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)

Apoptosis is a physiological process critical for tissue homeostasis. It is essential for the regulation of immune responses. A series of molecules transduce apoptoic signals and induce the characteristic morphological appearances of apoptotic cells. Infectious diseases modulate apoptosis and this contributes to disease pathogenesis. Infection with HIV results in enhanced levels of CD4 T-lymphocyte apoptosis in both directly infected cells and in uninfected bystander cells. A variety of HIV proteins including gp120 contribute to this process. A number of different pathways induce HIV-associated CD4 T-lymphocyte apoptosis and apoptosis of uninfected bystander cells is particularly associated with increased susceptibility to Fas. Other viruses including hepatitis viruses and the human herpesviruses also modulate apoptosis. Bacterial infection induces apoptosis which is frequently mediated by the direct activation of caspases in the absence of death receptor ligation. Bacterial induction of apoptosis may either be due to bacterial factors such as the invasin IpaB of Shigella flexneri or be the result of host immune responses which control infection as demonstrated in infections due to Mycobacterium spp. Apoptosis may be modulated by therapeutic strategies, such as antiretroviral therapy, and an improved understanding of infection-associated apoptosis modulation will aid the design of novel therapeutic approaches to control infectious diseases.
 ...
PMID:Apoptotic cell death in the pathogenesis of infectious diseases. 1154 64

M50054, 2,2'-methylenebis (1,3-cyclohexanedione), was identified as a novel inhibitor of apoptosis (programmed cell death) using an in vitro cell death assay system induced in human Fas-expressing WC8 cells by soluble human Fas ligand. Furthermore, M50054 inhibited the apoptotic cell death of U937, a human monocytic leukemic cell line, induced by anticancer agents such as etoposide; it was also confirmed that M50054 inhibited apoptotic features such as DNA fragmentation and phosphatidylserine exposure in these cells. These anti-apoptotic effects were attributable to inhibition of caspase-3 activation. Additionally, M50054 significantly inhibited anti-Fas-antibody-induced elevation of plasma alanine aminotransferase and aspartate aminotransferase. Alopecia (hair loss) symptoms were also significantly improved with topical treatment with M50054. In conclusion, M50054 inhibits apoptosis induced by a variety of stimuli via inhibition of caspase-3 activation, and may thus be effective for hepatitis and chemotherapy-induced alopecia.
 ...
PMID:Inhibitory effect of M50054, a novel inhibitor of apoptosis, on anti-Fas-antibody-induced hepatitis and chemotherapy-induced alopecia. 1175 32

This review addresses recent advances in specific mechanisms of hepatotoxicity. Because of its unique metabolism and relationship to the gastrointestinal tract, the liver is an important target of the toxicity of drugs, xenobiotics, and oxidative stress. In cholestatic disease, endogenously generated bile acids produce hepatocellular apoptosis by stimulating Fas translocation from the cytoplasm to the plasma membrane where self-aggregation occurs to trigger apoptosis. Kupffer cell activation and neutrophil infiltration extend toxic injury. Kupffer cells release reactive oxygen species (ROS), cytokines, and chemokines, which induce neutrophil extravasation and activation. The liver expresses many cytochrome P450 isoforms, including ethanol-induced CYP2E1. CYP2E1 generates ROS, activates many toxicologically important substrates, and may be the central pathway by which ethanol causes oxidative stress. In acetaminophen toxicity, nitric oxide (NO) scavenges superoxide to produce peroxynitrite, which then causes protein nitration and tissue injury. In inducible nitric oxide synthase (iNOS) knockout mice, nitration is prevented, but unscavenged superoxide production then causes toxic lipid peroxidation to occur instead. Microvesicular steatosis, nonalcoholic steatohepatitis (NASH), and cytolytic hepatitis involve mitochondrial dysfunction, including impairment of mitochondrial fatty acid beta-oxidation, inhibition of mitochondrial respiration, and damage to mitochondrial DNA. Induction of the mitochondrial permeability transition (MPT) is another mechanism causing mitochondrial failure, which can lead to necrosis from ATP depletion or caspase-dependent apoptosis if ATP depletion does not occur fully. Because of such diverse mechanisms, hepatotoxicity remains a major reason for drug withdrawal from pharmaceutical development and clinical use.
 ...
PMID:Mechanisms of hepatotoxicity. 1181 20

The pathogenesis of the fulminant hepatitis B is poorly understood and both viral factors and the hosts immune response play a role. Previous studies in liver tissues of patients with chronic hepatitis B showed overexpression of Fas antigen and this was correlated with the activity of the hepatitis. The present study was done to determine the role of Fas in fulminant hepatitis B and the virological characteristics of hepatitis B infection. We studied three patients with fulminant hepatitis B. HBV-DNA was detected by dot-blot hybridization and polymerase chain reaction. The S and C gene were sequenced. Levels of serum soluble Fas antigen were detected by enzymoimmunoassays procedure. Apoptosis was determined by the TUNEL technique. Fas antigen expression was evaluated by a immunoperoxidase method. Ten healthy subjects acted as controls. The three patients showed a high expression of Fas antigen particularly among infiltrating lymphocytes; in these areas we also found many cells with in situ DNA nick labelling signals in the nuclei of most viable hepatocytes. Serum levels of soluble Fas antigen were higher in patients with fulminant hepatitis B than in controls. No specific genome mutations of hepatitis B virus were found. These data suggest that the Fas system involved in the liver injury of patients with fulminant hepatitis B.
 ...
PMID:Apoptosis mediated by the Fas system in the fulminant hepatitis by hepatitis B virus. 1187 92

The role of apoptpsis in the occurrence of massive or submassive liver cell death was investigated. Of liver tissues removed from 49 autopsy cases of acute hepatic failure, 26 cases were fulminant hepatic failure (FHF), 13 were subacute hepatic failure (SAHF) and the remaining 10 were acute-on-chronic hepatic failure (AoCHF). Eleven cases were associated with HBV infection, 2 with HCV, 5 with non-A non-B hepatitis, 4 with drug medication and 4 with autoimmune disorder, while the etiology of 23 cases remained unknown. Examinations by the TUNEL method and immunohistochemistry using anti-Fas, -Bax, and -Bcl-2 antibodies were conducted. Most of the FHF and AoCHF cases and half of the SAHF cases showed massive or submassive hepatic lobular injury histopathologically. TUNEL positive cells were observed frequently, and the grade of lobular injury showed significant correlation with the frequency of TUNEL-positive liver cells. Bax and Fas were expressed on the remaining liver cells, while Bcl-2 was seen on the infiltrating lymphocytes. The frequency of TUNEL-positive liver cells showed a significant correlation with Bax expression and the grades of inflammatory cell infiltration, but a poor correlation with Fas and Bcl-2 expression. The results of the present study suggested that apoptosis plays an important role in massive and submassive hepatic cell death. Fas and Bcl-2 might not be involved in the apoptosis of liver cells, but the findings suggested that Bax might play a role in inducing liver cell apoptosis, though the mechanism could not be explained.
 ...
PMID:Apoptosis in acute hepatic failure: histopathological study of human liver tissue using the tunel method and immunohistochemistry. 1216 Feb 29

The Fas-Fas ligand system is important for apoptosis of activated immune cells. Perturbation of this system occurs in diseases with dysregulated inflammation. Increased soluble Fas (sFas) occurs in systemic inflammatory response syndrome (SIRS) and can block apoptosis. Increased shedding of FasL (sFasL) occurs in viral infection and hepatitis. Although dysregulated inflammation is associated with sepsis-induced multiple organ failure (MOF) in children, a role for Fas has not been established. We hypothesize that 1) sFas will be increased in children with severe and persistent sepsis-induced MOF and will correlate with inflammatory markers suggesting a role for sFas in inflammatory dysregulation in severe sepsis, and 2) sFasL will be increased when viral sepsis or sepsis-induced liver failure-associated MOF is present in children. Plasma sFas, sFasL, IL-6, IL-10, nitrite + nitrates, and organ failure scores were measured on d 1 and d 3 in 92 children with severe sepsis and 12 critically ill control children. sFas levels were increased in severe sepsis, continued to increase in persistent MOF and nonsurvivors, and were correlated with serum inflammatory markers (IL-6, IL-10, nitrite + nitrate levels). In contrast, sFasL was not increased in severe sepsis and did not correlate with inflammation. sFasL was, however, increased in liver failure-associated MOF and in nonsurvivors, and was associated with viral infection. At autopsy, hepatocyte destruction and lymphocyte infiltration were associated with increased sFas and sFasL levels. sFas may interfere with activated immune cell death and contribute to dysregulation of inflammation, worsening outcome from severe sepsis. sFasL may contribute to hepatic injury and the development of liver failure-associated MOF.
 ...
PMID:sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome. 1243 71

Viral infection of the liver causes accumulation of T cells in the infected organ, raising the question as to the signals that mediate this response. Employing an adenovirus induced hepatitis model in mice, we show that IP-10 and Mig are essential for T cell recruitment and that induction of the two chemokines occurs concomitant to production of IFNgamma. It is shown that while IFNgamma induces IP-10 and Mig in hepatocytes, for optimal chemokine induction, a co-stimulatory signal mediated by cross-linking of Fas on hepatocytes is required. Moreover, cross-linking of Fas by injection of anti-Fas antibody into mice triggers induction of IP-10 and Mig in the liver. The cells providing the two signals are shown to express NK1.1 and AsGM1; elimination of these cells leads to inhibition of IFNgamma and chemokine transcript induction. The conclusion is drawn that both NK cells and T cells provide the two signals for induction of IP-10 and Mig in the liver.
 ...
PMID:IP-10 and Mig facilitate accumulation of T cells in the virus-infected liver. 1247 67

The Jo2 anti-mouse CD95 monoclonal antibody induces lethality in mice characterized by hepatocyte death and liver hemorrhage. Mice bearing a defect in Fas expression or in the Fas-mediated apoptotic pathway are resistant to Jo2. Here we show that FcgammaRII knockout mice or mice with monoclonal antibody-blocked FcgammaRII are also resistant to Jo2. The critical FcgammaRII(+) cells are radioresistant and could not be reconstituted with splenic cells. Death of sinusoidal lining cells and destruction of sinusoids were observed, consistent with the characteristic liver hemorrhage and the selective FcgammaRII expression in sinusoidal lining cells but not hepatocytes. Hemorrhage developed coincident with hepatocyte death and the sharp rise of serum alanine aminotransferase and alanine aminotransferase. Invariably, moribund mice showed severe liver hemorrhage and destruction of sinusoids. The data demonstrate a novel mechanism by which the destruction of liver sinusoids, induced by the Jo2-mediated co-engagement of Fas and FcgammaRII, leads to severe hemorrhage and lethal fulminant hepatitis.
 ...
PMID:Anti-CD95-induced lethality requires radioresistant Fcgamma RII+ cells. A novel mechanism for fulminant hepatic failure. 1247 18

In viral hepatitis, binding of Fas ligand (FasL) with Fas expressed on the surfaces of infected hepatocytes induces apoptosis, removing hepatitis virus along with infected hepatocytes. We measured serum concentrations of soluble Fas (sFas) and FasL (sFasL), expression of membrane-bound FasL, and expression of FasL-mRNA in patients with chronic hepatitis C without cirrhosis (CH-C) and chronic hepatitis C with liver cirrhosis (LC-C). In CH-C, sFasL concentrations were lower and FasL-mRNA expression was significantly less than in volunteers. In LC-C, sFas concentrations were significantly greater than in healthy volunteers, while sFasL, membrane-bound FasL expression, and FasL-mRNA expression did not show significant differences. We also examined these variables over 24 h following the first interferon (IFN) treatment in patients with CH-C. Serum concentrations of sFas and sFasL, and FasL-mRNA expression increased markedly beyond amounts present before IFN injection until 12 h after IFN injection. However, membrane-bound FasL expression decreased until 6 h, followed by an increase until 24 h. Our findings suggest that the ratio of membrane-bound FasL to sFasL may be regulated to remove virally infected cells in CH-C. In addition, apoptosis mediated by the Fas/FasL system may be influenced by IFN injection for treatment of CH-C.
 ...
PMID:The expression of Fas and Fas ligand, and the effects of interferon in chronic liver diseases with hepatitis C virus. 1247 30

Derangement of the apoptotic program is considered an important cause of liver disease. It became clear that receptor-mediated apoptosis is of specific interest in this context, and CD95 and CD120a, both members of the tumor necrosis factor (TNF) receptor superfamily, are the most prominent cell death receptors involved. The death signal is induced upon ligand binding by recruitment of caspases via the adapter molecule MORT1/FADD to the receptor and their subsequent activation. To investigate the role of MORT1/FADD in hepatocyte apoptosis, we generated transgenic mice expressing liver-specific dominant negative mutant. Mice looked grossly normal; breeding and liver development were not different compared with wild-type littermates. Expression of the transgene completely protected animals from liver failure induced by the anti-Fas antibody Jo2, whereas control animals died as expected 3 to 6 hours after i.p. injection of 15 microg antibody from acute hemorrhagic liver failure. Histology demonstrated only moderate inflammatory changes in the transgenic animals, whereas severe hemorrhagic hepatitis was observed in controls. Similar results were obtained in a model of TNF-mediated liver failure, in which transgenic animals survived significantly better than wild-type animals. In conclusion, our experiments provide evidence that MORT1/FADD is indispensable for Fas and TNF-mediated hepatic injury. This is not only of great importance for targeting future therapies for liver disease but might also serve as an intriguing model to study other causes of liver injury.
 ...
PMID:Dominant negative MORT1/FADD rescues mice from CD95 and TNF-induced liver failure. 1250 Jan 97


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>