathways. Continuation of IL-6 production beyond this early phase, by some other pathway, seems to be harmful to hepatocytes.
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PMID:Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice. 1064 2

Orthotopic liver transplantation (OLT) is a successful treatment in patients with hepatitis C virus (HCV)-associated end-stage liver disease worldwide. T lymphocytes and their cytokines are believed to have a pivotal role in the defense against HCV and in allograft rejection. An immunosuppressive drug regimen may cause a cytokine imbalance toward a T helper (TH) cell type 2 profile that is associated with the persistence of infection and acceptance of the graft. The aim of this study is to assess whether cytokine imbalances toward a TH1- or TH2-type response may have a role in recurrent HCV infection and rejection after OLT. Twenty-one intrahepatic T-cell lines of 15 patients with recurrent HCV infection after OLT (group A) and 15 lines of 11 patients with rejection (group B) were studied. Both patient groups had received liver allografts because of HCV-associated end-stage liver disease. Patients with HCV-induced liver disease who did not undergo OLT served as controls: 17 patients with chronic hepatitis C (CH-C) and 8 patients with cirrhosis. At the time of liver biopsy, 14 blood-derived T-cell lines of 12 patients with recurrent HCV infection, 7 of 10 patients with rejection, and 18 of 18 control patients were also investigated. Regardless of the underlying disease (recurrent HCV infection, rejection, HCV-induced hepatitis, and cirrhosis), all liver tissue-derived T-cell lines produced interferon-gamma; some additionally produced interleukin-4 (IL-4), but none produced IL-10, indicating that the TH0/1 cytokine profile dominates. T-cell lines showing a TH1 cytokine profile derived from intrahepatic T cells could be established significantly more often in recurrent HCV infection and rejection than in controls with CH-C (Fisher's exact test, P <.05). The cytokine profile of intrahepatic T cells did not differ from that obtained in peripheral blood. TH0/1 cytokine profile dominates the intrahepatic and blood-derived immune response in recurrent HCV infection and rejection after OLT regardless of the mode of immunosuppression. The lymphokine profile of immunocompromised patients with recurrent HCV infection or rejection does not differ principally from that of patients with HCV-induced hepatitis and cirrhosis, but seems to show a TH1 profile significantly more often.
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PMID:Cytokine profile of liver- and blood-derived nonspecific T cells after liver transplantation: T helper cells type 1/0 lymphokines dominate in recurrent hepatitis C virus infection and rejection. 1071 24

To assess the relationship between serum cytokine behavior and treatment outcome in type 1 autoimmune hepatitis, serum levels of interferon-gamma, interleukin-2, interleukin-4, and interleukin-10 were measured by enzyme immunoassay in 43 patients and 20 normal subjects. Serum samples were similarly tested in 38 patients after corticosteroid treatment. Serum levels of interleukin-2 and interleukin-4 were significantly lower in patients than in normal subjects. Interleukin-2 was the least common cytokine detected before (3%), during (0%), or after treatment (0%). Serum levels of interleukin-10 at presentation did not differ from those of normal subjects but they did decrease during therapy, especially in patients who entered remission. Changes in these levels, however, did not always parallel treatment outcome or histological activity. We conclude that serum levels of interleukin-2 and interleukin-4 are lower than normal in type 1 autoimmune hepatitis. Serum concentrations of interleukin-10 diminish during corticosteroid therapy but changes do not closely reflect outcome. The rarity of interleukin-2 in serum may be a distinguishing feature.
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PMID:Nature and behavior of serum cytokines in type 1 autoimmune hepatitis. 1079 72

Aminoguanidine is an inhibitor of the inducible form of nitric oxide synthase (iNOS). In the present study, the effect of aminoguanidine on concanavalin A-induced hepatitis was examined. Treatment of mice with concanavalin A (10 mg/kg, i.v.) induced interferon-gamma and iNOS mRNA expression in the liver before the elevation of plasma alanine aminotransferase activity. Immunohistochemical study showed the induction of iNOS protein expression in the area of necrosis. Aminoguanidine (1, 3 and 10 mg/kg, i.p.) inhibited the concanavalin A-induced elevation of alanine aminotransferase activity. Aminoguanidine (10 mg/kg, i.p.) did not inhibit concanavalin A-induced interleukin-2, interferon-gamma, tumor necrosis factor-alpha or iNOS mRNA expression in the liver. The plasma nitrite/nitrate level was elevated at 6 and 24 h after concanavalin A treatment. The elevation of nitrite/nitrate was inhibited by aminoguanidine (10 mg/kg, i.p.). From these results, we conclude that nitric oxide formed by iNOS may be involved in the development of concanavalin A-induced hepatitis.
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PMID:Aminoguanidine prevents concanavalin A-induced hepatitis in mice. 1082 65

The interferon-gamma (IFN-gamma) transgenic mouse expresses the exogenous IFN-gamma gene in the liver and develops chronic hepatitis. For the present experiment, four IFN-gamma transgene (+) mice of 48 weeks of age and 16 IFN-gamma transgene (+) mice of 8 weeks of age were used. The four IFN-gamma transgene (+) mice of 48 weeks of age showed significantly elevated plasma alanine aminotransferase (ALT) and expressed the inducible form of nitric oxide synthase (iNOS) mRNA in the liver. Of the 16 IFN-gamma transgene (+) mice of 8 weeks of age, iNOS mRNA was expressed in the livers of three. These three mice exhibited higher plasma ALT levels than the other mice of 8 weeks of age. The present results suggest that iNOS mRNA expression in the liver might be correlated with the progression of hepatitis.
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PMID:Expression of the inducible form of the nitric oxide synthase gene in the livers of mice with chronic hepatitis. 1093 96

Inchinko-to (TJ-135) is a herbal medicine consisting of three kinds of crude drugs, and in Japan it is administered mainly to patients with cholestasis. The present study evaluated the effects of TJ-135 on concanavalin A (con A)-induced hepatitis in mice in vivo and con A-induced cytokine production in vitro. When mice were pretreated with oral TJ-135 for 1 week before intravenous con A injection, the activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were significantly decreased 8 h after con A administration (-82%, -96% and -66% respectively). In histological investigations, sub-massive hepatic necrosis accompanying inflammatory cell infiltration was not observed in mice pretreated with TJ-135. Serum levels of interleukin-12 (IL-12), interferon-gamma (IFN-gamma) and IL-2 were significantly lower in mice pretreated with TJ-135 compared with controls, while IL-10 levels were higher in these mice. Intrasplenic IL-12 levels were significantly lower in mice pretreated with TJ-135, while intrasplenic IL-10 levels were higher in these mice. In vitro, IL-10 production by splenocytes was increased by the addition of TJ-135 to the culture medium, whereas the production of IL-12 and IFN-gamma was inhibited. These results suggest that con A-induced hepatitis was ameliorated by pretreatment with TJ-135. With regard to the mechanism of these effects of TJ-135, we speculate that TJ-135 inhibits the production of inflammatory cytokine and enhances the production of anti-inflammatory cytokines. Therefore administration of TJ-135 may be useful in patients with severe acute hepatitis accompanying cholestasis or in those with autoimmune hepatitis.
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PMID:Effects of the Japanese herbal medicine 'Inchinko-to' (TJ-135) on concanavalin A-induced hepatitis in mice. 1105 23


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