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)

Ribavirin, a synthetic guanosine analogue, possesses a broad spectrum of activity against DNA and RNA viruses. It has been previously shown to attenuate the course of fulminant hepatitis in mice produced by murine hepatitis virus strain 3. We therefore studied the effects of ribavirin on murine hepatitis virus strain 3 replication, macrophage production of proinflammatory mediators including TNF, IL-1, and the procoagulant activity (PCA), fgl2 prothrombinase; and Th1/Th2 cytokine production. Although ribavirin had inhibitory effects on viral replication (<1 log), even at high concentrations complete eradication of the virus was not seen. In contrast, at physiologic concentrations (up to 500 microg/ml), ribavirin markedly reduced viral-induced parameters of macrophage activation. With ribavirin treatment, the concentrations of PCA, TNF-alpha and IL-1beta all decreased to basal concentrations: PCA from 941 +/- 80 to 34 +/- 11 mU/10(6) cells; TNF-alpha from 10.73 +/- 2.15 to 2.74 +/- 0.93 ng/ml; and IL-1beta from 155.91 +/- 22.62 to 5.74 +/- 0.70 pg/ml. The inhibitory effects of ribavirin were at the level of gene transcription as evidenced by Northern analysis. Both in vitro and in vivo, ribavirin inhibited the production of IL-4 by Th2 cells, whereas it did not diminish the production of IFN-gamma in Th1 cells. In contrast, ribavirin had no inhibitory effect on TNF-alpha and IL-1beta production in LPS-stimulated macrophages. These results suggest that the beneficial effects of ribavirin are mediated by inhibition of induction of macrophage proinflammatory cytokines and Th2 cytokines while preserving Th1 cytokines.
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PMID:Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. 953 10

Apoptosis is a physiologic process that serves to eliminate cells during development or in response to immunologic regulation. In acute inflammation, however, apoptosis triggered by the overproduction of "death factors" such as TNF-alpha or Fas ligand (FasL) may contribute to tissue injury. Both TNF-alpha and FasL are presumed to convey an apoptotic signal by activating a cascade of cysteine-aspartate proteases, which includes IL-1beta-converting enzyme or caspase-1. In the present study, we evaluated the contribution of TNF-alpha and FasL, as well as the role of caspase-1, in Con A-induced hepatitis. We report here that TNF-alpha and FasL mRNA and protein levels are both increased in the livers of Con A-challenged mice. Using a novel inhibitor of TNF-alpha, we can confirm that Con A-induced hepatitis is primarily TNF-alpha dependent. Blockade of FasL with a soluble Fas immunoadhesin does not prevent liver injury in animals treated with Con A alone. However, administration of a matrix metalloproteinase inhibitor exacerbates liver injury, in part through a FasL-dependent process, since pretreatment with the soluble Fas immunoadhesin reduces liver injury in this model. In addition, mice lacking functional caspase-1 are resistant to Con A-induced hepatitis, even after pretreatment with a matrix metalloproteinase inhibitor. We conclude that TNF-alpha plays a predominant role in Con A-induced liver injury, although concomitant activation of FasL can also lead to apoptotic injury. Furthermore, Con A-induced hepatitis is caspase-1 dependent.
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PMID:Disparate roles for TNF-alpha and Fas ligand in concanavalin A-induced hepatitis. 955 19

In chronic viral hepatitis, autoimmune hepatitis, and some chronic cholestatic liver diseases, T-lymphocytes serve as effector cells of the immunostimulatory processes. Cellular interactions of immune cells with extracellular matrix (ECM) components are regulated primarily via the beta 1 subfamily of integrin receptors. The target epitope of several such integrin receptors is the Arg-Gly-Asp (RGD) sequence, a cell adhesion motif shared by several matrix-associated adhesive glycoproteins. We review the use of synthetic nonpeptidic analogues of RGD and of soluble receptor of tumor necrosis factor (TNF)-alpha in the prevention of immune-mediated, concanavalin A-induced liver damage in mice and of RGD analogues in inhibiting the development of liver cirrhosis in rats. The concanavalin A-induced elevation of serum transaminases and TNF-alpha, and the infiltration of liver tissue by inflammatory cells, were inhibited by pretreatment of the mice with the synthetic RGD mimetics and soluble TNF receptor. In rats, the progression of thioacetamide-induced liver cirrhosis was markedly inhibited by the coadministration of the RGD mimetic SF-6,5. The compounds described here may be examined therapeutically for pathological conditions in the liver, manifested as necroinflammation, cholestasis and fibrosis.
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PMID:The use of synthetic analogues of Arg-Gly-Asp (RGD) and soluble receptor of tumor necrosis factor to prevent acute and chronic experimental liver injury. 962 59

Liver macrophages, which are involved in the different types of hepatitis, may indirectly induce hepatic fibrogenesis, since they have the possibility to activate hepatic stellate cells and fibroblasts by secretion of TGF-beta, TNF-alpha and IL-1. To evaluate variations of the number of liver macrophages and their subpopulations, a quantification was carried out in normal human liver tissue, fatty liver, fatty liver hepatitis and hepatitis B. Identification was performed by the mab PG-M1 (anti-CD68) and, comparatively, four lectins, Griffonia simplicifolia agglutinin I (GSA-I), Erythrina cristagalli agglutinin (ECA), peanut agglutinin (PNA) and soybean agglutinin (SBA). A slight decrease in the frequency of macrophages in pericentral fields was observable in fatty liver and fatty liver hepatitis as compared to normal liver tissue. On the other hand, the number of CD68+ cells was significantly enhanced in hepatitis B with moderate and severe inflammatory activity. The highest incidence of macrophages was found in portal tracts of liver with fatty liver hepatitis and, particularly, hepatitis B. The fraction of cells stained by ECA, PNA or SBA did not increase significantly under pathological conditions. In contrast, the percentage of GSA-I binding macrophages was higher in liver parenchyma of hepatitis B and in portal tract macrophages in fatty liver hepatitis and also hepatitis B. In conclusion, our results indicate that GSA-I may aid in the detection of the subpopulation of activated macrophages which are assumed to play a pivotal role in liver pathology.
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PMID:Comparative quantitative analysis of macrophage populations defined by CD68 and carbohydrate antigens in normal and pathologically altered human liver tissue. 969 43

Propagermanium (3-oxygermylpropionic acid polymer) is an organic germanium compound that activates the immune system. In this study, we investigated the action of propagermanium on T-cell-mediated murine hepatic injury induced by concanavalin A (Con A). Oral administration of propagermanium inhibited the development of liver injury about 10 h after ConA injection. Histological analysis demonstrated that propagermanium attenuated the extent of liver damage compared with controls, reducing infiltration by leucocytes, especially CD11b-positive cells. Infiltration by CD4-positive cells was not affected. Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma are crucial for the development of hepatitis in this model. Propagermanium treatment induced significant inhibition of subsequent TNF-alpha production about 10 h after Con A injection, without affecting IFN-gamma, interleukin (IL)-10, IL-4 and IL-12 production. This effect on TNF-production coincided with the inhibition of aminotransferase activity late in the progression of Con A-induced liver injury. These facts suggest that this compound affects the macrophages (Mphi) function in the liver sinusoid. Therefore, Mphi were cultured with liver sinusoidal endothelial cells (SEC) and the effect of propagermanium on TNF-alpha production in the presence of IFN-gamma was determined. TNF-alpha production was reduced significantly in the coculture of Mphi and SEC when Mphi was treated with propagermanium. These results might explain the mechanisms by which propagermanium inhibits Con-A-induced liver injury. That is, propagermanium improves hepatitis through mechanisms including the reduced production of TNF-alpha, without modification of Th1- and Th2-cell function.
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PMID:Protection against concanavalin A-induced murine liver injury by the organic germanium compound, propagermanium. 987 94

Toxoplasmosis has gained particular attention in the AIDS era as the most common opportunistic encephalitis in HIV-infected patients. Since there are important parallels between the human and rodent infection, experimental murine toxoplasmosis is widely used to study the immune reactions to this protozoal parasite. Oral application of low-virulent Toxoplasma (T.) gondii cysts leads to a biphasic disease characterized by an acute, generalized phase followed by a chronic stage confined to the brain, where an encephalitis with persistence of the parasite develops. Immunity to T. gondii is T cell mediated, and there is increasing evidence for a critical role of cytokines for an effective immune response. In order to address the functional role of interferon (IFN)-gamma in toxoplasmosis, we took advantage of mice lacking the IFN-gamma-receptor. Inactivation of the IFN-gamma-receptor rendered mice highly susceptible to T. gondii, and they died of a fulminant acute toxoplasmosis. Among the various organs affected, hepatitis was severe enough to cause death. In contrast to wild type animals, IFN-gamma-receptor-deficient mice were unable to activate their macrophages as evidenced by a lack of major histocompatibility complex (MHC) class II antigen induction and the absence of an upregulation of tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS) mRNA transcripts, two macrophage effector molecules. These observations prompted the investigation of TNF- and TNF-receptor-mediated effects in toxoplasmosis by use of mice deficient in either the TNF-receptor type 1 (TNFR1) and/or the TNF-receptor type 2 (TNFR2). The lethal outcome of T. gondii-infected TNFR1/2- and TNFR1-deficient mice, but not of TNFR2-deficient and wild type animals, illustrated the important role of TNF-alpha and TNFR1-mediated signalling, respectively, in this infection. Histopathology attributed death of TNFR1- and TNFR1/2-deficient mice to a severe, necrotizing encephalitis. Unrestricted intracerebral parasite replication in these strains was associated with reduced numbers of iNOS+ leukocytes and a lack of iNOS mRNA induction in their brains as compared to resistant wild type and TNFR2-deficient mice. To precisely identify the cellular sources of cytokines in the brain, flow cytometry of leukocytes isolated from the brain, in situ hybridization, immunohistochemistry and RT-PCR analysis of cytokine mRNA transcripts of magnetically purified leukocyte populations were performed. These studies disclosed that both CD4+, CD8+ T lymphocytes and macrophages recruited to the brain as well as resident cell populations of the CNS including neurons, astrocytes and microglia contributed to the intracerebral cytokine synthesis. Each population was characterized by a specific cytokine pattern. Interestingly, activation of brain cells is a hallmark of Toxoplasma encephalitis. The marked induction of a variety of immunologically important cell surface molecules as MHC class I and II antigens, cell adhesion molecules and their ligands on microglia points to a particular important role of this cell type for the immune response to T. gondii, since the expression of these molecules is a prerequisite for cellular interactions with T cells. The observation of a prominent interleukin (IL)-10 production in the T. gondii-infected brain initiated studies addressing the function of this powerful immunosuppressive mediator in chronic Toxoplasma encephalitis. Neutralization experiments revealed that IL-10 facilitates persistence of the parasite in the brain by downregulating the intracerebral immune response. On the other hand, IL-10 may exert a regulatory role and may be necessary to prevent immunopathological effects of an uncontrolled immune response. In conclusion, these studies demonstrate the important role of the cytokines IFN-gamma and TNF-alpha and their receptors, respectively, for an effective control of T. gondii. In the CNS, the target organ of the parasite, a
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PMID:[Rudolf-Virchow Prize 1998. Award lecture. Toxoplasmosis: a model infection for studying systemic and intracerebral immune reactions]. 1009 13

Experimental models of sepsis using endotoxin challenges, including studies with sensitized animals with D-galactosamine, have largely contributed to the basic rationale for innovative clinical trials in human septic shock, which have, to date, failed. The ability of these models to reproduce human disease has been highly discussed. We report here that the widely used D-galactosamine/LPS model does not account for septic shock. Treatment with YVAD-CMK, a potent tetrapeptide inhibitor of caspases of the interleukin (IL)-1beta converting enzyme (ICE) family, protects from LPS-induced liver apoptosis and mortality in D-galactosamine-sensitized mice when administered either before or up to 2 h after the lethal challenge. This curative effect is related to complete inhibition of caspase-3 activity in the liver. However, YVAD-CMK does not affect LPS-induced release of IL-1beta and does not protect from a lethal dose of LPS in unsensitized mice. These experiments demonstrate the difference between these two widely recognized experimental models of sepsis. LPS toxicity in D-galactosamine-treated mice, leading to blocked gene transcription, results from tumor necrosis factor (TNF)-alpha-induced caspase-3-dependent liver injury, not from the systemic inflammatory response. These results provide evidence that inhibitors of the ICE caspase family can prevent or even overcome the ongoing hepatic injury induced by TNF-alpha during sepsis, ischemia-reperfusion, or severe hepatitis.
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PMID:LPS challenge in D-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock. 1019 82

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

Although impaired liver regeneration is thought to be a major cause of death in patients with fulminant hepatitis, the mechanisms are not well defined. Since IL-12 synthesis has been reported to be up-regulated in murine hepatitis virus infection, we studied the influence of continuous IL-12 stimulation on murine liver regeneration using flow cytometric and functional analyses. In non-hepatectomized mice, interestingly, the number of hepatic NK cells was significantly decreased on day 7, after six IL-12 injections, and day 14, after 13 IL-12 injections. The number of hepatic NKT cells was markedly increased on day 7 and day 14 of daily IL-12 treatment. The cytotoxic activity of hepatic lymphocytes against both YAC-1 and p815 cells was enhanced on day 2, after single IL-12 injection, and day 7, after six IL-12 injections. In contrast, hepatic lymphocytes isolated 24 h after partial hepatectomy with IL-12 pretreatment did not show any cytolytic activity against either YAC-1 cells or p815 cells. However, continuous IL-12 stimulation resulted in a significantly higher serum alanine aminotransferase (sALT) level 24 h after the partial hepatectomy as compared with sALT levels in mice subjected to either partial hepatectomy or IL-12 pretreatment alone. On the other hand, the expression of hepatic TNF-alpha mRNA was markedly enhanced by continuous IL-12 stimulation even 24 h after partial hepatectomy, as compared with that in non-treated mice and hepatectomy alone. Simultaneous administration of anti-tumor necrosis factor (TNF)-alpha mAb completely inhibited IL-12-induced in vivo enhancement of liver damage after partial hepatectomy. In conclusion, IL-12 induces the specific cytolytic activity against regenerating hepatocytes in vivo mainly through the enhancement of TNF-alpha synthesis.
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PMID:IL-12 induces specific cytotoxicity against regenerating hepatocytes in vivo. 1033 Feb 71

In liver injury induced by carbon tetrachloride, secondary hepatic injury occurs from inflammatory processes originating from products released by activated Kupffer cells, which play a central role in hepatic inflammation. The purpose of our study was to demonstrate, in rats, the relationships between a function of the hepatic macrophages, TNF-alpha production and the state of activation of these cells, characterized by their phenotype, in the different phases of the process and development of fibrosis in a carbon tetrachloride-induced cirrhosis model. The immunohistochemical localization of proinflammatory cytokine TNF-alpha and surface surface makers (ED1 and ED2) was studied in hepatitis and cirrhosis in response to 3 and 9 weeks ingestion of carbon tetrachloride. After carbon tetrachloride ingestion, accompanying the increased necrosis, immunohistochemical analysis of liver tissue sections demonstrated the significantly increased number of cells expressing ED1, ED2 and TNF-alpha, compared to normal. The number of cells expressing the surface phenotypic markers of liver macrophages increased and this change was concomitantly associated with an increased cellular expression of TNF-alpha. Local macrophage proliferation and influx of newly recruited blood monocytes resulted in an increase of the macrophage population. The populational changes involved difference in functional activity and enhanced TNF-alpha expression. This cytokine expressed in the carbon tetrachloride-induced inflammatory process is associated with the development of fibrosis and may contribute to disease severity.
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PMID:Expression of TNF-alpha and immunohistochemical distribution of hepatic macrophage surface markers in carbon tetrachloride-induced chronic liver injury in rats. 1057 17


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