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)

Hepatocytes isolated from woodchucks (Marmota monax) were shown to produce nitrite in vitro from L-arginine after stimulation with lipopolysaccharide (LPS). Hepatocytes isolated from woodchucks that were chronic carriers of woodchuck hepatitis virus formed twice as much nitrite as hepatocytes from noninfected animals. Nitrite synthesis by hepatocytes was directly related to L-arginine and LPS concentrations in the tissue culture medium and reached a plateau at 0.5 mM L-arginine and 1.0 micrograms/ml LPS. LPS-stimulated hepatocytes nitrosated morpholine to form N-nitrosomorpholine in the presence of L-arginine at a physiological pH of 7.4. There was a 10-fold increase in N-nitrosomorpholine production when hepatocytes were stimulated with LPS compared to unstimulated hepatocytes under similar conditions when both nitrite and morpholine were directly added to the medium. NG-monomethyl-L-arginine, a selective inhibitor of nitric oxide synthase, inhibited formation of both nitrite and N-nitrosomorpholine. These results demonstrate that nitrosating agents are formed in hepatocytes via the L-arginine-nitric oxide pathway. This suggests that endogenous formation of carcinogenic N-nitroso compounds could influence the process of hepatocarcinogenesis in woodchucks with chronic woodchuck hepatitis virus infection.
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PMID:Nitrite and nitrosamine synthesis by hepatocytes isolated from normal woodchucks (Marmota monax) and woodchucks chronically infected with woodchuck hepatitis virus. 163 28

Mice infected with the neurotropic JHM strain of mouse hepatitis virus (MHV-JHM) develop a demyelinating encephalomyelitis several weeks after infection. Astrogliosis and infiltration of inflammatory cells are prominent findings in the brains and spinal cords of infected mice. In this report, astrocytes in infected spinal cords were analyzed for expression of three pleiotropic cytokines, TNF-alpha, IL-1 beta, and IL-6; Type 2 nitric oxide synthase (iNOS); and MHC class I and II antigen. The data show that all three cytokines and iNOS are expressed by astrocytes in chronically infected spinal cords. These activated astrocytes are localized to areas of virus infection and demyelination, although most of the astrocytes expressing these proteins are not MHV-infected. MHC class I and II antigen can be detected in these spinal cords as well, but not in cells with the typical morphology of astrocytes. TNF-alpha, IL-6, and iNOS are also evident in the brains of mice with MHV-induced acute encephalitis, but in marked contrast to the results obtained with the chronically infected mice, most of the cells expressing these cytokines or iNOS had the morphology of macrophages or other mononuclear cells and very few appeared to be astrocytes. Additionally, astrocytes and, most likely, oligodendrocytes are infected in the spinal cords of mice with chronic demyelination. These results are consistent with a role for both viral infection of glial cells and high localized levels of proinflammatory cytokines and nitric oxide in the demyelinating process in mice infected with MHV-JHM. They also show that analogously to the human demyelinating disease, multiple sclerosis, astrocytes are a major cellular source for these cytokines in mice with chronic, but not acute disease.
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PMID:Activation of astrocytes in the spinal cord of mice chronically infected with a neurotropic coronavirus. 749 73

Chronic inflammatory states frequently lead to the increased production of nitric oxide (NO) via inducible NO synthase (NOS-2). In addition, NO may produce mutagenesis through several mechanisms such as DNA oxidation, DNA deamination, and the formation of N-nitroso compounds. As there is a strong association between human hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC), we were interested in whether human HCV hepatitis leads to induction of NOS-2 and if the mutation repair system of p53/p21 was upregulated. Reverse transcriptase-polymerase chain reaction (RT-PCR) for human NOS-2 message was performed on RNA samples from both liver biopsies and whole liver from HCV-positive and control patients (normal liver from hepatic resections for metastases). Immunohistochemistry (IHC) for p53 and Western blot analysis for p21 were also performed on the whole liver samples. From the liver biopsies, 60% of HCV-positive patients expressed NOS-2 by RT-PCR. Looking at the whole liver samples, 100% of the HCV-positive patients expressed NOS-2 vs 12.5% in the normal samples. p53 was not detected in either group but there was upregulation of p21 over baseline expression in a number of the HCV-positive patients. Human HCV hepatitis leads to consistent upregulation of hepatic NOS-2 message, but message is not predictably present in "normal" human liver. There is also induction of p21 in some patients with HCV hepatitis. Chronic expression of NO in HCV hepatitis may play a role in DNA mutagenesis and the development of HCC.
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PMID:Chronic hepatitis C virus infection in humans: induction of hepatic nitric oxide synthase and proposed mechanisms for carcinogenesis. 922

The strain-specific spectrum of liver disease following murine hepatitis virus type 3 (MHV-3) infection is dependent on inflammatory mediators released by macrophages. Production of nitric oxide (NO) by macrophages has been implicated in resistance to a number of viruses, including ectromelia virus, vaccinia virus, and herpes simplex virus type 1. This study was undertaken to define the role of NO in MHV-3 infection. Gamma interferon-induced production of NO inhibited growth of MHV-3 in a murine macrophage cell line (RAW 264.7). Viral inhibitory activity was reproduced by the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP), whereas N-acetyl-DL-pencillamine (NAP), an inactive analog of SNAP, had no effect. Electron microscopy studies confirmed the inhibitory effects of NO on viral replication. Peritoneal macrophages isolated from A/J mice known to be resistant to MHV-3 produced a fivefold-higher level of NO and higher levels of mRNA transcripts of inducible NO synthase in response to gamma interferon than macrophages from susceptible BALB/cJ mice. SNAP inhibited growth of MHV-3 in macrophages from both strains of mice to similar degrees. In vivo inhibition of NO by N-monomethyl-L-arginine resulted in loss of resistance to MHV-3 in A/J mice. These results collectively demonstrate a defect in the production of NO in macrophages from susceptible BALB/cJ mice and define the importance of endogenous NO in resistance to MHV-3 infection in resistant A/J mice.
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PMID:Resistance to murine hepatitis virus strain 3 is dependent on production of nitric oxide. 969 1

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

Acyclic nucleoside phosphonates (ANPs) are potent broad-spectrum antivirals, also effective against immunodeficiency viruses and hepatitis viruses. Effects of several ANPs on in vitro cytokine gene expression and nitric oxide (NO) production by murine peritoneal macrophages were investigated. Included in the study were 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; Adefovir), 9-(R)-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; Tenofovir], 9-(S)-[2-(phosphonomethoxy)propyl]adenine; (S)-PMPA), 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP), 9-(R)-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), and 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG). Some of them, i.e. (R)-PMPA, (S)-PMPA, and PMEG, stimulate secretion of TNF-alpha and IL-10 in a concentration-dependent manner, and enhance the IFN-gamma-induced secretion of TNF-alpha. Although unable to activate production of nitric oxide (NO) on their own, these compounds substantially augment NO formation induced by IFN-gamma. Analysis of the expression of inducible NO synthase mRNA indicates that the NO-enhancing effect of ANPs is mediated posttranscriptionally. In contrast to IFN-gamma, production of NO triggered by lipopolysaccharide (LPS) alone, or synergistically by LPS+IFN-gamma, remains unaltered by ANPs. The immunomodulatory effects have been differentially expressed in distinct genotypes of inbred strains of mice, including the low NO-responders Balb/c and high NO-responders C3H/HeN. Although less effectively, PMEG and (R)-PMPA also increase production of TNF-alpha and NO by the IFN-gamma- but not LPS-co-stimulated macrophages from C3H/HeJ mice, which are otherwise hypo-responsive to major immune stimuli provided by IFN-gamma and LPS. It can be concluded that the expression of immunomodulatory properties of ANPs depends on the immune state of cells and its activation by distinct priming signals.
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PMID:Macrophage activation by antiviral acyclic nucleoside phosphonates in dependence on priming immune stimuli. 1113 19

Coxsackieviral infections have been linked etiologically to multiple diseases. The serotype CB4 is associated with acute pancreatitis and autoimmune type 1 diabetes. To delineate the mechanisms of host survival after an acute infection with CB4 (strain E2), we have investigated the role of nitric oxide (NO), generated by the inducible form of nitric oxide synthase (NOS2), in viral clearance and pancreatic beta-cell maintenance. Mice deficient in NOS2 (NOS2-/- mice) and their wild-type (wt) counterparts were injected with CB4, after which both groups developed severe pancreatitis, hepatitis, and hypoglycemia within 3 days. Within 4 to 7 days postinfection (p.i.), most of the NOS2-/- mice died and at a strikingly higher mortality rate than wt mice. Histological examination of pancreata from both infected NOS2-/- and infected wt mice revealed early and complete destruction of the pancreatic acinar tissue, but intact, insulin-stained islets. When examined up to 8 weeks p.i., neither surviving NOS2-/-mice nor surviving wt mice developed hyperglycemia. However, the clearance of infectious CB4 was different between the mice. The spleens of NOS2-/- survivors were cleared of infectious virus with kinetics similar to that of wt mice, but the livers, pancreata, kidneys, and hearts of the NOS2-/- groups cleared virus more slowly than those of the wt group. This delayed clearance was particularly prominent in the livers of infected NOS2-/- mice, which also showed prolonged histopathological features of viral hepatitis. Taken together, this outcome suggests that NOS2 (and NO) is not required for the prevention of pancreatic beta-cell depletion after CB4 infection. Instead the critical actions of NOS2 apparently occur early in the host immune response, allowing mice to survive and clear virus. Moreover, the data support the existence of an organ-specific dependency on NO for a rapid clearance of CB4.
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PMID:A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection. 1127 93

High concentrations of nitric oxide (NO) are generated by the inducible form of the enzyme nitric oxide synthase (iNOS), which is expressed in activated macrophages and in hepatocytes. Increased expression of iNOS in hepatocytes or macrophages might be expected in chronic HCV liver disease and HIV infections. This might in turn be reflected in increased serum NO levels in these two conditions. In view of the discrepant findings in published reports, we measured serum NO levels in a large number of chronic HCV-infected patients and patients with chronic HIV infections with or without AIDS-related opportunistic infection. We also localized HCV and iNOS antigens by immunohistochemistry, in liver biopsy tissue from patients with chronic HCV-related hepatitis, HCV-related cirrhosis, and HCV-related hepatocellular carcinoma. A group of 121 subjects with serological evidence of HCV with or without HIV infection were studied. These were compared with 14 controls without HIV or HCV disease (group A). Among the subjects with HCV, 35 were negative for HIV (group B), 66 were HIV positive (group C), and 20 had AIDS-related opportunistic infection (group D). The serum NO concentration was determined by the Brucine method. A well-characterized commercially available antibody (HCV88) directed against a synthetic NS3 peptide fragment of HCV, which localizes to the hepatocyte nuclei, and an antibody to human macrophage iNOS, were both used to detect these proteins in liver biopsy tissue by immunohistochemistry. Mean serum NO values in HIV negative/HCV negative control patients (group A) (54.6+/-12 microM) were similar to those in HIV negative/HCV positive patients (group B) (55.0+/-13 microM) and HIV positive without AIDS-related disease/HCV positive patients (group C) (47.2+/-25 microM). By contrast, the mean serum NO (70.1+/-24 microM) was significantly increased in HCV-positive patients with AIDS-related infection (group D) compared to controls (P = 0.02). HCV NS3 and iNOS antibody staining hepatocytes were not detected in any of the control non-HCV-infected biopsy samples. In early chronic HCV hepatitis (fibrosis scores F0-F2), HCV NS3 antigen localized focally to only a small number of hepatocytes. In cirrhosis (fibrosis score F4) with or without hepatocellular carcinoma, the majority of hepatocyte nuclei stained positively with HCV NS3 antibody. The majority of hepatocytes in chronic HCV hepatitis expressed iNOS, irrespective of histological disease severity. The staining was present uniformly in the cytoplasm. In chronic HCV and HIV coinfection, the pattern and number of iNOS staining cells were similar to that in patients with chronic HCV infection alone. In conclusion, there is widespread expression of iNOS in hepatocytes in chronic HCV liver disease, irrespective of liver disease stage. However, elevated NO levels in serum were related only to active AIDS-related bacterial, protozoan, and fungal infections, rather than to chronic viral infection with HCV or HIV alone. NO may play a role in the local control of chronic viral infections at tissue level, but this is not reflected in serum levels.
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PMID:Nitric oxide and chronic HCV and HIV infections. 1134 51

Ozone is one of the most powerful oxidants available, with many applications in industry and medicine. Medically relevant features of ozone include bacterial and virucidal properties, disinfection, sterilization, circulatory stimulation, and disruption of malignant cells. Ozone therapy is administered in various ways, including intravenously, intramuscularly, and intrarectally. The latter modality is used for the treatment of colitis and hepatitis. Our aim was to examine the effect of ozone water enema on normal and inflamed rat colonic mucosa. Ozone water (20 microg/ml) was prepared via ozone generator and administered intrarectally (0.5 ml) daily. Rats were killed one, three, and seven days after rectal ozone water administration, and their colons resected, rinsed, and weighed (grams per 10 cm). Damage was assessed macro- and microscopically and tissue processed for myeloperoxidase and nitric oxide synthase activity. Rats receiving saline served as controls. In an additional experiment colitis was induced by intrarectal iodoacetamide. Ozone therapy caused no macroscopic damage. Ozone therapy induced microscopic colitis, which lasted for at least a week and was accompanied by increase in segmental weight, myeloperoxidase and nitric oxide activity, and prostaglandin E2 generation. Ozone therapy had no protective effect on inflamed mucosa. In conclusion, ozone water therapy had a deleterious effect on normal colonic mucosa, suggesting intrarectal administration be reevaluated. Ozone water enema may serve as a model of microscopic colitis.
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PMID:Ozone enema: a model of microscopic colitis in rats. 1171 63


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