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

Oral pretreatment with E3330, a novel quinone derivative, attenuated liver injury induced with tumor necrosis factor-alpha in galactosamine-sensitized mice. Tumor necrosis factor-alpha is known to induce inflammatory mediators such as leukotrienes and prostanoids. An in vitro study showed that E3330 inhibited the generation of leukotriene B4 and thromboxane B2, but enhanced prostaglandin E2 generation from rat peritoneal exudate cells stimulated with the Ca(2+)-ionophore, A23187. These findings suggest that the protective effect of E3330 on galactosamine/tumor necrosis factor-alpha hepatitis is due at least in part to its inhibition of the generation of leukotrienes. The inhibition of thromboxane B2 generation or the enhancement of prostaglandin E2 generation by E3330 may also contribute to its hepatoprotective effect.
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PMID:Protective effects of E3330, a novel quinone derivative, on galactosamine/tumor necrosis factor-alpha-induced hepatitis in mice. 133 20

Tumor necrosis factor (TNF) toxicity was induced in vivo by intravenous administration of 15 micrograms of recombinant murine TNF-alpha per kg to galactosamine-sensitized mice. Within 8 h, the animals developed a fulminant hepatitis. Intravenous administration of 0.5 mg of colchicine per kg at 19 and 4 h prior to TNF challenge protected the animals against hepatitis. Lipopolysaccharide (LPS)-stimulated, bone marrow-derived macrophages from C3H/HeN mice released significant amounts of TNF in vitro. When such macrophages were intravenously given to LPS-resistant galactosamine-sensitized C3H/HeJ mice, these animals died within 24 h. Preincubation of these transferred macrophages with colchicine did not suppress the LPS-inducible TNF release from these cells. Concordantly, administration of macrophages exposed to colchicine in vitro resulted in full lethality. However, in vivo pretreatment of C3H/HeJ mice with colchicine 19 and 4 h prior to the transfer of LPS-stimulated macrophages prevented lethality. In LPS-responsive NMRI mice which had been protected against galactosamine-LPS-induced hepatitis by pretreatment with colchicine, TNF was still released into the blood. We conclude from our findings that the in vivo protection by colchicine is mediated by blocking TNF action on target cells while the effector cells of LPS toxicity, i.e., the macrophages, remain responsive.
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PMID:Colchicine prevents tumor necrosis factor-induced toxicity in vivo. 156 85

We investigated lipopolysaccharide-induced tumor necrosis factor production in vitro by peripheral blood monocytes from patients with various liver diseases. Tumor necrosis factor production was found to be significantly reduced in patients with chronic hepatitis B (n = 17; 135 +/- 30 pg tumor necrosis factor/ml; mean +/- S.E.M.) and patients with chronic non-A, non-B hepatitis (n = 15; 212 +/- 22 pg tumor necrosis factor/ml) compared with healthy control individuals (n = 47; 411 +/- 40 pg tumor necrosis factor/ml; p less than 0.0005 and p less than 0.01, respectively). This reduced tumor necrosis factor production was not only seen with an optimal stimulating concentration of lipopolysaccharide (100 ng/ml) but also with suboptimal concentrations (0.1 ng/ml). In contrast to patients with chronic viral hepatitis, monocytes from patients with alcohol-induced cirrhosis (n = 26; 444 +/- 49 pg tumor necrosis factor/ml), primary biliary cirrhosis (n = 7; 412 +/- 81 pg tumor necrosis factor/ml) and alcohol-induced fatty liver changes (n = 5; 401 +/- 62 pg tumor necrosis factor/ml) produced normal amounts of tumor necrosis factor when stimulated with an optimal concentration of lipopolysaccharide. Lipopolysaccharide (0.1 ng lipopolysaccharide/ml)-stimulated peripheral blood monocytes of patients with chronic hepatitis B (n = 15; 102 +/- 32 pg/ml) or non-A, non-B hepatitis (n = 13; 97+/- 16 pg/ml) could not be induced to produce more tumor necrosis factor either when prestimulated with gamma-interferon (170 +/- 45 pg/ml and 149 +/- 32 pg/ml, respectively), a lymphokine known to activate monocytes, or with the cyclooxygenase inhibitor indomethacin to reduce the suppressive effect of prostaglandin E2 (148 +/- 40 pg/ml and 153 +/- 45 pg/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired lipopolysaccharide-inducible tumor necrosis factor production in vitro by peripheral blood monocytes of patients with viral hepatitis. 212 37

Fulminant hepatitis is associated with an 80% mortality rate. Surviving patients do not develop chronic liver disease. Failure to produce adequate amounts of interferon and to achieve an antiviral state seem to be the basic defects in this condition. Tumor necrosis factor (TNF) has been shown to be induced by viruses. By rapid lysis of virus infected cells, it also prevents optimal viral replication thus reducing the viral yield and the infection rate and extent. On the other hand, it has growth promoting characteristics. We postulate that TNF has a dual role in fulminant hepatitis: (a) It acts as an antiviral agent by eliminating virus infected cells thus reducing viral yields and limiting spread of infection; (b) it may be the signal for hepatocyte regeneration. Only those patients, in whom the regeneration rate exceeds lysis of infected hepatocyte by TNF, survive.
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PMID:Does tumor necrosis factor play a role in the pathogenesis of fulminant hepatitis? 246 60

We investigated the effect of inflammatory cytokines on the intercellular adhesion molecule-1 expression on primary cultured murine hepatocytes. Tumor necrosis factor-alpha, interferon-gamma and interleukin-1 alpha up-regulated the intercellular adhesion molecule-1 expression on hepatocytes in a dose-dependent fashion; however, interleukin-6 did not. On the basis of kinetic analysis, the expression level reached a peak 24 hr after stimulation, and both cycloheximide and actinomycin D inhibited the expression. Furthermore, T lymphocytes bind more to interferon-gamma-stimulated hepatocytes than to unstimulated hepatocytes. The binding was dependent on the concentration of interferon-gamma. The binding was also up-regulated by stimulating T lymphocytes with phorbol myristate acetate. Tumor necrosis factor-alpha and interleukin-1 alpha demonstrated the same effect as interferon-gamma, whereas interleukin-6 did not increase T-lymphocyte adhesion to the hepatocytes. The adhesion induced by interferon-gamma or tumor necrosis factor-alpha was inhibited by antibody against either intercellular adhesion molecule-1 or lymphocyte function-associated antigen-1, a ligand for intercellular adhesion molecule-1, but was not inhibited by CD44 antibodies. These results demonstrate that inflammatory lymphokines enhance the T-lymphocyte adhesion to primary cultured hepatocytes by up-regulating the intercellular adhesion molecule-1 expression on the stimulated hepatocytes by activating the de novo pathway. This mechanism may play an important role in the pathogenesis of hepatitis.
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PMID:Inflammatory cytokines up-regulate intercellular adhesion molecule-1 expression on primary cultured mouse hepatocytes and T-lymphocyte adhesion. 790 80

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

We assessed the effect of acteoside, a naturally occurring antioxidative phenylethanoid, on hepatic apoptosis and the subsequent liver failure induced by D-Galactosamine (D-GalN) and lipopolysaccharide (LPS). A co-administration of D-GalN (700 mg/kg) and LPS (35 microg/kg) to mice evoked typical hepatic apoptosis characterized by DNA fragmentation and apoptotic body formation, resulting in fulminant hepatitis and lethality of mice. Pre-administration of acteoside at 10 or 50 mg/kg subcutaneously at 12 and 1 h prior to D-GalN/LPS intoxication significantly inhibited hepatic apoptosis, hepatitis and lethality. Tumor necrosis factor-alpha (TNF-alpha) secreted from LPS-stimulated macrophages is an important mediator of apoptosis in this model. Acteoside showed no apparent effect on the marked elevation of serum TNF-alpha, but it partially prevented in vitro TNF-alpha (100 ng/ml)-induced cell death in D-GalN (0.5 mM)-sensitized hepatocytes at the concentrations of 50, 100 and 200 microM. These results indicated that D-GalN/LPS-induced hepatic apoptosis can be blocked by an exogenous antioxidant, suggesting the involvement of reactive oxygen intermediates (ROIs) in TNF-alpha-dependent hepatic apoptosis.
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PMID:Acteoside inhibits apoptosis in D-galactosamine and lipopolysaccharide-induced liver injury. 1042 28

Tumor necrosis factor (TNF) induces hepatitis when injected in human beings or in rodents. The molecular mechanism by which TNF induces hepatic distress remains largely unknown, although induction of apoptosis of hepatocytes appears to be an essential step. In order to increase the therapeutic value of TNF, we have studied the protective activity of several molecules and found that four chemically totally different substances confer significant protection in the model of TNF-induced lethal hepatitis in mice sensitized with D-(+)-galactosamine (GalN), but not in mice sensitized with actinomycin-D (ActD) or against anti-Fas-induced lethal hepatitis. Verapamil, a calcium-channel blocker, tannic acid, picotamide, a thromboxane A(2) receptor antagonist, and K76COOH, an inhibitor, amongst others, of complement, protected significantly against induction of lethality, release of the liver-specific enzyme alanine aminotransferase (ALT) and induction of apoptosis in the liver after TNF/GalN, except for K76COOH, which paradoxically increased ALT values after challenge, and which also protected against TNF/GalN in complement-deficient mice. The data suggest that activation of platelets and neutrophils, as well as induction of inflammation occur in the TNF/GalN model, but not in the TNF/ActD or anti-Fas models, in which direct induction of apoptosis of hepatocytes may be more relevant. The protective activity of the drugs may lead to an increase in therapeutic value of TNF.
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PMID:Tumor necrosis factor-induced lethal hepatitis: pharmacological intervention with verapamil, tannic acid, picotamide and K76COOH. 1067 38

Tumor necrosis factor (TNF) is an essential mediator in the pathogenesis of Gram-negative septic shock. Injection of TNF into normal mice leads to systemic, lethal inflammation, which is indistinguishable from lipopolysaccharide (LPS)-induced lethal inflammation. alpha(2)-macroglobulin (A2M) is a major positive acute phase protein with broad-spectrum protease-inhibitory activity. Mouse A2M-deficient (MAM-/-) mice were significantly protected against lethal systemic inflammation induced by TNF. The protection is not due to faster clearance of the injected TNF. The induction of tolerance to TNF-induced lethality by repetitive administration of small doses of human TNF for five consecutive days was equally efficient in both mutant mice compared to wild-type mice. In D-(+)-galactosamine (GalN)-sensitized mice, TNF induces lethal inflammatory hepatitis. MAM(-/-) mice are equally sensitive to the lethal combination of TNF/GalN. Furthermore, interleukin-1-induced desensitization to TNF/GalN was not impaired in MAM(-/-) mice. We conclude that MAM plays a mediating role in TNF-induced lethal shock and that MAM deficiency does not reduce changes in efficiency of tolerance and desensitization to TNF and TNF/GalN-induced lethality, respectively.
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PMID:Differential response of a(2)-macroglobulin-deficient mice in models of lethal TNF-induced inflammation. 1112 2

Anorexia that develops in chronic hepatitis is associated with cytokine expression in the brain. Treatment of mice with concanavalin A (12.5 mg/kg, i.v.) elevated the plasma alanine aminotransferase activity at 8.5 h after treatment. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta mRNA expression was induced at 6 and 24 h after concanavalin A treatment in both the liver and brain. Treatment of mice with concanavalin A reduced the body weight at 24 h after treatment and this decreased body weight was accompanied by a decreased food intake. Glycyrrhizin (200 mg/kg, i.p.) inhibited the concanavalin A-induced elevation of plasma alanine aminotransferase activity, however, it did not inhibit the concanavalin A-induced decreased body weight. The present results indicate that treatment of mice with concanavalin A caused the development of anorexia and that this anorexia might develop independently of the induction of hepatitis.
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PMID:Development of anorexia in concanavalin A-induced hepatitis in mice. 1117 20


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