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Liver Inflammation (liver + inflammation)
Selected AbstractsNatural killer cells in viral hepatitis: facts and controversiesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2010Mario U. Mondelli Eur J Clin Invest 2010; 40 (9): 851,863 Abstract Background, Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major human hepatotropic pathogens responsible for a large number of chronic infections worldwide. Their persistence is thought to result from inefficiencies of innate and adaptive immune responses; however, very little information is available on the former. Natural killer (NK) cells are a major component of innate immunity and their activity is tightly regulated by several inhibitory and activating receptors. Design, In this review, we examine controversial findings regarding the role of NK cells in the pathogenesis of acute and chronic liver disease caused by HCV and HBV. Results, Recent studies built up on technical advances to identify NK receptors and their functional correlates in this setting. While NK cells seem to behave correctly during acute hepatitis, it would appear that the NK cytotoxic potential is generally conserved in chronic hepatitis, if not increased in the case of HCV. In contrast, their ability to secrete antiviral cytokines such as interferon ex vivo or after cytokine stimulation is severely impaired. Conclusions, Current evidence suggests the existence of an NK cell functional dichotomy, which may contribute to virus persistence, while maintaining low-level chronic liver inflammation. The study of liver-infiltrating NK cells is still at the very beginning, but it is likely that it will shed more light on the role of this simple and at the same time complex innate immune cell in liver disease. [source] ME3738 protects from concanavalin,A-induced liver failure via an IL-6-dependent mechanismEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2003Christian Klein Abstract ME3738 is a new compound that attenuates liver disease in several models of acute and chronic liver inflammation. We used the concanavalin,A (Con,A) model to elucidate the molecular mechanismsof ME3738 to block liver cell damage. Pretreatment of BALB/c mice with ME3738 prior to Con,A injection resulted in a significant reduction in liver injury. The protective effect of ME3738 prior to Con,A injection was associated with a reduction in IL-6 serum levels and NF-,B DNA binding in liver nuclear extracts. However, STAT3 DNA binding was induced via ME3738 prior to Con,A injection. Further analysis showed that ME3738 induces IL-6 serum levels and activates STAT3 DNA binding and target gene transcription. The relevance of this finding was assessed in IL-6,/, mice. Inthese animals, ME3738 induced no increase in IL-6 serum expression, and activation of IL-6-dependent pathways was not found. In addition, ME3738 did not protect IL-6,/, animals from Con,A-induced liver failure, while IL-6 injection was still effective. Therefore, we demonstrate that ME3738 triggers IL-6 expression, which activates pathways that are relevant to protect from Con,A-induced liver failure. [source] CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice,HEPATOLOGY, Issue 4 2010Tomonori Aoyama Chronic liver disease is associated with hepatocyte injury, inflammation, and fibrosis. Chemokines and chemokine receptors are key factors for the migration of inflammatory cells such as macrophages and noninflammatory cells such as hepatic stellate cells (HSCs). The expression of CX3CR1 and its ligand, CX3CL1, is up-regulated in chronic liver diseases such as chronic hepatitis C. However, the precise role of CX3CR1 in the liver is still unclear. Here we investigated the role of the CX3CL1-CX3CR1 interaction in a carbon tetrachloride (CCl4),induced liver inflammation and fibrosis model. CX3CR1 was dominantly expressed in Kupffer cells in the liver. In contrast, the main source of CX3CL1 was HSCs. Mice deficient in CX3CR1 showed significant increases in inflammatory cell recruitment and cytokine production [including tumor necrosis factor , (TNF-,); monocyte chemoattractant protein 1; macrophage inflammatory protein 1,; and regulated upon activation, normal T cell expressed, and secreted (RANTES)] after CCl4 treatment versus wild-type (WT) mice. This suggested that CX3CR1 signaling prevented liver inflammation. Kupffer cells in CX3CR1-deficient mice after CCl4 treatment showed increased expression of TNF-, and transforming growth factor , and reduced expression of the anti-inflammatory markers interleukin-10 (IL-10) and arginase-1. Coculture experiments showed that HSCs experienced significantly greater activation by Kupffer cells from CCl4 -treated CX3CR1-deficient mice versus WT mice. Indeed, augmented fibrosis was observed in CX3CR1-deficient mice versus WT mice after CCl4 treatment. Finally, CX3CL1 treatment induced the expression of IL-10 and arginase-1 in WT cultured Kupffer cells through CX3CR1, which in turn suppressed HSC activation. Conclusion: The CX3CL1-CX3CR1 interaction inhibits inflammatory properties in Kupffer cells/macrophages and results in decreased liver inflammation and fibrosis. (Hepatology 2010) [source] Deletion of interleukin-6 in mice with the dominant negative form of transforming growth factor , receptor II improves colitis but exacerbates autoimmune cholangitis,HEPATOLOGY, Issue 1 2010Weici Zhang The role of interleukin-6 (IL-6) in autoimmunity attracts attention because of the clinical usage of monoclonal antibodies to IL-6 receptor (IL-6R), designed to block IL-6 pathways. In autoimmune liver disease, activation of the hepatocyte IL-6/STAT3 (signal transducer and activator of transcription 3) pathway is associated with modulating pathology in acute liver failure, in liver regeneration, and in the murine model of concanavalin A,induced liver inflammation. We have reported that mice expressing a dominant negative form of transforming growth factor , receptor II (dnTGF,RII) under control of the CD4 promoter develop both colitis and autoimmune cholangitis with elevated serum levels of IL-6. Based on this observation, we generated IL-6,deficient mice on a dnTGF-,RII background (dnTGF,RII IL-6,/,) and examined for the presence of antimitochondrial antibodies, levels of cytokines, histopathology, and immunohistochemistry of liver and colon tissues. As expected, based on reports of the use of anti,IL-6R in inflammatory bowel disease, dnTGF,RII IL-6,/, mice manifest a dramatic improvement in their inflammatory bowel disease, including reduced diarrhea and significant reduction in intestinal lymphocytic infiltrates. Importantly, however, autoimmune cholangitis in dnTGF,RII IL-6,/, mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells, and worsening hepatic pathology. Conclusion: The data from these observations emphasize that there are distinct mechanisms involved in inducing pathology in inflammatory bowel disease compared to autoimmune cholangitis. These data also suggest that patients with inflammatory bowel disease may not be the best candidates for treatment with anti,IL-6R if they have accompanying autoimmune liver disease and emphasize caution for therapeutic use of anti,IL-6R antibody. HEPATOLOGY 2010 [source] Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell,specific signal transducer and activator of transcription 3 gene knockout mice,HEPATOLOGY, Issue 5 2010Norio Horiguchi Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl4) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti-inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl4 injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum interleukin-6 (IL-6) and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis but decreased liver inflammation. Conclusion: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl4 in myeloid-specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases. Hepatology 2010 [source] Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity,HEPATOLOGY, Issue 4 2010Hua Wang Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. Here, we show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. Conclusion: An interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. (HEPATOLOGY 2010.) [source] The CCR5,32 allele is associated with reduced liver inflammation in hepatitis C virus infectionINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2004O. Wald Summary CCR5,32 is a deletion mutation in the chemokine receptor CCR5. Liver inflammatory activity was found to be significantly reduced (P = 0.005) in Jewish Israeli patients infected with the hepatitis C virus (HCV) carrying the CCR5,32 allele. The CCR5,32 allele does not alter susceptibility to HCV infection; however, it may play a role in the progression and outcome of the disease. [source] NF- ,B in liver diseases: a target for drug therapyJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2009Pablo Muriel Abstract There are five nuclear factor- ,B (NF- ,B) transcription factors with important roles in innate immunity, liver inflammation, fibrosis and apoptosis prevention. Several inhibitors of NF- ,B, like caffeic acid, captopril, curcumin, pyrrolidine dithiocarbamate, resveratrol, silymarin and thalidomide, have demonstrated antinecrotic, anticholestatic, antifibrotic and anticancer activities in the liver. A link between inflammation and hepatocellular carcinoma through the NF- ,B pathway has been observed, providing ample experimental support for the tumor-promoting function of NF- ,B in various models of cancer. NF- ,B has been associated with the induction of proinflammatory gene expression and has attracted interest as a target for the treatment of inflammatory disease. However, despite much attention being focused on the deleterious effects of NF- ,B, activation of this factor during the resolution of inflammation is associated with the production of antiinflammatory molecules like interleukin (IL)-10 and the onset of apoptosis. This suggests that NF- ,B has an antiinflammatory role in vivo involving the regulation of the resolution of inflammation. Also, NF- ,B promotes liver regeneration by upregulating IL-6 and other molecules like hepatocyte growth factor. It has been postulated that the beneficial properties of NF- ,B are due to p50 homodimers, whose activation prevents cholestatic and chronic liver injury. More basic understanding on the function of the diverse NF- ,B factors is urgently needed in different physiological and pathological conditions, because depending on the subunit composition of the dimmer, the disease and the stage of the illness, inhibition of the factor may result in a beneficial or in a deleterious response. Copyright © 2008 John Wiley & Sons, Ltd. [source] Moderate Alcohol Consumption Aggravates High-Fat Diet Induced Steatohepatitis in RatsALCOHOLISM, Issue 3 2010Yan Wang Background:, Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition. Methods:, Sprague-Dawley rats were first fed ad libitum with Lieber-DeCarli high-fat diet (71% energy from fat) for 6 weeks to induce NASH, as demonstrated previously. Afterwards, these rats were continuously fed with high-fat diet (HFD, 55% total energy from fat) or high fat plus alcohol diet (HFA, 55% energy from fat and 16% energy from alcohol) for an additional 4 weeks. Pathological lesions including fat accumulation and inflammatory foci in liver were examined and graded. Lipid peroxidation and apoptotic hepatocytes in the liver were assessed. The mRNA expressions of tumor necrosis factor-, (TNF,) and TNF receptor 1 (TNF-R1), Fas death receptor (Fas) and Fas ligant (FasL), IL-1, and IL-12 were determined by real-time PCR. Protein levels of total and cleaved caspase-3, CYP2E1, Bax, and Bcl-2 were measured by western blotting. Results:, The number of hepatic inflammatory foci and apoptotic hepatocytes were significantly increased in rats fed with HFA as compared with those in HFD-fed rats. The aggravated inflammatory response and cellular apoptosis mediated by HFA were associated with elevated mRNA expression of Fas/FasL and cleaved caspase-3 protein. Although no significant differences were observed between HFD and HFA groups, the levels of lipid peroxidation, Bax and Bcl-2 protein concentration, and mRNA levels of other inflammatory cytokines were significantly higher in these 2 groups than those in the control group. Conclusions:, These data suggest that even moderate alcohol consumption can cause more hepatic inflammation and cellular apoptosis in a pre-existing NASH condition. [source] Apoptotic cytokeratin 18 neoepitopes in serum of patients with chronic hepatitis CJOURNAL OF VIRAL HEPATITIS, Issue 3 2005B. Kronenberger Summary., In patients with chronic hepatitis C, alanine aminotransferase (ALT) levels do not accurately reflect the extent of liver inflammation. The discrepancy between ALT level and liver damage could be related to the mode of cell death. In the present study, we quantified serum levels of apoptotic cytokeratin 18 (CK-18) neoepitopes that are generated by activated caspases during apoptosis. Apoptotic CK-18 neoepitopes were quantified by enzyme linked immunosorbent assay in sera from patients with chronic hepatitis C and elevated ALT levels (n = 72), patients with chronic hepatitis C and persistently normal ALT levels (n = 27) and healthy controls (n = 19). Serum CK-18 neoepitope levels were strongly correlated with ALT (r = 0.659, P < 0.0001) and the histology activity index (r = 0.374, P < 0.001). Patients with chronic hepatitis C and persistently normal ALT levels had higher apoptotic CK-18 neoepitope levels than healthy controls (P = 0.03) but lower levels than patients with chronic hepatitis C and elevated ALT levels (P < 0.001). Highest serum CK-18 neoepitope levels were observed in patients with cirrhosis (P = 0.002). Hence apoptotic CK-18 neoepitopes in serum of patients with chronic hepatitis C are associated with ALT level and histological liver damage. Serum apoptotic CK-18 neoepitope levels are elevated both in patients with chronic hepatitis C and elevated ALT levels as well as in patients with normal ALT levels indicating that also patients with chronic hepatitis C and normal ALT have an increased hepatocyte loss by apoptosis. [source] Apoptosis in hepatitis CJOURNAL OF VIRAL HEPATITIS, Issue 5 2003J. Kountouras Summary. The apoptotic process appears to be a host defence mechanism against viral infections and tumourigenesis. However, many viral genomes encode proteins, which repress apoptosis so as to escape from immune attack by the host. Therefore, virus,host interactions may determine viral persistence, extent and severity of liver inflammation and possibly viral hepatocarcinogenesis. Apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. Pathomorphologic features of increased apoptosis include shrinkage and fragmentation of nuclei/cytoplasm in piecemeal necrosis areas, acidophilic bodies, and focal cell dropout in the liver lobule. The hepatitis C virus (HCV) core protein exhibits both proapoptotic or antiapoptotic actions. Modulation of apoptosis may involve binding of HCV core protein to the intracellular signal transducing portion of death receptors and displacement of signalling molecules. Apoptosis may occur in the absence of significant transaminase elevation, thereby explaining the lack of correlation between biochemical activity and liver cell histological injury. Monitoring caspase activation might provide a reliable tool to estimate the efficacy of HCV therapy, and might open challenging therapeutic strategies in HCV infection. The antiviral effect of interferon may be mediated through induction of apoptosis. Lastly, administration of the antiapoptotic ursodeoxycholic acid in HCV infection is compatible with the notion that apoptosis may represent a mechanism for viral shedding rather than for viral elimination, thereby raising the concept that inhibition of apoptosis could ameliorate hepatitis C. [source] Review article: success and failure of nucleoside and nucleotide analogues in chronic hepatitis BALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2007W. F. LEEMANS SUMMARY Background, Strong suppression of viral replication and normalization of alanine aminotransferase is feasible with nucleos(t)ide analogues. It is estimated viral replication and liver inflammation can be controlled in 90% of patients with chronic hepatitis B with the current available treatments. Aim, To review the studies currently available on the management of chronic hepatitis B with nucleos(t)ide analogues. Results, Although very potent, nucleos(t)ide analogues are not effective in every patient. Some factors are known to influence treatment outcome, but many host and viral factors are still unknown. Stopping rules have to be defined to assess treatment efficacy in an early stage and change the regimen. Discontinuation of nucleos(t)ide analogues is often followed by reactivation of HBV. Data on the risk factors for relapse are necessary in order to decide if treatment can be safely discontinued. Another major drawback of nucleos(t)ide analogues is the emergence of resistance. The efficacy of compounds for the treatment of mutant virus and the impact of cross-resistance is largely unknown. The use of combination therapy to prevent resistance looks promising, but has to be proven. Conclusions, HBV has become a treatable disease, however much research is needed to optimize treatment for individual patients and treatment failures. [source] Association among Fas expression in leucocytes, serum Fas and Fas-ligand concentrations and hepatic inflammation and fibrosis in chronic hepatitis CLIVER INTERNATIONAL, Issue 3 2010Anatol Panasiuk Abstract Background: Replication of the hepatitis C virus (HCV) in peripheral blood mononuclear cells (PBMC) may impair immune functions and establish persistent infection. The aim of this study was to assess the influence of HCV on PBMC and their susceptibility to apoptosis in relation to liver inflammation and fibrosis. Methods: Eighty-one patients with chronic hepatitis C (CHC) were enrolled in this study. Flow cytometry was used to determine the amount of T cells (CD4+, CD8+), B cells (CD19+), monocytes (CD14+) and natural killer cells (CD16+) in the peripheral blood and the expression of CD95+ (CD95/APO-1) in each subset. Serum concentrations of sFas and sFasL were assessed by the enzyme-linked immunosorbent assay method. Results: An increased expression of Fas was observed in CD4+ and CD8+ cells in CHC. There was a more prominent expression of Fas on CD4+ cells in HCV genotype 1b in contrast to 3a. Increased Fas expression on CD4+ cells was seen in advanced stages of liver disease. Fas expression on monocytes was lower in advanced stages of liver inflammation and fibrosis. Serum sFas concentration was higher in CHC compared with the control group. There was an association between sFasL concentration and inflammatory activity in the liver. Serum sFasL concentration correlated positively with the mean intensity of fluorescence of the Fas receptor in CD4+ and CD8+ cells, granulocytes and monocytes. Conclusion: These findings indicate that there is an increased susceptibility of PBMC to apoptosis, which can be attributed to the constant contact of leucocytes with the inflamed liver tissue, or from direct HCV influence. [source] A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-, expressionLIVER TRANSPLANTATION, Issue 11 2009Haley E. Ramsey The nuclear factor-,B inhibitory protein A20 demonstrates hepatoprotective abilities through combined antiapoptotic, anti-inflammatory, and pro-proliferative functions. Accordingly, overexpression of A20 in the liver protects mice from toxic hepatitis and lethal radical hepatectomy, whereas A20 knockout mice die prematurely from unfettered liver inflammation. The effect of A20 on oxidative liver damage, as seen in ischemia/reperfusion injury (IRI), is unknown. In this work, we evaluated the effects of A20 upon IRI using a mouse model of total hepatic ischemia. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer. Although only 10%-25% of control mice injected with saline or the control rAd., galactosidase survived IRI, the survival rate reached 67% in mice treated with rAd.A20. This significant survival advantage in rAd.A20-treated mice was associated with improved liver function, pathology, and repair potential. A20-treated mice had significantly lower bilirubin and aminotransferase levels, decreased hemorrhagic necrosis and steatosis, and increased hepatocyte proliferation. A20 protected against liver IRI by increasing hepatic expression of peroxisome proliferator-activated receptor alpha (PPAR,), a regulator of lipid homeostasis and of oxidative damage. A20-mediated protection of hepatocytes from hypoxia/reoxygenation and H2O2 -mediated necrosis was reverted by pretreatment with the PPAR, inhibitor MK886. In conclusion, we demonstrate that PPAR, is a novel target for A20 in hepatocytes, underscoring its novel protective effect against oxidative necrosis. By combining hepatocyte protection from necrosis and promotion of proliferation, A20-based therapies are well-poised to protect livers from IRI, especially in the context of small-for-size and steatotic liver grafts. Liver Transpl 15:1613,1621, 2009. © 2009 AASLD. [source] Serum biomarkers of hepatitis B virus infected liver inflammation: A proteomic studyPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2003Qing-Yu He Abstract Hepatitis B virus (HBV), a serious infectious and widespread human pathogen, represents a major health problem worldwide. Chronic HBV infection has a very high risk of evolving into hepatocellular carcinoma. Although considerable progress was made during the recent past, the pathogenesis of HBV infection is still elusive and a definite diagnosis of HBV infected liver information still relies on biopsy histological test. In this report, we used proteomics technology to globally examine HBV infected serum samples aiming at searching for disease-associated proteins that can be used as serological biomarkers for diagnosis and/or target proteins for pathogenetic study. By comparing with normal and HBV negative serum samples, we found that at least seven proteins were significantly changed in HBV infected sera. These greatly altered proteins were identified to be haptoglobin , and ,2 chain, apolipoprotein A-I and A-IV, ,1-antitrypsin, transthyretin and DNA topoisomerase II,. The alteration of these proteins is displayed not only in quantity but also in patterns (or specificity), which can be correlated with necroinflammatory scores. In particular, apolipoprotein A-I presents heterogeneous change in expression level with different isoforms and ,1-antitrypsin produces evidently different fragments implying diverse cleavage pathways. These unique phenomena appear specific to HBV infection. A combination simultaneously considering the quantities and isoforms of these proteins could be a useful serum biomarker (or index) for HBV diagnosis and therapy. [source] | ||||||||||||||||||||||||||||