UMLS:C0239946 - FACTA Search

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Query: UMLS:C0239946 (liver fibrosis)
8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diminished activity of peroxisome proliferator-activated receptor gamma (PPARgamma) is implicated in activation of hepatic stellate cells (HSC), a critical event in the development of liver fibrosis. In the present study, we investigated PPARgamma regulation by TNF-alpha in an HSC line designated as BSC. In BSC, TNF-alpha decreased both basal and ligand (GW1929)-induced PPARgamma mRNA levels without changing its protein expression. Nuclear extracts from BSC treated with TNF-alpha showed decreased binding of PPARgamma to PPAR-responsive element (PPRE) as determined by electrophoretic mobility shift assay. In BSC transiently transfected with a PPARgamma1 expression vector and a PPRE-luciferase reporter gene, TNF-alpha decreased both basal and GW1929-induced transactivation of the PPRE promoter. TNF-alpha increased activation of ERK1/2 and JNK, previously implicated in phosphorylation of Ser(82) of PPARgamma1 and resultant negative regulation of PPARgamma transactivity. In fact, TNF-alpha failed to inhibit transactivity of a Ser(82)Ala PPARgamma1 mutant in BSC. TNF-alpha-mediated inhibition of PPARgamma transactivity was not blocked with a Ser(32)Ala/Ser(36)Ala mutant of inhibitory NF-kappaBalpha (IkappaBalpha). These results suggest that TNF-alpha inhibits PPARgamma transactivity in cultured HSC, at least in part, by diminished PPARgamma-PPRE (DNA) binding and ERK1/2-mediated phosphorylation of Ser(82) of PPARgamma1, but not via the NF-kappaB pathway.
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PMID:Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational level in hepatic stellate cells. 1465 14

Recent attention has focused on the liver profibrogenic role of leptin in animal models. The purpose of this study was to evaluate the role of leptin and TNF-alpha in the severity of liver fibrosis in patients with chronic hepatitis C (CHC). We used a radioimmunoassay to determine serum leptin concentrations in 77 consecutive patients with CHC and 22 healthy controls. Leptin was correlated with liver histological (METAVIR) and metabolic indices. Sixty five patients had none to moderate liver fibrosis (F0-F2) and twelve severe fibrosis (F3-F4). Steatosis was observed in all but 27 patients. Leptin was significantly increased in patients compared with controls and was significantly more elevated in females both in patients and controls. The age, age at infection, prothrombin index, body mass index (BMI), triglycerides, glycaemia, ferritin, leptin and TNF-alpha, were associated with severe fibrosis. Steatosis was significantly more pronounced in patients with severe than those without or moderate fibrosis (P = 0.04). Only leptin was significantly and independently associated with severe fibrosis (OR = 1.2, CI 95%: 1.1-1.4, P = 0.03). Leptin was significantly associated with BMI (r = 0.64, P < 0.001) and glycaemia (r = 0.43, P < 0.001). Significant correlations were found between steatosis and BMI (r = 0.30, P < 0.01) and glycaemia (r = 0.30, P < 0.01). In patients with CHC and higher BMI and glycaemia levels, the severity of liver fibrosis is associated with serum leptin. TNF-alpha is a putative candidate involved in the mechanism.
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PMID:The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C. 1473 64

Leptin is involved in the regulation of food intake and is mainly secreted by adipocytes. Major secretagogues are cytokines such as TNF-alpha or IL-1. Leptin in turn upregulates inflammatory immune responses. Elevated leptin serum levels have been detected in patients with liver cirrhosis, a disease frequently associated with elevated levels of circulating cytokines as well as hypermetabolism and altered body weight. Recently, leptin has been detected in activated hepatic stellate cells in vitro and an involvement of leptin in liver fibrogenisis has been suggested. The current study was designed to further clarify the role of leptin in liver disease by characterizing leptin and leptin receptor expression in the development and onset of experimental liver fibrosis. Liver fibrosis and cirrhosis was induced in rats by use of phenobarbitone and increasing doses of CCl (4). Leptin and leptin receptor mRNA expression was determined by semiquantitative RT-PCR, protein expression by Western blot analysis and localization of leptin and its receptor by immunohistochemistry. Normal liver tissue does not express leptin, but leptin receptor mRNA. Increasing levels of leptin mRNA were detected in fibrotic and cirrhotic livers correlated to the degree of fibrosis. Leptin receptor mRNA expression was not significantly altered in damaged livers. Increasing levels of leptin were detected in fibrotic and cirrhotic livers, whereas protein expression of the receptor remained unchanged. Throughout different stages of liver fibrosis, leptin immunoreactivity was localized in activated hepatic stellate cells only, whereas immunoreactivity for the receptor was mainly seen on hepatocytes. In conclusion, leptin is expressed at increasing levels in activated hepatic stellate cells in vivo, which may therefore be a source of increased leptin tissue and serum levels contributing to the pathophysiology and morphological changes of chronic liver disease.
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PMID:Expression of leptin and leptin receptor during the development of liver fibrosis and cirrhosis. 1475 66

Obesity and type 2 diabetes are associated with nonalcoholic steatohepatitis (NASH), but an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steatohepatitis and liver fibrosis in obese and type 2 diabetic db/db mice in a nutritional model of NASH and determined the relationship of the expressions of osteopontin (OPN) and leptin receptors to the pathogenesis of NASH. db/db mice and the corresponding lean and nondiabetic db/m mice were fed a diet deficient in methionine and choline (MCD diet) or control diet for 4 wk. Leptin-deficient obese and diabetic ob/ob mice fed similar diets were used for comparison. MCD diet-fed db/db mice exhibited significantly greater histological inflammation and higher serum alanine aminotransferase levels than db/m and ob/ob mice. Trichrome staining showed marked pericellular fibrosis in MCD diet-fed db/db mice but no significant fibrosis in db/m or ob/ob mice. Collagen I mRNA expression was increased 10-fold in db/db mice, 4-fold in db/m mice, and was unchanged in ob/ob mice. mRNA expressions of OPN, TNF-alpha, TGF-beta, and short-form leptin receptors (Ob-Ra) were significantly increased in db/db mice compared with db/m or ob/ob mice. Parallel increases in OPN and Ob-Ra protein levels were observed in db/db mice. Cultured hepatocytes expressed only Ob-Ra, and leptin stimulated OPN mRNA and protein expression in these cells. In conclusion, our results demonstrate the development of an obese/diabetic experimental model for NASH in db/db mice and suggest an important role for Ob-Ra and OPN in the pathogenesis of NASH.
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PMID:Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. 1525 62

The immunological response in HTLV-1 infected individuals is characterized by a prominent Type-1 cytokine response with high production of IFN-gamma and TNF-alpha. In contrast, helminthic infections and in particular chronic schistosomiasis are associated with a predominant production of IL-4, IL-5, IL-10 and IL-13. Liver fibrosis is the main pathological finding in schistosomiasis that occurs after many years of infection. This pathology is T cell dependent but the immune response mechanisms are not completely understood. The North-east region of Brazil is endemic for both HTLV-1 and schistosomiasis. In the present study the immune response, clinical severity, and therapeutic response to praziquantel of patients with schistosomiasis coinfected with HTLV-1 were compared with patients infected only with S. mansoni. Patients with HTLV-1 and S. mansoni had lower levels of IL-5 (P < 0.05) and higher levels of IFN-gamma (P < 0.05) in cultures stimulated with S. mansoni antigen and decreased S. mansoni antigen specific IgE levels when compared with patients with schistosomiasis without HTLV-1 coinfection. Liver fibrosis was mild in all HTLV-1 coinfected patients and efficacy of praziquantel was lower in patients dually infected than in patients infected only with S. mansoni.
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PMID:HTLV-1 modifies the clinical and immunological response to schistosomiasis. 1527 Aug 62

In this study we investigated TNF-alpha and leptin levels in two different liver fibrosis models induced by carbon tetrachloride (CCl(4)) and common bile duct ligation (CBDL). A total of 36 male rats of Albino-Wistar strain were allocated to three groups. One of the groups was the control. The second group received 0.15 ml 100 g(-1) CCl(4) subcutaneously for 6 weeks, 3 days per week. The third group underwent common bile duct ligation (CBDL) and was monitored for 4 weeks. Histopathological investigation included fibrosis, steatosis and inflammation. Serum IL-6 and TNF-alpha levels were analysed by ELISA methods and leptin was analysed by RIA. Fibrosis and steatosis increased significantly in the CCl(4) group in comparison with the CBDL group (p < 0.01; p < 0.001). Leptin and TNF-alpha levels in CCl(4) group were higher than those in the CBDL and control groups (p < 0.05). TNF-alpha and leptin levels were not related to each another in either the CCl(4) group or the CBDL group (r=0.22, p > 0.05; r=0.19, p > 0.05). The IL-6 level was higher in the CCl(4) group in relation to severity of inflammation (p < 0.05). TNF-alpha and leptin levels were higher in animals with liver fibrosis induced by CCl(4), than they were in those whose liver fibrosis was induced by common bile duct ligation. Leptin and TNF-alpha may be less effective on the development of liver fibrosis in the group which underwent common bile duct ligation.
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PMID:TNF-alpha and leptin in experimental liver fibrosis models induced by carbon tetrachloride and by common bile duct ligation. 1538 44

Liver fibrosis is an over-accumulation of extra-cellular matrix (ECM) and the hepatic stellate cell (Ito cell) play a central role in the pathogenesis of liver fibrosis. There are a lot of growth factors and cytokines involved in the activation of hepatic stellate cell, including of transforming growth factor (TGF-alpha, TGF-beta1), platelet-derived growth factor (PDGF), interleukin (IL-1alpha,beta, IL-6) and tumor necrosis factor (TNF-alpha). Sho-saiko-to (TJ-9; Xiao-Chai-Hu-Tang in Chinese) was the most popular herbal medicine for the treatment of chronic liver disease in Chinese and Japanese. Our aim of the current study was to examine whether TJ-9 regulated the growth factors and cytokines in the fibrogenesis of bile duct ligated model. Therefore, we assessed the TJ-9's potential in regulating TGF-beta1, PDGF mRNA expression, the amount of IL-1alpha, IL-1beta, IL-6, TNF-alpha and the fibrotic marker "PIII NP" in the serum. Then, using the immunohistochemical stain to observe the TGF-beta1 expression in the tissue. Our results showed that TJ-9 at a dose of 0.5 g/(kgday) significantly reduced the serum level of PIII NP, the mRNA expression of TGF-beta1 and PDGF. For the cytokines involved in the activation of Ito cell, TJ-9 at a dose of 0.5 g/(kgday) significantly suppressed the increasing tendency of IL-1beta and enhanced the production of TNF-alpha. Finally, we concluded that: (1) TJ-9 at a dose of 0.5g/(kgday) significantly reduced the serum fibrotic marker PIII NP in the bile duct ligated model, and its mechanism was partly by means of downregulating the mRNA of TGF-beta1 and PDGF. These results also confirmed by the immunohistochemical staining of TGF-beta1. (2) TJ-9 at a dose of 0.5 g/(kgday) suppressed the increasing tendency of IL-1beta and stimulated the production of TNF-alpha to inhibit Ito cell proliferation and collagen formation.
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PMID:The role of TGF-beta 1 and cytokines in the modulation of liver fibrosis by Sho-saiko-to in rat's bile duct ligated model. 1565 68

Taurine is an abundant organic osmolyte with antioxidant and immunomodulatory properties. Its role in the pathogenesis of chronic liver disease is unknown. The liver phenotype was studied in taurine transporter knockout (taut-/-) mice. Hepatic taurine levels were ~21, 15 and 6 mumol/g liver wet weight in adult wild-type, heterozygous (taut+/-) and homozygous (taut-/-) mice, respectively. Immunoelectronmicroscopy revealed an almost complete depletion of taurine in Kupffer and sinusoidal endothelial cells, but not in parenchymal cells of (taut-/-) mice. Compared with wild-type mice, (taut-/-) and (taut+/-) mice developed moderate unspecific hepatitis and liver fibrosis with increased frequency of neoplastic lesions beyond 1 year of age. Liver disease in (taut-/-) mice was characterized by hepatocyte apoptosis, activation of the CD95 system, elevated plasma TNF-alpha levels, hepatic stellate cell and oval cell proliferation, and severe mitochondrial abnormalities in liver parenchymal cells. Mitochondrial dysfunction was suggested by a significantly lower respiratory control ratio in isolated mitochondria from (taut-/-) mice. Taut knockout had no effect on taurine-conjugated bile acids in bile; however, the relative amount of cholate-conjugates acid was decreased at the expense of 7-keto-cholate-conjugates. In conclusion, taurine deficiency due to defective taurine transport triggers chronic liver disease, which may involve mitochondrial dysfunction.
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PMID:Chronic liver disease is triggered by taurine transporter knockout in the mouse. 1642 Dec 46

The expression of TNF-alpha in the liver at different periods post Schistosoma japonica infection and the effect on liver fibrosis after supplementary injection of these cytokines were investigated. The mice infected with schistosome cercariae were divided into 3 groups: normal control group, TNF-alpha-untreated infection group and TNF-alpha-treated infection group. ABC immunohistochemistry and pathologic image multimedia quantification system were applied to dynamically detect the activity of TNF-alpha. The results showed that the levels of TNF-alpha in the liver in TNF-alpha-untreated infection group were slowly decreased with prolongation of infection time (from 8th, 11th, 14th to 18th week), while in the TNF-alpha-treated infection group, those were increased significantly after intraperitoneal injection of TNF-alpha at 6th week after infection. At first to 8th week after the final injection of TNF-alpha, the intrahepatic TNF-alpha levels in the TNF-alpha-treated infection group were significantly higher than in the other two groups (P < 0.01), and the granulomatous inflammation and fibrosis in the liver were also milder in the normal control group. It was concluded that at the early stage of Schistosoma japonica infection mouse liver mainly released Th1 cytokine and TNF-alpha from Th1 activated macrophages. Six weeks after infection (post egg deposition), exogenous supplement with intraperitoneal injection of TNF-alpha could induce the enhanced expression of Th1 cytokines and alleviate the liver granulomatous inflammation and fibrosis.
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PMID:Dynamic observation of liver fibrosis in mice infected with Schistosoma japonica. 1646 65

The disease manifestations of schistosomiasis arise from the mammalian host-mediated type 2 T-helper cell-induced (Th2) fibro-granulomatous inflammatory response to eggs trapped within host tissues. Activated hepatic stellate cells are well described as the effector cells of hepatic fibrosis in a variety of human diseases and rodent models. The aim of this study was to further understand the mechanism of fibrosis and the role of hepatic stellate cells in hepatic schistosomiasis progression. Groups of female CBA mice, which produce an intermediate degree of Schistosoma japonicum-induced liver fibrosis, were infected with S. japonicum, perfused at fortnightly time points and the liver tissue and contained egg granulomas examined by immunohistochemistry and cytokine and chemokine analysis using quantitative PCR. Immunohistochemistry demonstrated the presence of activated hepatic stellate cells in the periphery of egg granulomas, adjacent to fibrotic areas. Time course analysis demonstrated that the transcription of smooth muscle actin-alpha type 1 collagen, IL-4, IL-13, IL-13Ralpha2 and tissue inhibitor of metalloproteinase-1 mirrored the initial increase and subsequent down-modulation of granuloma diameter in mice. However, the transcription of monocyte chemo-attractant protein-1, Regulated upon Activation Normal T Cell Expressed and Secreted (RANTES), TNF-alpha, IFN-gamma and matrix metalloproteinase-9 paralleled the evolution of the total liver disease burden. Transforming growth factor-beta1 transcription did not appear to be of biological significance in this mouse model. Immunohistochemical analysis of human hepatic granulomas showed close association of smooth muscle actin-alpha-expressing cells with fibrosis in five available cases of end-stage (advanced) schistosomiasis japonica. We conclude that activated hepatic stellate cells play a contributory role in the granulomatous, fibrotic process induced by S. japonicum eggs, both in the murine model and in human disease.
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PMID:A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis. 1680 22

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