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Sample records for attenuates liver fibrosis

  1. Oleoylethanolamide, an endogenous PPAR-α ligand, attenuates liver fibrosis targeting hepatic stellate cells.

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    Chen, Ling; Li, Long; Chen, Junde; Li, Lei; Zheng, Zihan; Ren, Jie; Qiu, Yan

    2015-12-15

    Oleoylethanolamide (OEA), an endocannabinoid-like molecule, was revealed to modulate lipid metabolism through a peroxisome proliferator-activated receptor-α (PPAR-α) mediated mechanism. In present study, we further investigated the activities and mechanisms of OEA in ameliorating hepatic fibrosis in Sv/129 mice induced by a methionine choline-deficient (MCD) diet or thioacetamide (TAA) treatment. Liver fibrosis development was assessed by Hematoxylin-eosin and Sirius red staining. Treatment with OEA (5 mg/kg/day, intraperitoneal injection, i.p.) significantly attenuated the progress of liver fibrosis in both two experimental animal models by blocking the activation of hepatic stellate cells (HSCs). Gene expression analysis of hepatic tissues indicated that OEA inhibited the expression of α-smooth muscle action (α-SMA) and collagen matrix, fibrosis markers, and genes involved in inflammation and extracellular matrix remodeling. In vitro studies showed that OEA inhibited transforming growth factor β1-stimulated HSCs activation through suppressing Smad2/3 phosphorylation, α-SMA expression and myofibroblast transformation. These improvements could not be observed in PPAR-α knockout mice models with OEA administration, which suggested all the anti-fibrotic effects of OEA in vivo and in vitro were mediated by PPAR-α activation. Collectively, our results suggested that OEA exerted a pharmacological effect on modulating hepatic fibrosis development through the inhibition of HSCs activation in liver and therefore may be a potential therapeutic agent for liver fibrosis. PMID:26729705

  2. Triplex Forming Oligonucleotides against Type α 1(I) Collagen attenuates Liver Fibrosis induced by Bile Duct ligation

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    Panakanti, Ravikiran; Pratap, Akshay; Yang, Ningning; JACKSON, JOHN S.; Mahato, Ram I.

    2010-01-01

    Liver fibrosis is a consequence of chronic liver disorders which lead to the accumulation of extracellular matrix (ECM). Particularly, there is an increased accumulation of collagen in the fibrotic liver. We have therefore used a triplex forming oligonucleotide (TFO) against the type α 1 (I) collagen and evaluated, whether it can attenuate liver fibrosis induced by common bile duct ligation (CBDL) in rats. There was a significant decrease in hydroxyproline levels and Masson’s trichrome staini...

  3. MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis

    OpenAIRE

    Csak, Timea; Bala, Shashi; Lippai, Dora; Kodys, Karen; Catalano, Donna; Iracheta-Vellve, Arvin; Szabo, Gyongyi

    2015-01-01

    Background & Aim MicroRNAs (miRs) regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis. Methods Wild type (WT) and miR-155-deficient (KO) mice were fed methionine-choline-deficient (MCD) or -supplemented (MCS) control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed. Re...

  4. The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice.

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    Rehman, Hasibur; Liu, Qinlong; Krishnasamy, Yasodha; Shi, Zengdun; Ramshesh, Venkat K; Haque, Khujista; Schnellmann, Rick G; Murphy, Michael P; Lemasters, John J; Rockey, Don C; Zhong, Zhi

    2016-01-01

    Oxidative stress plays an essential role in liver fibrosis. This study investigated whether MitoQ, an orally active mitochondrial antioxidant, decreases liver fibrosis. Mice were injected with corn oil or carbon tetrachloride (CCl4, 1:3 dilution in corn oil; 1 µl/g, ip) once every 3 days for up to 6 weeks. 4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress. MitoQ attenuated oxidative stress after CCl4. Collagen 1α1 mRNA and hydroxyproline increased markedly after CCl4 treatment, indicating increased collagen formation and deposition. CCl4 caused overt pericentral fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy. MitoQ blunted fibrosis after CCl4. Profibrotic transforming growth factor-β1 (TGF-β1) mRNA and expression of smooth muscle α-actin, an indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-β fibrogenic effects, was also activated after CCl4 treatment. MitoQ blunted HSC activation, TGF-β expression, and Smad2/3 activation after CCl4 treatment. MitoQ also decreased necrosis, apoptosis and inflammation after CCl4 treatment. In cultured HSCs, MitoQ decreased oxidative stress, inhibited HSC activation, TGF-β1 expression, Smad2/3 activation, and extracellular signal-regulated protein kinase activation. Taken together, these data indicate that mitochondrial reactive oxygen species play an important role in liver fibrosis and that mitochondria-targeted antioxidants are promising potential therapies for prevention and treatment of liver fibrosis. PMID:27186319

  5. Ghrelin Attenuates Liver Fibrosis through Regulation of TGF-β1 Expression and Autophagy

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    Yuqing Mao

    2015-09-01

    and maintaining the balance between MMP2 and TIMP1. Our results demonstrated that ghrelin attenuates liver fibrosis via inhibition of the TGF-β1/Smad3 and NF-κB signaling pathways, as well as autophagy suppression.

  6. Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress.

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    Yang, Ji Hye; Kim, Sang Chan; Kim, Kyu Min; Jang, Chang Ho; Cho, Sam Seok; Kim, Seung Jung; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2016-07-15

    Hepatic fibrosis is considered integral to the progression of chronic liver diseases, leading to the development of cirrhosis and hepatocellular carcinoma. Activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. We investigated the ability of isorhamnetin, the 3'-O-methylated metabolite of quercetin, to protect against hepatic fibrosis in vitro and in vivo. Isorhamnetin inhibited transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and collagen in primary murine HSCs and LX-2 cells. The TGF-β1- or Smad-induced luciferase reporter activity of Smad binding elements was significantly decreased by isorhamnetin with a concomitant decrease in Smad2/3 phosphorylation. Isorhamnetin increased the nuclear translocation of Nrf2 in HSCs and increased antioxidant response element reporter gene activity. Furthermore, isorhamnetin blocked TGF-β1-induced reactive oxygen species production. The specific role of Nrf2 in isorhamnetin-mediated suppression of PAI-1 and phosphorylated Smad3 was verified using a siRNA against Nrf2. To examine the anti-fibrotic effect of isorhamnetin in vivo, liver fibrosis was induced by CCl4 in mice. Isorhamnetin significantly prevented CCl4-induced increases in serum alanine transaminase and aspartate transaminase levels, and caused histopathological changes characterized by decreases in hepatic degeneration, inflammatory cell infiltration, and collagen accumulation. Moreover, isorhamnetin markedly decreased the expression of phosphorylated Smad3, TGF-β1, α-SMA, and PAI-1. Isorhamnetin attenuated the CCl4-induced increase in the number of 4-hydroxynonenal and nitrotyrosine-positive cells, and prevented glutathione depletion. We propose that isorhamnetin inhibits the TGF-β/Smad signaling pathway and relieves oxidative stress, thus inhibiting HSC activation and preventing liver fibrosis. PMID:27151496

  7. Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice.

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    Motiño, Omar; Agra, Noelia; Brea Contreras, Rocío; Domínguez-Moreno, Marina; García-Monzón, Carmelo; Vargas-Castrillón, Javier; Carnovale, Cristina E; Boscá, Lisardo; Casado, Marta; Mayoral, Rafael; Valdecantos, M Pilar; Valverde, Ángela M; Francés, Daniel E; Martín-Sanz, Paloma

    2016-09-01

    Cyclooxygenase-2 (COX-2) is involved in different liver diseases but little is known about the significance of COX-2 in the development and progression of non-alcoholic steatohepatitis (NASH). This study was designed to elucidate the role of COX-2 expression in hepatocytes in the pathogenesis of steatohepatitis and hepatic fibrosis. In the present work, hepatocyte-specific COX-2 transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either fed methionine-and-choline deficient (MCD) diet to establish an experimental non-alcoholic steatohepatitis (NASH) model or injected with carbon tetrachloride (CCl4) to induce liver fibrosis. In our animal model, hCOX-2-Tg mice fed MCD diet showed lower grades of steatosis, ballooning and inflammation than Wt mice, in part by reduced recruitment and infiltration of hepatic macrophages, with a corresponding decrease in serum levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice showed a significant attenuation of the MCD diet-induced increase in oxidative stress and hepatic apoptosis observed in Wt mice. Even more, hCOX-2-Tg mice treated with CCl4 had significantly lower stages of fibrosis and less hepatic content of collagen, hydroxyproline and pro-fibrogenic markers than Wt controls. Collectively, our data indicates that constitutive hepatocyte COX-2 expression ameliorates NASH and liver fibrosis development in mice by reducing inflammation, oxidative stress and apoptosis and by modulating activation of hepatic stellate cells, respectively, suggesting a possible protective role for COX-2 induction in NASH/NAFLD progression. PMID:27321932

  8. Biomarkers for liver fibrosis

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    Jacobs, Jon M.; Burnum-Johnson, Kristin E.; Baker, Erin M.; Smith, Richard D.; Gritsenko, Marina A.; Orton, Daniel

    2015-09-15

    Methods and systems for diagnosing or prognosing liver fibrosis in a subject are provided. In some examples, such methods and systems can include detecting liver fibrosis-related molecules in a sample obtained from the subject, comparing expression of the molecules in the sample to controls representing expression values expected in a subject who does not have liver fibrosis or who has non-progressing fibrosis, and diagnosing or prognosing liver fibrosis in the subject when differential expression of the molecules between the sample and the controls is detected. Kits for the diagnosis or prognosis of liver fibrosis in a subject are also provided which include reagents for detecting liver fibrosis related molecules.

  9. MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis.

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    Timea Csak

    Full Text Available MicroRNAs (miRs regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis.Wild type (WT and miR-155-deficient (KO mice were fed methionine-choline-deficient (MCD or -supplemented (MCS control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed.MCD diet resulted in steatohepatitis and increased miR-155 expression in total liver, hepatocytes and Kupffer cells. Steatosis and expression of genes involved in fatty acid metabolism were attenuated in miR-155 KO mice after MCD feeding. In contrast, miR-155 deficiency failed to attenuate inflammatory cell infiltration, nuclear factor κ beta (NF-κB activation and enhanced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα and monocyte chemoattractant protein-1 (MCP1 in MCD diet-fed mice. We found a significant attenuation of apoptosis (cleaved caspase-3 and reduction in collagen and α smooth muscle actin (αSMA levels in miR-155 KO mice compared to WTs on MCD diet. In addition, we found attenuation of platelet derived growth factor (PDGF, a pro-fibrotic cytokine; SMAD family member 3 (Smad3, a protein involved in transforming growth factor-β (TGFβ signal transduction and vimentin, a mesenchymal marker and indirect indicator of epithelial-to-mesenchymal transition (EMT in miR-155 KO mice. Nuclear binding of CCAAT enhancer binding protein β (C/EBPβ a miR-155 target involved in EMT was significantly increased in miR-155 KO compared to WT mice.Our novel data demonstrate that miR-155 deficiency can reduce steatosis and fibrosis without decreasing inflammation in steatohepatitis.

  10. Angiogenesis and liver fibrosis

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    Gülsüm ?zlem Elpek

    2015-01-01

    Recent data indicate that hepatic angiogenesis,regardless of the etiology, takes place in chronic liverdiseases (CLDs) that are characterized by inflammationand progressive fibrosis. Because antiangiogenictherapy has been found to be efficient inthe prevention of fibrosis in experimental models ofCLDs, it is suggested that blocking angiogenesis couldbe a promising therapeutic option in patients withadvanced fibrosis. Consequently, efforts are beingdirected to revealing the mechanisms involved inangiogenesis during the progression of liver fibrosis.Literature evidences indicate that hepatic angiogenesisand fibrosis are closely related in both clinical andexperimental conditions. Hypoxia is a major inducer ofangiogenesis together with inflammation and hepaticstellate cells. These profibrogenic cells stand at theintersection between inflammation, angiogenesis andfibrosis and play also a pivotal role in angiogenesis.This review mainly focuses to give a clear view on therelevant features that communicate angiogenesis withprogression of fibrosis in CLDs towards the-end point ofcirrhosis that may be translated into future therapies.The pathogenesis of hepatic angiogenesis associatedwith portal hypertension, viral hepatitis, non-alcoholicfatty liver disease and alcoholic liver disease are alsodiscussed to emphasize the various mechanisms involvedin angiogenesis during liver fibrogenesis.

  11. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831 a novel NOX4/NOX1 inhibitor in vivo

    OpenAIRE

    Jiang, Joy X.; Chen, Xiangling; Serizawa, Nobuko; Szyndralewiez, Cedric; Page, Patrick; Schröder, Katrin; Brandes, Ralf P.; Devaraj, Sridevi; Török, Natalie J.

    2012-01-01

    Reactive oxygen species (ROS) play a key role in chronic liver injury and fibrosis. Homologues of NADPH oxidases (NOXs) are major sources of ROS, but the exact role of the individual homologues in liver disease is unknown. Our goal was to determine the role of NOX4 in liver fibrosis induced by bile duct ligation (BDL) with the aid of the pharmacological inhibitor GKT137831, and genetic deletion of NOX4 in mice. GKT136731 was either applied for the full term of BDL (preventive arm), or startin...

  12. S-nitroso-N-acetylcysteine attenuates liver fibrosis in experimental nonalcoholic steatohepatitis [Corrigendum

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    Mazo DF

    2013-09-01

    Full Text Available Mazo DF, de Oliveira MG, Pereira IV, Cogliati B, Stefano JT, de Souza GF, Rabelo F, Lima FR, Ferreira Alves VA, Carrilho FJ, de Oliveira CP. Drug Des Devel Ther. 2013:7:553–563. On page 554, the sentence "Therefore, we chose SNAC as a potential antifibrinogenic NO donor drug for treating fibrosis..." contains an error. The term "antifibrinogenic" should be replaced by "antifibrogenic". On page 558, Figure 3 (D, the intermediate block corresponding to SNAC is missing. View original paper by Mazo et al

  13. S-nitroso-N-acetylcysteine attenuates liver fibrosis in experimental nonalcoholic steatohepatitis

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    Mazo DF

    2013-06-01

    Full Text Available Daniel FC Mazo,1 Marcelo G de Oliveira,2 Isabel VA Pereira,1 Bruno Cogliati,3 José T Stefano,1 Gabriela FP de Souza,2 Fabíola Rabelo,1 Fabiana R Lima,4 Venâncio A Ferreira Alves,4 Flair J Carrilho,1 Claudia PMS de Oliveira1 1University of São Paulo School of Medicine, Department of Gastroenterology, Clinical Division, Hepatology Branch (LIM-07, Sao Paulo, Brazil; 2Institute of Chemistry, University of Campinas, Campinas, Sao Paulo, Brazil; 3University of Sao Paulo School of Veterinary Medicine and Animal Science, Department of Pathology, Sao Paulo, Brazil; 4University of São Paulo School of Medicine, Department of Pathology (LIM14, São Paulo, Brazil Abstract: S-Nitroso-N-acetylcysteine (SNAC is a water soluble primary S-nitrosothiol capable of transferring and releasing nitric oxide and inducing several biochemical activities, including modulation of hepatic stellate cell activation. In this study, we evaluated the antifibrotic activity of SNAC in an animal model of nonalcoholic steatohepatitis (NASH induced in Sprague-Dawley rats fed with a choline-deficient, high trans fat diet and exposed to diethylnitrosamine for 8 weeks. The rats were divided into three groups: SNAC, which received oral SNAC solution daily; NASH, which received the vehicle; and control, which received standard diet and vehicle. Genes related to fibrosis (matrix metalloproteinases [MMP]-13, -9, and -2, transforming growth factor ß-1 [TGFß-1], collagen-1a, and tissue inhibitors of metalloproteinase [TIMP-1 and -2] and oxidative stress (heat-shock proteins [HSP]-60 and -90 were evaluated. SNAC led to a 34.4% reduction in the collagen occupied area associated with upregulation of MMP-13 and -9 and downregulation of HSP-60, TIMP-2, TGFß-1, and collagen-1α. These results indicate that oral SNAC administration may represent a potential antifibrotic treatment for NASH. Keywords: nitric oxide, S-nitroso-N-acetylcysteine, fibrogenesis, NASH, diethylnitrosamine

  14. Transient elastography (FibroScan(®)) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease - Where do we stand?

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    Mikolasevic, Ivana; Orlic, Lidija; Franjic, Neven; Hauser, Goran; Stimac, Davor; Milic, Sandra

    2016-08-28

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Currently, the routinely used modalities are unable to adequately determine the levels of steatosis and fibrosis (laboratory tests and ultrasonography) or cannot be applied as a screening procedure (liver biopsy). Among the non-invasive tests, transient elastography (FibroScan(®), TE) with controlled attenuation parameter (CAP) has demonstrated good accuracy in quantifying the levels of liver steatosis and fibrosis in patients with NAFLD, the factors associated with the diagnosis and NAFLD progression. The method is fast, reliable and reproducible, with good intra- and interobserver levels of agreement, thus allowing for population-wide screening and disease follow-up. The initial inability of the procedure to accurately determine fibrosis and steatosis in obese patients has been addressed with the development of the obese-specific XL probe. TE with CAP is a viable alternative to ultrasonography, both as an initial assessment and during follow-up of patients with NAFLD. Its ability to exclude patients with advanced fibrosis may be used to identify low-risk NAFLD patients in whom liver biopsy is not needed, therefore reducing the risk of complications and the financial costs.

  15. Transient elastography (FibroScan®) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease - Where do we stand?

    Science.gov (United States)

    Mikolasevic, Ivana; Orlic, Lidija; Franjic, Neven; Hauser, Goran; Stimac, Davor; Milic, Sandra

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Currently, the routinely used modalities are unable to adequately determine the levels of steatosis and fibrosis (laboratory tests and ultrasonography) or cannot be applied as a screening procedure (liver biopsy). Among the non-invasive tests, transient elastography (FibroScan®, TE) with controlled attenuation parameter (CAP) has demonstrated good accuracy in quantifying the levels of liver steatosis and fibrosis in patients with NAFLD, the factors associated with the diagnosis and NAFLD progression. The method is fast, reliable and reproducible, with good intra- and interobserver levels of agreement, thus allowing for population-wide screening and disease follow-up. The initial inability of the procedure to accurately determine fibrosis and steatosis in obese patients has been addressed with the development of the obese-specific XL probe. TE with CAP is a viable alternative to ultrasonography, both as an initial assessment and during follow-up of patients with NAFLD. Its ability to exclude patients with advanced fibrosis may be used to identify low-risk NAFLD patients in whom liver biopsy is not needed, therefore reducing the risk of complications and the financial costs. PMID:27621571

  16. Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis.

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    Jeftic, Ilija; Jovicic, Nemanja; Pantic, Jelena; Arsenijevic, Nebojsa; Lukic, Miodrag L; Pejnovic, Nada

    2015-01-01

    The importance of Galectin-3 (Gal-3) in obesity-associated liver pathology is incompletely defined. To dissect the role of Gal-3 in fibrotic nonalcoholic steatohepatitis (NASH), Gal-3-deficient (LGALS3(-/-)) and wild-type (LGALS3(+/+)) C57Bl/6 mice were placed on an obesogenic high fat diet (HFD, 60% kcal fat) or standard chow diet for 12 and 24 wks. Compared to WT mice, HFD-fed LGALS3(-/-) mice developed, in addition to increased visceral adiposity and diabetes, marked liver steatosis, which was accompanied with higher expression of hepatic PPAR-γ, Cd36, Abca-1 and FAS. However, as opposed to LGALS3(-/-) mice, hepatocellular damage, inflammation and fibrosis were more extensive in WT mice which had an elevated number of mature myeloid dendritic cells, proinflammatory CD11b(+)Ly6C(hi) monocytes/macrophages in liver, peripheral blood and bone marrow, and increased hepatic CCL2, F4/80, CD11c, TLR4, CD14, NLRP3 inflammasome, IL-1β and NADPH-oxidase enzymes mRNA expression. Thus, obesity-driven greater steatosis was uncoupled with attenuated fibrotic NASH in Gal-3-deficient mice. HFD-fed WT mice had a higher number of hepatocytes that strongly expressed IL-33 and hepatic CD11b(+)IL-13(+) cells, increased levels of IL-33 and IL-13 and up-regulated IL-33, ST2 and IL-13 mRNA in liver compared with LGALS3(-/-) mice. IL-33 failed to induce ST2 upregulation and IL-13 production by LGALS3(-/-) peritoneal macrophages in vitro. Administration of IL-33 in vivo enhanced liver fibrosis in HFD-fed mice in both genotypes, albeit to a significantly lower extent in LGALS3(-/-) mice, which was associated with less numerous hepatic IL-13-expressing CD11b(+) cells. The present study provides evidence of a novel role for Gal-3 in regulating IL-33-dependent liver fibrosis. PMID:26018806

  17. Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-κB signaling pathway

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    Liu, Min; Xu, Youwei; Han, Xu; Yin, Lianhong; Xu, Lina; Qi, Yan; Zhao, Yanyan; Liu, Kexin; Peng, Jinyong

    2015-01-01

    The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet, and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation, and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor κB (NF-κB), interleukin (IL)-1, IL-6 and tumour necrosis factor-α by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-κB, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-κB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-β1, α-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-κB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future. PMID:26655640

  18. Potent effects of dioscin against liver fibrosis

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    Zhang, Xiaoling; Han, Xu; Yin, Lianhong; Xu, Lina; Qi, Yan; Xu, Youwei; Sun, Huijun; Lin, Yuan; Liu, Kexin; Peng, Jinyong

    2015-01-01

    We previously reported the promising effects of dioscin against liver injury, but its effect on liver fibrosis remains unknown. The present work investigated the activities of dioscin against liver fibrosis and the underlying molecular mechanisms. Dioscin effectively inhibited the cell viabilities of HSC-T6, LX-2 and primary rat hepatic stellate cells (HSCs), but not hepatocytes. Furthermore, dioscin markedly increased peroxisome proliferator activated receptor-γ (PPAR-γ) expression and significantly reduced a-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), collagen α1 (I) (COL1A1) and collagen α1 (III) (COL3A1) levels in vitro. Notably, dioscin inhibited HSCs activation and induced apoptosis in activated HSCs. In vivo, dioscin significantly improved body weight and hydroxylproline, laminin, α-SMA, TGF-β1, COL1A1 and COL3A1 levels, which were confirmed by histopathological assays. Dioscin facilitated matrix degradation, and exhibited hepatoprotective effects through the attenuation of oxidative stress and inflammation, in addition to exerting anti-fibrotic effects through the modulation of the TGF-β1/Smad, Wnt/β-catenin, mitogen-activated protein kinase (MAPK) and mitochondrial signaling pathways, which triggered the senescence of activated HSCs. In conclusion, dioscin exhibited potent effects against liver fibrosis through the modulation of multiple targets and signaling pathways and should be developed as a novel candidate for the treatment of liver fibrosis in the future. PMID:25853178

  19. Dendritic Cells and Liver Fibrosis

    OpenAIRE

    Rahman, Adeeb H.; Aloman, Costica

    2013-01-01

    Dendritic cells are a relative rare population of specialized antigen presenting cells that are distributed through most lymphoid and non-lymphoid tissues and play a critical role in linking the innate and adaptive arms of the immune system. The liver contains a heterogeneous population of dendritic cells that may contribute to liver inflammation and fibrosis through a number of mechanisms. This review summarizes current knowledge on the development and characterization of liver dendritic cel...

  20. Liver manifestations of cystic fibrosis

    International Nuclear Information System (INIS)

    Chronic liver disease is one of the major complications of cystic fibrosis (CF). Significant liver disease is seen in 13-25% of children with CF. Improved life expectancy and prolonged follow-up have favored better characterization of the hepatic manifestations of CF and allowed direct observation of an increasing number of liver-related events. Liver disease typically develops in the first decade of life, with the incidence dropping rapidly after the age of 10 years. The wide spectrum of liver disease ranging from asymptomatic gallbladder abnormalities to biliary cirrhosis will be reviewed in this article

  1. BIOCONJUGATION OF OLIGONUCLEOTIDES FOR TREATING LIVER FIBROSIS

    OpenAIRE

    Ye, Zhaoyang; Hajj Houssein, Houssam S.; Mahato, Ram I.

    2007-01-01

    Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductul...

  2. Curcumin and hemopressin treatment attenuates cholestasis-induced liver fibrosis in rats: role of CB1 receptors.

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    El Swefy, Sahar; Hasan, Rehab A; Ibrahim, Amal; Mahmoud, Mona F

    2016-01-01

    Curcumin exerts hepatoprotective effects via poorly defined mechanisms. Recently, some studies suggested that this effect was mediated by antagonizing CB1 receptors in hepatic stellate cells. The current study aimed to investigate whether CB1 antagonist, hemopressin, could potentiate the hepatoprotective effect of curcumin, in comparison with silymarin in bile duct-ligated (BDL) rats. Curcumin and hemopressin each alone and in combination ameliorated biochemical and structural fibrotic injury, and downregulated cyclooxygenase-2 (COX-2) and both mRNA and protein levels of nuclear factor kappa B (NF-κB) in fibrotic liver. In contrast to the previous studies, curcumin alone did not affect the gene expression of cannabinoid receptors. However, the combination of hemopressin and curcumin reduced the expression of CB1 in fibrotic liver. Surprisingly, silymarin upregulated CB2 receptors and downregulated CB1 at mRNA level more than all the administered drugs. Both curcumin and hemopressin each alone decreased lipid peroxidation product, malondialdehyde (MDA), while the combination increased the reduced glutathione content. All the administered drugs increased the hepatic antiapoptotic marker, Bcl2. Our study suggests that hemopressin potentiates the hepatoprotective effect of curcumin on fibrotic liver. We identified a new mechanism of the hepatoprotective effect of silymarin via modulation of cannabinoid receptors in fibrotic liver.

  3. Noninvasive Biomarkers of Liver Fibrosis: An Overview

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    Hind I. Fallatah

    2014-01-01

    Full Text Available Chronic liver diseases of differing etiologies are among the leading causes of mortality and morbidity worldwide. Establishing accurate staging of liver disease is very important for enabling both therapeutic decisions and prognostic evaluations. A liver biopsy is considered the gold standard for assessing the stage of hepatic fibrosis, but it has many limitations. During the last decade, several noninvasive markers for assessing the stage of hepatic fibrosis have been developed. Some have been well validated and are comparable to liver biopsy. This paper will focus on the various noninvasive biochemical markers used to stage liver fibrosis.

  4. A Novel Matrine Derivative WM130 Inhibits Activation of Hepatic Stellate Cells and Attenuates Dimethylnitrosamine-Induced Liver Fibrosis in Rats

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    Yang Xu

    2015-01-01

    Full Text Available Activation of hepatic stellate cells (HSCs is a critical event in process of hepatic fibrogenesis and cirrhosis. Matrine, the active ingredient of Sophora, had been used for clinical treatment of acute/chronic liver disease. However, its potency was low. We prepared a high potency and low toxicity matrine derivate, WM130 (C30N4H40SO5F, which exhibited better pharmacological activities on antihepatic fibrosis. This study demonstrated that WM130 results in a decreased proliferative activity of HSC-T6 cells, with the half inhibitory concentration (IC50 of 68 μM. WM130 can inhibit the migration and induce apoptosis in HSC-T6 cells at both concentrations of 68 μM (IC50 and 34 μM (half IC50. The expression of α-SMA, Collagen I, Collagen III, and TGF-β1 could be downregulated, and the protein phosphorylation levels of EGFR, AKT, ERK, Smad, and Raf (p-EGFR, p-AKT, p-ERK, p-Smad, and p-Raf were also decreased by WM130. On the DMN-induced rat liver fibrosis model, WM130 can effectively reduce the TGF-β1, AKT, α-SMA, and p-ERK levels, decrease the extracellular matrix (ECM formation, and inhibit rat liver fibrosis progression. In conclusion, this study demonstrated that WM130 can significantly inhibit the activation of HSC-T6 cells and block the rat liver fibrosis progression by inducing apoptosis, suppressing the deposition of ECM, and inhibiting TGF-β/Smad and Ras/ERK pathways.

  5. Toward surface quantification of liver fibrosis progression

    Science.gov (United States)

    He, Yuting; Kang, Chiang Huen; Xu, Shuoyu; Tuo, Xiaoye; Trasti, Scott; Tai, Dean C. S.; Raja, Anju Mythreyi; Peng, Qiwen; So, Peter T. C.; Rajapakse, Jagath C.; Welsch, Roy; Yu, Hanry

    2010-09-01

    Monitoring liver fibrosis progression by liver biopsy is important for certain treatment decisions, but repeated biopsy is invasive. We envision redefinition or elimination of liver biopsy with surface scanning of the liver with minimally invasive optical methods. This would be possible only if the information contained on or near liver surfaces accurately reflects the liver fibrosis progression in the liver interior. In our study, we acquired the second-harmonic generation and two-photon excitation fluorescence microscopy images of liver tissues from bile duct-ligated rat model of liver fibrosis. We extracted morphology-based features, such as total collagen, collagen in bile duct areas, bile duct proliferation, and areas occupied by remnant hepatocytes, and defined the capsule and subcapsular regions on the liver surface based on image analysis of features. We discovered a strong correlation between the liver fibrosis progression on the anterior surface and interior in both liver lobes, where biopsy is typically obtained. The posterior surface exhibits less correlation with the rest of the liver. Therefore, scanning the anterior liver surface would obtain similar information to that obtained from biopsy for monitoring liver fibrosis progression.

  6. Noninvasive Markers to Assess Liver Fibrosis.

    Science.gov (United States)

    Czul, Frank; Bhamidimarri, Kalyan R

    2016-07-01

    Chronic liver disease represents a major public health problem, accounting for significant morbidity and mortality worldwide. Their prognosis and management greatly depends on the amount and progression of liver fibrosis with time and the risk of development of cirrhosis. Historically, liver biopsy was considered to be the gold standard for the detection of fibrosis. Nevertheless, liver biopsy is an invasive procedure that has limitations in terms of patient acceptance, risk-benefit ratio, cost-effectiveness, and its availability in various geographic regions. Moreover, it is a questionable gold standard due to significant sampling error and intraobserver and interobserver variability. These limitations have led to the development of noninvasive techniques for assessing the presence and the degree of liver fibrosis. This review aims to revise the most recent data from the literature about noninvasive methods useful in the evaluation of liver fibrosis. PMID:27105176

  7. HIV Infection Accelerates Hepatitis C-Related Liver Fibrosis

    Science.gov (United States)

    ... HIV Infection Accelerates Hepatitis C–Related Liver Fibrosis HIV Infection Accelerates Hepatitis C–Related Liver Fibrosis Email ... the progression of other chronic diseases as well. HIV and Fibrosis Dr. Kirk and his team tapped ...

  8. Doxycycline Attenuated Pulmonary Fibrosis Induced by Bleomycin in Mice

    OpenAIRE

    Fujita, Masaki; Ye, Qing; Ouchi, Hiroshi; Harada, Eiji; Inoshima, Ichiro; Kuwano, Kazuyoshi; Nakanishi, Yoichi

    2006-01-01

    The administration of doxycycline prior to bleomycin in mice attenuated pulmonary fibrosis. Bronchoalveolar neutrophil influx and gelatinase activity, but not caseinolytic activity, were attenuated by doxycycline. Established fibrosis was not affected by doxycycline. Thus, doxycycline might be useful for slowing down pulmonary fibrosis by biological activity other than antibacterial activity.

  9. Transient elastography for liver fibrosis diagnosis

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Christensen, Peer Brehm; Weis, Nina

    2009-01-01

    Liver biopsy is considered the "golden standard" for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems....... Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate...... fibrosis. Most of the studies have been conducted on patients with chronic hepatitis but a few studies have also covered fibrosis and cirrhosis due to other etiologies, and they also demonstrate the high sensitivity and specificity. Transient elastography for assessment of fibrosis may turn out...

  10. Transient elastography for liver fibrosis diagnosis

    DEFF Research Database (Denmark)

    Andersen, Ellen Sloth; Christensen, Peer Brehm; Weis, Nina

    2008-01-01

    Liver biopsy is considered the "golden standard" for assessment of hepatic fibrosis. However, the procedure has limitations because of inconvenience and rare but serious complications as bleeding. Furthermore, sampling errors are frequent, and interobserver variability often poses problems....... Recently, a modified ultrasound scanner (transient elastography) has been developed to assess fibrosis. The device measures liver elasticity, which correlates well with the degree of fibrosis. Studies have shown that transient elastography is more accurate in diagnosing cirrhosis than minor to moderate...... fibrosis. Most of the studies have been conducted on patients with chronic hepatitis but a few studies have also covered fibrosis and cirrhosis due to other etiologies, and they also demonstrate the high sensitivity and specificity. Transient elastography for assessment of fibrosis may turn out...

  11. Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    Ning-Li Chai; Qiang Fu; Hui Shi; Chang-Hao Cai; Jun Wan; Shi-Ping Xu; Ben-Yan Wu

    2012-01-01

    AIM:To investigate the potential mechanism of ArgGly-Asp (RGD) peptide-labeled liposome loading oxymatrine (OM) therapy in CCl4-induced hepatic fibrosis in METHODS:We constructed a rat model of CCl4-induced hepatic fibrosis and treated the rats with different formulations of OM.To evaluate the antifibrotic effect of OM,we detected levels of alkaline phosphatase,hepatic histopathology (hematoxylin and eosin stain and Masson staining) and fibrosis-related gene expression of matrix metallopeptidase (MMP)-2,tissue inhibitor of metalloproteinase (TIMP)-1 as well as type Ⅰ procollagen via quantitative real-time polymerase chain reaction.To detect cell viability and apoptosis of hepatic stellate cells (HSCs),we performed 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay and flow cytometry.To reinforce the combination of oxymatrine with HSCs,we constructed fluorescein-isothiocyanate-conjugated Arg-Gly-Asp peptide-labeled liposomes loading OM,and its targeting of HSCs was examined by fluorescent microscopy.RESULTS:OM attenuated CCl4-induced hepatic fibrosis,as defined by reducing serum alkaline phosphatase (344.47 ± 27.52 U/L vs 550.69 ± 43.78 U/L,P < 0.05),attenuating liver injury and improving collagen deposits (2.36% ± 0.09% vs 7.70% ± 0.60%,P < 0.05) and downregulating fibrosis-related gene expression,that is,MMP-2,TIMP-1 and type Ⅰ procollagen (P < 0.05).OM inhibited cell viability and induced apoptosis of HSCs in vitro.RGD promoted OM targeting of HSCs and enhanced the therapeutic effect of OM in terms of serum alkaline phosphatase (272.51 ± 19.55 U/L vs 344.47 ± 27.52 U/L,P < 0.05),liver injury,collagen deposits (0.26% ± 0.09% vs 2.36% ± 0.09%,P < 0.05) and downregulating fibrosis-related gene expression,that is,MMP-2,TIMP-1 and type Ⅰ procollagen (P < 0.05).Moreover,in vitro assay demonstrated that RGD enhanced the effect of OM on HSC viability and apoptosis.CONCLUSION:OM attenuated hepatic fibrosis by

  12. Targeting the PDGF-B/PDGFR-β Interface with Destruxin A5 to Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Xingqi Wang

    2016-05-01

    Full Text Available PDGF-BB/PDGFR-ββ signaling plays very crucial roles in the process of many diseases such as liver fibrosis. However, drug candidates with selective affinities for PDGF-B/PDGFR-β remain deficient. Here, we identified a natural cyclopeptide termed destruxin A5 that effectively inhibits PDGF-BB-induced PDGFR-β signaling. Interestingly and importantly, the inhibitory mechanism is distinct from the mechanism of tyrosine kinase inhibitors because destruxin A5 does not have the ability to bind to the ATP-binding pocket of PDGFR-β. Using Biacore T200 technology, thermal shift technology, microscale thermophoresis technology and computational analysis, we confirmed that destruxin A5 selectively targets the PDGF-B/PDGFR-β interaction interface to block this signaling. Additionally, the inhibitory effect of destruxin A5 on PDGF-BB/PDGFR-ββ signaling was verified using in vitro, ex vivo and in vivo models, in which the extent of liver fibrosis was effectively alleviated by destruxin A5. In summary, destruxin A5 may represent an efficacious and more selective inhibitor of PDGF-BB/PDGFR-ββ signaling.

  13. Outcome in cystic fibrosis liver disease.

    LENUS (Irish Health Repository)

    Rowland, Marion

    2011-01-01

    Evidence suggests that cystic fibrosis liver disease (CFLD) does not affect mortality or morbidity in patients with cystic fibrosis (CF). The importance of gender and age in outcome in CF makes selection of an appropriate comparison group central to the interpretation of any differences in mortality and morbidity in patients with CFLD.

  14. Role of NADPH Oxidases in Liver Fibrosis

    OpenAIRE

    Paik, Yong-Han; Kim, Jonghwa; Aoyama, Tomonori; De Minicis, Samuele; Bataller, Ramon; Brenner, David A

    2014-01-01

    Significance: Hepatic fibrosis is the common pathophysiologic process resulting from chronic liver injury, characterized by the accumulation of an excessive extracellular matrix. Multiple lines of evidence indicate that oxidative stress plays a pivotal role in the pathogenesis of liver fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. In addition to...

  15. Correlation between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models

    Institute of Scientific and Technical Information of China (English)

    Qing-He Nie; Ya-Fei Zhang; Yu-Mei Xie; Xin-Dong Luo; Bin Shao; Jun Li; Yong-Xing Zhou

    2006-01-01

    AIM: To evaluate serum TIMP-1 level and the correlation between TIMP-1 expression and liver fibrosis in immuneinduced and CCL4-induced liver fibrosis models in rats.METHODS: Immune-induced and CCL4-induced liver fibrosis models were established by dexamethasone (0.01 mg) and CCL4 respectively. Serum TIMP-1 level was detected with ELISA, while histopathological grade of liver biopsy was evaluated. Spearman rankcorrelation test was used to analyse the difference of the correlation between the TIMP-1 expression and hepatic fibrosis in the two fibrosis models. Furthermore,in situ hybridization was used to determine the expression difference of TIMP-1 mRNA in the two models.RESULTS: Positive correlation existed between serum TIMP-1 level of immune induced group and the histopathological stages of fibrosis liver of corresponding rats (Spearman rank-correlation test, rs = 0.812, P < 0.05), and the positivein situ hybridization signal of TIMP-1 mRNA was strong. In CCL4-induced liver fibrosis model, the correlation between the serum TIMP-1 level and the severity of hepatic fibrosis was not statistically significant(Spearman rank-correlation test, rs = 0.229, P > 0.05). And compared with immune-induced model,the positive in situ hybridization signal of TIMP-1 mRNA was weaker, while the expression variation was higher in hepatic fibrosis of the same severity.CONCLUSION: The correlations between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models are different. In immune-induced model, serum TIMP-1 level could reflect the severity of liver fibrosis,while in CCL4-induced model, the correlation between the serum TIMP-1 level and the severity of hepatic fibrosis was not statistically significant.

  16. Bioconjugation of oligonucleotides for treating liver fibrosis.

    Science.gov (United States)

    Ye, Zhaoyang; Houssein, Houssam S Hajj; Mahato, Ram I

    2007-01-01

    Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is urgently needed to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remain the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of alpha1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in-depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed. PMID:18154454

  17. Geranylgeranylacetone attenuates hepatic fibrosis by increasing the expression of heat shock protein 70.

    Science.gov (United States)

    He, Wei; Zhuang, Yun; Wang, Liangzhi; Qi, Lei; Chen, Binfang; Wang, Mei; Shao, Dong; Chen, Jianping

    2015-10-01

    Increasing evidence has demonstrated that the heat shock protein 70 (HSP70) gene may be closely associated with tissue fibrosis; however, the association between HSP70 and liver fibrosis remains to be fully elucidated. The present study hypothesized that geranylgeranylacetone (GGA) exerts beneficial effects on liver fibrosis though upregulation of the expression of HSP70. Liver fibrosis was induced in rats using carbon tetrachloride (CCl4). The rats were subsequently divided into three groups: Control group, CCl4 model group and CCl4 model + GGA group. Liver fibrosis in the rats was evaluated using hematoxylin and eosin staining, Masson's trichrome staining and Sirius red staining. The levels of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin were determined using an automated biochemistry analyzer. The levels of total hepatic hydroxyproline were also determined. The expression levels of α‑smooth muscle actin (α‑SMA) and transforming growth factor‑β1 (TGF‑β1) were determined using immunofluorescence staining and western blotting, and the protein expression levels of HSP70 were determined using western blotting. The CCl4‑induced rats exhibited liver fibrosis, increased hydroxyproline content, impaired liver function, upregulated expression levels of the α‑SMA and TGF‑β1 pro‑fibrogenic proteins, and increased expression of HSP70, compared with the control group. These changes were attenuated by treatment with GGA. These results demonstrated that GGA exerted beneficial effects in CCl4‑induced liver fibrosis via upregulating the expression of HSP70. PMID:26165998

  18. Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

    Institute of Scientific and Technical Information of China (English)

    En-tong YI; Rui-xia LIU; Yan WEN; Cheng-hong YIN

    2012-01-01

    Aim: To evaluate the antifibrotic effect of telmisartan,an angiotensin Ⅱ receptor blocker,in bile duct-ligated rats.Methods: Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats,model rats underwent common bile duct ligation (BDL),and BDL rats treated with telmisartan (8 mg/kg,po,for 4 weeks).The animals were sacrificed on d 29,and liver histology was examined,the Knodell and Ishak scores were assigned,and the expression of angiotensin-converting enzyme (ACE) and ACE2 was evaluated with immunohistochemical staining.The mRNAs and proteins associated with liver fibrosis were evaluated using RTQ-PCR and Western blot,respectively.Results: The mean fibrosis score of BDL rats treated with telmisartan was significantly lower than that of the model rats (1.66±0.87 vs 2.13±0.35,P=0.015).However,there was no significant difference in inflammation between the two groups,both of which showed moderate inflammation.Histologically,treatment with telmisartan significantly ameliorated BDL-caused the hepatic fibrosis.Treatment with telmisartan significantly upregulated the mRNA levels of ACE2 and MAS,and decreased the mRNA levels of ACE,angiotensin Ⅱ type 1 receptor (AT1-R),collagen type Ⅲ,and transforming growth factor β1 (TGF-β1).Moreover,treatment with telmisartan significantly increased the expression levels of ACE2 and MAS proteins,and inhibited the expression levels of ACE and AT1-R protein.Conclusion: Telmisartan attenuates liver fibrosis in bile duct-ligated rats via increasing ACE2 expression level.

  19. Mouse models of liver fibrosis mimic human liver fibrosis of different etiologies.

    Science.gov (United States)

    Martínez, Allyson K; Maroni, Luca; Marzioni, Marco; Ahmed, Syed T; Milad, Mena; Ray, Debolina; Alpini, Gianfranco; Glaser, Shannon S

    2014-12-01

    The liver has the amazing capacity to repair itself after injury; however, the same processes that are involved in liver regeneration after acute injury can cause serious consequences during chronic liver injury. In an effort to repair damage, activated hepatic stellate cells trigger a cascade of events that lead to deposition and accumulation of extracellular matrix components causing the progressive replacement of the liver parenchyma by scar tissue, thus resulting in fibrosis. Although fibrosis occurs as a result of many chronic liver diseases, the molecular mechanisms involved depend on the underlying etiology. Since studying liver fibrosis in human subjects is complicated by many factors, mouse models of liver fibrosis that mimic the human conditions fill this void. This review summarizes the general mouse models of liver fibrosis and mouse models that mimic specific human disease conditions that result in liver fibrosis. Additionally, recent progress that has been made in understanding the molecular mechanisms involved in the fibrogenic processes of each of the human disease conditions is highlighted. PMID:25396098

  20. Serum parameters of liver fibrosis

    OpenAIRE

    Zanten, R. A A

    1991-01-01

    textabstractChronic liver disease is often associated with deposition of fibrous tissue, a process which together with the destruction of normal liver and liver cell regeneration, leads to the condition called cirrhosis. Cirrhosis is known to be associated with a reduction in life expectancy. In recent years there has been an increasing interest in the pathogenesis of cirrhosis and in the possibilities reversing the process of fibrogenesis. Liver biopsy is the present "gold standard" for dete...

  1. Serum parameters of liver fibrosis

    NARCIS (Netherlands)

    R.A.A. van Zanten

    1991-01-01

    textabstractChronic liver disease is often associated with deposition of fibrous tissue, a process which together with the destruction of normal liver and liver cell regeneration, leads to the condition called cirrhosis. Cirrhosis is known to be associated with a reduction in life expectancy. In rec

  2. Assessment of liver fibrosis: Noninvasive means

    Directory of Open Access Journals (Sweden)

    Poynard Thierry

    2008-01-01

    Full Text Available Liver biopsy, owing to its limitations and risks, is an imperfect gold standard for assessing the severity of the most frequent chronic liver diseases chronic hepatitis C (HCV, B (HBV non alcoholic (NAFLD and alcoholic (ALD fatty liver diseases. This review summarizes the advantages and the limits of the available biomarkers of liver fibrosis. Among a total of 2,237 references, a total of 14 validated serum biomarkers have been identified between 1991 and 2008. Nine were not patented and five were patented. Two alternatives to liver biopsy were the most evaluated FibroTest and Fibroscan. For FibroTest, there was a total of 38 different populations including 7,985 subjects with both FibroTest and biopsy (4,600 HCV, 1,580 HBV, 267 NAFLD, 524 ALD, and 1014 mixed. For Fibroscan, there was a total of 11 published studies including 2,260 subjects (1,466 HCV, 95 cholestatic liver disease, and 699 mixed. For FibroTest, the mean diagnostic value for the diagnosis of advanced fibrosis assessed using standardized area under the ROC curves was 0.84 (95% confidence interval 0.83-0.86, without a significant difference between the causes of liver disease, hepatitis C, hepatitis B, and alcoholic or non alcoholic fatty liver disease. High-risk profiles of false negative/false positive of FibroTest, mainly Gilbert syndrome, hemolysis and acute inflammation, are present in 3% of the populations. In case of discordance between biopsy and FibroTest, half of the failures can be due to biopsy; the prognostic value of FibroTest is at least similar to that of biopsy in HCV, HBV and ALD. In conclusion this overview of evidence-based data suggests that biomarkers could be used as an alternative to liver biopsy for the first line assessment of fibrosis stage in the four most common chronic liver diseases, namely HCV, HBV, NAFLD and ALD. Neither biomarkers nor biopsy alone is sufficient for taking a definite decision in a given patient; all the clinical and biological data

  3. Deficiency of DJ-1 Ameliorates Liver Fibrosis through Inhibition of Hepatic ROS Production and Inflammation

    Science.gov (United States)

    Yu, Yingxue; Sun, Xuehua; Gu, Jinyang; Yu, Chang; Wen, Yankai; Gao, Yueqiu; Xia, Qiang; Kong, Xiaoni

    2016-01-01

    Liver fibrosis is a global health problem and previous studies have demonstrated that reactive oxygen species (ROS) play important roles in fibrogenesis. Parkinson disease (autosomal recessive, early onset) 7 (Park7) also called DJ-1 has an essential role in modulating cellular ROS levels. DJ-1 therefore may play functions in liver fibrogenesis and modulation of DJ-1 may be a promising therapeutic approach. Here, wild-type (WT) and DJ-1 knockout (DJ-1 KO) mice were administrated with carbon tetrachloride (CCl4) to induce liver fibrosis or acute liver injury. Results showed that DJ-1 depletion significantly blunted liver fibrosis, accompanied by marked reductions in liver injury and ROS production. In the acute CCl4 model, deficiency of DJ-1 showed hepatic protective functions as evidenced by decreased hepatic damage, reduced ROS levels, diminished hepatic inflammation and hepatocyte proliferation compared to WT mice. In vitro hepatic stellate cells (HSCs) activation assays indicated that DJ-1 has no direct effect on the activation of HSCs in the context of with or without TGFβ treatment. Thus our present study demonstrates that in CCl4-induced liver fibrosis, DJ-1 deficiency attenuates mice fibrosis by inhibiting ROS production and liver injury, and further indirectly affecting the activation of HSCs. These results are in line with previous studies that ROS promote HSC activation and fibrosis development, and suggest the therapeutic value of DJ-1 in treatment of liver fibrosis.

  4. Biopsy-controlled liver fibrosis staging using the enhanced liver fibrosis (ELF score compared to transient elastography.

    Directory of Open Access Journals (Sweden)

    Kristin Wahl

    Full Text Available BACKGROUND AND AIMS: Chronic liver diseases are characterized by inflammatory and fibrotic liver injuries that often result in liver cirrhosis with its associated complications such as portal hypertension and hepatocellular carcinoma. Liver biopsy still represents the reference standard for fibrosis staging, although transient elastography is increasingly used for non-invasive monitoring of fibrosis progression. However, this method is not generally available and is associated with technical limitations emphasizing the need for serological biomarkers staging of liver fibrosis. The enhanced liver fibrosis (ELF score was shown to accurately predict significant liver fibrosis in different liver diseases, although extracellular matrix components detected by this score may not only mirror the extent of liver fibrosis but also inflammatory processes. METHODS: In this prospective biopsy-controlled study we evaluated the utility of the ELF score in comparison to transient elastography to predict different stages of fibrosis in 102 patients with chronic liver diseases. RESULTS: Both techniques revealed similar area under receiver operating characteristic curve values for prediction of advanced fibrosis stages. Compared to transient elastography, the ELF score showed a broader overlap between low and moderate fibrosis stages and a stronger correlation with inflammatory liver injury. CONCLUSIONS: Both the ELF score as well as transient elastography allowed for high quality fibrosis staging. However, the ELF score was less discriminative in low and moderate fibrosis stages and appeared more strongly influenced by inflammatory liver injury. This should be considered when making clinical interpretations on the basis of ELF score values.

  5. Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection

    Directory of Open Access Journals (Sweden)

    Lindsey J. Reese

    2012-01-01

    Full Text Available Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P<0.001. There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.

  6. Promising Therapy Candidates for Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Ping eWang

    2016-02-01

    Full Text Available Liver fibrosis is a wound-healing process in response to repeated and chronic injury to hepatocytes and/or cholangiocytes. Ongoing hepatocyte apoptosis or necrosis lead to increase in ROS production and decrease in antioxidant activity, which recruits inflammatory cells from the blood and activate hepatic stellate cells changing to myofibroblasts. Injury to cholangiocytes also recruits inflammatory cells to the liver and activates portal fibroblasts in the portal area, which release molecules to activate and amplify cholangiocytes. No matter what origin of myofibroblasts, either hepatic stellate cells or portal fibroblasts, they share similar characteristics, including being positive for -smooth muscle actin and sproducing extra cellular matrix. Based on the extensive pathogenesis knowledge of liver fibrosis, therapeutic strategies have been designed to target each step of this process, including hepatocyte apoptosis, cholangiocyte proliferation, inflammation, and activation of myofibroblasts to deposit extracellular matrix, yet the current therapies are still in early-phase clinical development. There is an urgent need to translate the molecular mechanism of liver fibrosis to effective and potent reagents or therapies in human.

  7. Natural Killer cells and liver fibrosis

    Directory of Open Access Journals (Sweden)

    Frank eFasbender

    2016-01-01

    Full Text Available In the 40 years since the discovery of Natural Killer (NK cells it has been well established that these innate lymphocytes are important for early and effective immune responses against transformed cells and infections with different pathogens. In addition to these classical functions of NK cells, we now know that they are part of a larger family of innate lymphoid cells and that they can even mediate memory-like responses. Additionally, tissue resident NK cells with distinct phenotypical and functional characteristics have been identified. Here we focus on the phenotype of different NK cell subpopulations that can be found in the liver and summarize the current knowledge about the functional role of these cells with a special emphasis on liver fibrosis. NK cell cytotoxicity can contribute to liver damage in different forms of liver disease. However, NK cells can limit liver fibrosis by killing hepatic stellate cell-derived myofibroblasts, which play a key role in this pathogenic process. Therefore, liver NK cells need to be tightly regulated in order to balance these beneficial and pathological effects.

  8. Modeling the mechanical properties of liver fibrosis in rats.

    Science.gov (United States)

    Zhu, Ying; Chen, Xin; Zhang, Xinyu; Chen, Siping; Shen, Yuanyuan; Song, Liang

    2016-06-14

    The progression of liver fibrosis changes the biomechanical properties of liver tissue. This study characterized and compared different liver fibrosis stages in rats in terms of viscoelasticity. Three viscoelastic models, the Voigt, Maxwell, and Zener models, were applied to experimental data from rheometer tests and then the elasticity and viscosity were estimated for each fibrosis stage. The study found that both elasticity and viscosity are correlated with the various stages of liver fibrosis. The study revealed that the Zener model is the optimal model for describing the mechanical properties of each fibrosis stage, but there is no significant difference between the Zener and Voigt models in their performance on liver fibrosis staging. Therefore the Voigt model can still be effectively used for liver fibrosis grading. PMID:27017300

  9. Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

    Science.gov (United States)

    Liu, Ziyi; Cao, Zongxian; Jourdan, Tony; Erdelyi, Katalin; Godlewski, Grzegorz; Szanda, Gergő; Liu, Jie; Park, Joshua K.; Mukhopadhyay, Bani; Rosenberg, Avi Z.; Liow, Jeih-San; Lorenz, Robin G.; Pacher, Pal; Innis, Robert B.; Kunos, George

    2016-01-01

    Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases. Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group. In mouse models of fibrosis induced by CCl4 or bile duct ligation, the hybrid CB1R/iNOS antagonist surpassed the antifibrotic efficacy of the CB1R antagonist rimonabant or the iNOS inhibitor 1400W, without inducing anxiety-like behaviors or CB1R occupancy in the CNS. The hybrid inhibitor also targeted CB1R-independent, iNOS-mediated profibrotic pathways, including increased PDGF, Nlrp3/Asc3, and integrin αvβ6 signaling, as judged by its ability to inhibit these pathways in cnr1−/− but not in nos2−/− mice. Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

  10. Taurine attenuates radiation-induced lung fibrosis in C57/Bl6 fibrosis prone mice.

    LENUS (Irish Health Repository)

    Robb, W B

    2010-03-01

    The amino acid taurine has an established role in attenuating lung fibrosis secondary to bleomycin-induced injury. This study evaluates taurine\\'s effect on TGF-beta1 expression and the development of lung fibrosis after single-dose thoracic radiotherapy.

  11. Liver Fibrosis: From Pathogenesis to Novel Therapies.

    Science.gov (United States)

    Weiskirchen, Ralf; Tacke, Frank

    2016-01-01

    Chronic liver injury is accompanied by a dysbalanced scarring process, termed fibrosis. This process is mainly driven by chronic inflammation and an altered activity of a multitude of different chemokines and cytokines, resulting in the infiltration by immune cells (especially macrophages) and increase of matrix-expressing cell types. These processes might lead to cirrhosis representing the end-stage of fibrosis. Recent clinical studies comprising patients successfully treated for viral hepatitis showed that liver fibrogenesis and even cirrhosis may be reverted. The hepatic capacity to remodel scar tissue and to revert into a normal liver follows specific mechanistic principles that include the termination of chronic tissue damage, shifting the cellular bias from inflammation to resolution, initiation of myofibroblast apoptosis or senescence and, finally, fibrinolysis of excess scar tissue. The plurality of molecular and cellular triggers involved in initiation, progression and resolution of hepatic fibrogenesis offers an infinite number of therapeutic possibilities. For instance, inflammatory macrophages can be targeted via inhibition of chemokine CCL2 or its receptor CCR2 (e.g., by cenicriviroc) as well as by transfer of restorative macrophage subsets. Another target is galectin-3 that acts at various stages along the continuum from acute to chronic inflammation. Profibrogenic cytokines (e.g., transforming growth factor-β), matricellular proteins (e.g., CCN1/CYR61) or signaling pathways involved in fibrogenesis offer further possible targets. Other options are the application of therapeutic antibodies directed against components involved in biogenesis or remodeling of connective tissue such as lysyl oxidase-like-2 or synthetic bile acids like obeticholic acid that activate the farnesoid X receptor and was antifibrotic in a phase 2 study (FLINT trial). Factors affecting the gut barrier function or the intestinal microbiome further expanded the repertoire of drug

  12. [Noncirrhotic liver fibrosis after chronic arsenic poisoning].

    Science.gov (United States)

    Piontek, M; Hengels, K J; Borchard, F; Strohmeyer, G

    1989-10-27

    A 67-year-old woman with portal hypertension, splenomegaly without portal vein thrombosis, leucopenia and thrombocytopenia of splenic origin had repeated episodes of life-threatening haemorrhage from esophageal varices. Since childhood she had suffered from psoriasis and had been treated over a period of 15 years with Fowler's solution (in all about 25 g of arsenic trioxide). She had the characteristic skin lesions of arsenical poisoning-palmar hyperkeratoses and two basal cell carcinomas on the trunk. Histological examination of a wedge biopsy from the liver showed definite structural changes with fibrosis around the central veins and in the portal tracts. There was no evidence of cirrhotic alteration. The hepatocytes were normal by light microscopy and electron microscopy. This case of noncirrhotic hepatic fibrosis is considered to have been caused by chronic arsenical poisoning.

  13. Nephrogenic Systemic Fibrosis Risk and Liver Disease

    Directory of Open Access Journals (Sweden)

    Robert F. Hanna

    2014-01-01

    Full Text Available Objective. Evaluate the incidence of nephrogenic systemic fibrosis (NSF in patients with liver disease in the peritransplant period. Materials and Methods. This IRB approved study retrospectively reviewed patients requiring transplantation for cirrhosis, hepatocellular carcinoma (HCC, or both from 2003 to 2013. Records were reviewed identifying those having gadolinium enhanced MRI within 1 year of posttransplantation to document degree of liver disease, renal disease, and evidence for NSF. Results. Gadolinium-enhanced MRI was performed on 312 of 837 patients, including 23 with severe renal failure (GFR 30. Two of 23 patients with renal failure developed NSF compared to zero NSF cases in 289 patients with GFR > 30 (0/289; P<0.003. High dose gadodiamide was used in the two NSF cases. There was no increased incidence of NSF with severe liver disease (1/71 compared to nonsevere liver disease (1/241; P=0.412. Conclusion. Renal disease is a risk factor for NSF, but in our small sample our evidence suggests liver disease is not an additional risk factor, especially if a low-risk gadolinium agent is used. Noting that not all patients received high-risk gadolinium, a larger study focusing on patients receiving high-risk gadolinium is needed to further evaluate NSF risk in liver disease in the peritransplant period.

  14. [Are non-invasive tests going to replace liver biopsy for diagnosis of liver fibrosis?].

    Science.gov (United States)

    Restellini, Sophie; Spahr, Laurent

    2012-06-27

    Liver fibrosis is associated with chronic liver diseases, and may evolve into cirrhosis that may be complicated by liver failure and portal hypertension. Detection and quantification of liver fibrosis is a key point in the follow-up of patients with chronic liver diseases. Liver biopsy is the gold standard method to assess and quantify fibrosis, but its invasiveness is a limiting factor in everyday clinical practice. Non invasive markers using either biological or radiological parameters have been developed and may decrease the need for liver biopsy in some cases. However, information is limited to fibrosis, and cut-offs values and diagnostic accuracies for significant fibrosis may vary according to the etiology of liver disease. Liver biopsy allows the assessment of intermediate stages of fibrosis and describes accompanying lesions.

  15. Liver fibrosis caused by choledocholith to regress after biliary drainage

    Institute of Scientific and Technical Information of China (English)

    Zuo-Bing Chen; Shu-Sen Zheng; Guo-Zhi Hu; Yuan Gao; Chen-Yan Ding; Yun Zhang; Xue-Hong Zhao; Lin-Mei Ni

    2005-01-01

    AIM: To study the correlation between liver fibrosis severity and biliary drainage in patients with choledocholith.METHODS: A follow-up study on seven patients with liver fibrosis due to choledocholith was made. The data, including biochemical tests (aspartate aminotransferase, alanine aminotransferase) and liver histological features before and after biliary drainage, were collected and studied. The fibrosis severity was scored on a scale from 0 to 3, with 0 denoting none, 1 portal and periportal fibrosis, 2 the presence of numerous fiber septa, and 3 cirrhosis. The average liver fibrosis severity scores of the first and second biopsy were compared with statistical method.RESULTS: The first, second liver fibrosis severity scores of these seven patients were 2,1; 2,1; 1,0; 1,1; 2,1; 2,1;1,0 respectively. The results showed that the average liver fibrosis severity score of the second liver biopsy decreased significantly compared with the first liver biopsy (n = 7, t = 4.25, P<0.05).CONCLUSION: Liver fibrosis due to choledocholith may regress after biliary drainage.

  16. Accuracy of FibroScan for diagnosing liver fibrosis

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    Jian ZHANG

    2011-11-01

    Full Text Available Objective To evaluate the accuracy of transient elastometry(FibroScan for the detection of liver fibrosis.Methods A total of 323 patients diagnosed with chronic liver disease based on pathological examination in the 302 Hospital of the People’s Liberation Army from April to December of 2009 were involved in the current study.Among them,141 patients were subjected to liver biopsy.Their liver function,coagulant index,B-ultrasound and blood cell count were examined clinically.Four examinations related to liver fibrosis were done on some of the patients.Meanwhile,FibroScan was used for liver stiffness measurement(LSM of every patient.The correlation between liver stiffness and the serologic index and liver fibrosis degree was analyzed.The Receive Operating Characteristic(ROC curve was adopted to analyze the accuracy of FibroScan for diagnosing liver fibrosis.Results Each serologic index was significantly correlated with liver stiffness(P < 0.001,and liver stiffness was closely related to the stage of liver fibrosis(r=0.74,P < 0.001.The statistical results of the 141 patients who underwent pathologic examination show that the areas under the ROC curve were 0.97(0.94,1.00 for patients with portal fibrosis(F1,0.96(0.93,0.99 for patients with significant fibrosis(F2,0.99(0.98,1.00 for patients with severe fibrosis(F3,and 0.97(0.94,0.99 for patients with cirrhosis(F4.The cutoff values were 4.4KPa,6.8KPa,9.7KPa,and 10.0KPa,respectively.Conclusion FibroScan is valuable for the diagnosis of liver fibrosis.It can be used as the basis for follow-up and management of patients with chronic liver diseases.

  17. The Orphan Nuclear Receptor SHP Attenuates Renal Fibrosis

    OpenAIRE

    Jung, Gwon-Soo; Kim, Mi-Kyung; Choe, Mi Sun; Lee, Kyeong-Min; Kim, Hye-Soon; Park, Young Joo; Choi, Hueng-Sik; Lee, Ki-Up; Park, Keun-Gyu; Lee, In-Kyu

    2009-01-01

    The accumulation of extracellular matrix proteins is a common feature of fibrotic kidney diseases. Accumulating evidence suggests that TGF-β and plasminogen activator inhibitor type 1 (PAI-1) promote the development of renal fibrosis by stimulating the generation and inhibiting the removal of matrix proteins. The small heterodimer partner (SHP) represses PAI-1 expression in the liver by inhibiting TGF-β signaling, but whether SHP inhibits renal fibrosis is unknown. Here, unilateral ureteral o...

  18. Liver fibrosis in vitro : Cell culture models and precision-cut liver slices

    NARCIS (Netherlands)

    de Bovenkamp, M. Van; Groothuis, G. M. M.; Meijer, D. K. F.; Olinga, P.

    2007-01-01

    Chronic liver injury of various etiologies can cause liver fibrosis, which is characterized by the progressive accumulation of connective tissue in the liver. As no effective treatment for liver fibrosis is available yet, extensive research is ongoing to further study the mechanisms underlying the d

  19. Simvastatin attenuates bleomycin-induced pulmonary fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    OU Xue-mei; FENG Yu-lin; WEN Fu-qiang; HUANG Xiang-yang; XIAO Jun; WANG Ke; WANG Tao

    2008-01-01

    Background Bleomycin-induced fibrosis is extensively used to model aspects of the pathogenesis of interstitial pulmonary fibrosis. This study aimed to determine the benefic effects and mechanisms of simvastatin on bleomycin-induced pulmonary fibrosis in mice.Methods Bleomycin-induced pulmonary fibrosis mice were administered with simvastatin in different doses for 28 days.We measured inflammatory response, fibrogenic cytokines and profibrogenic markers in both bleomycin-stimulated and control lungs, and correlated these parameters with pulmonary fibrosis.Results Simvastatin attenuated the histopathological change of bleomycin-induced pulmonary fibrosis and prevented the increase of lung hydroxyproline content and collagen (Ⅰand Ⅲ) mRNA expression induced by bleomycin. Moreover,simvastatin down-regulated the increased expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) induced by bleomycin at both gene and protein levels. Simultaneously, the accumulation of neutrophils and lymphocytes and the increased production of tumor necrosis factor-(] (TNF-a) in bronchial alveolar lavage fluid were inhibited by simvastatin in early inflammatory phase after bleomycin infusion. The higher dose of simvastatin was associated with a more significant reduction in these inflammatory and fibrotic parameters. Furthermore,the inactivation of p38, RhoA and Smad2/3 signaling pathways was observed during simvastatin administration.Conclusions Simvastatin attenuated bleomycin-induced pulmonary fibrosis, as indicated by decreases in Ashcroft score and lung collagen accumulation. The inhibitory effect of simvastatin on the progression of pulmonary fibrosis may be demonstrated by reducing inflammatory response and production of TGF-βI and CTGF. These findings indicate that simvastatin may be used in the treatment of pulmonary fibrosis.

  20. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease

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    Pietrobattista Andrea

    2009-05-01

    Full Text Available Abstract Background Liver fibrosis is a stage of non-alcoholic fatty liver disease (NAFLD which is responsible for liver-related morbidity and mortality in adults. Accordingly, the search for non-invasive markers of liver fibrosis has been the subject of intensive efforts in adults with NAFLD. Here, we developed a simple algorithm for the prediction of liver fibrosis in children with NAFLD followed at a tertiary care center. Methods The study included 136 male and 67 female children with NAFLD aged 3.3 to 18.0 years; 141 (69% of them had fibrosis at liver biopsy. On the basis of biological plausibility, readily availability and evidence from adult studies, we evaluated the following potential predictors of liver fibrosis at bootstrapped stepwise logistic regression: gender, age, body mass index, waist circumference, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase, albumin, prothrombin time, glucose, insulin, triglycerides and cholesterol. A final model was developed using bootstrapped logistic regression with bias-correction. We used this model to develop the 'pediatric NAFLD fibrosis index' (PNFI, which varies between 0 and 10. Results The final model was based on age, waist circumference and triglycerides and had a area under the receiver operating characteristic curve of 0.85 (95% bootstrapped confidence interval (CI with bias correction 0.80 to 0.90 for the prediction of liver fibrosis. A PNFI ≥ 9 (positive likelihood ratio = 28.6, 95% CI 4.0 to 201.0; positive predictive value = 98.5, 95% CI 91.8 to 100.0 could be used to rule in liver fibrosis without performing liver biopsy. Conclusion PNFI may help clinicians to predict liver fibrosis in children with NAFLD, but external validation is needed before it can be employed for this purpose.

  1. Current Strategies for Quantitating Fibrosis in Liver Biopsy

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    Yan Wang

    2015-01-01

    Full Text Available Objective: The present mini-review updated the progress in methodologies based on using liver biopsy. Data Sources: Articles for study of liver fibrosis, liver biopsy or fibrosis assessment published on high impact peer review journals from 1980 to 2014. Study Selection: Key articles were selected mainly according to their levels of relevance to this topic and citations. Results: With the recently mounting progress in chronic liver disease therapeutics, comes by a pressing need for precise, accurate, and dynamic assessment of hepatic fibrosis and cirrhosis in individual patients. Histopathological information is recognized as the most valuable data for fibrosis assessment. Conventional histology categorical systems describe the changes of fibrosis patterns in liver tissue; but the simplified ordinal digits assigned by these systems cannot reflect the fibrosis dynamics with sufficient precision and reproducibility. Morphometric assessment by computer assist digital image analysis, such as collagen proportionate area (CPA, detects change of fibrosis amount in tissue section in a continuous variable, and has shown its independent diagnostic value for assessment of advanced or late-stage of fibrosis. Due to its evident sensitivity to sampling variances, morphometric measurement is feasible to be taken as a reliable statistical parameter for the study of a large cohort. Combining state-of-art imaging technology and fundamental principle in Tissue Engineering, structure-based quantitation was recently initiated with a novel proof-of-concept tool, qFibrosis. qFibrosis showed not only the superior performance to CPA in accurately and reproducibly differentiating adjacent stages of fibrosis, but also the possibility for facilitating analysis of fibrotic regression and cirrhosis sub-staging. Conclusions: With input from multidisciplinary innovation, liver biopsy assessment as a new "gold standard" is anticipated to substantially support the accelerated

  2. Current Strategies for Quantitating Fibrosis in Liver Biopsy

    Institute of Scientific and Technical Information of China (English)

    Yan Wang; Jin-Lin Hou

    2015-01-01

    Objective:The present mini-review updated the progress in methodologies based on using liver biopsy.Data Sources:Articles for study of liver fibrosis,liver biopsy or fibrosis assessment published on high impact peer review journals from 1980 to 2014.Study Selection:Key articles were selected mainly according to their levels of relevance to this topic and citations.Results:With the recently mounting progress in chronic liver disease therapeutics,comes by a pressing need for precise,accurate,and dynamic assessment of hepatic fibrosis and cirrhosis in individual patients.Histopathological information is recognized as the most valuable data for fibrosis assessment.Conventional histology categorical systems describe the changes of fibrosis patterns in liver tissue; but the simplified ordinal digits assigned by these systems cannot reflect the fibrosis dynamics with sufficient precision and reproducibility.Morphometric assessment by computer assist digital image analysis,such as collagen proportionate area (CPA),detects change of fibrosis amount in tissue section in a continuous variable,and has shown its independent diagnostic value for assessment of advanced or late-stage of fibrosis.Due to its evident sensitivity to sampling variances,morphometric measurement is feasible to be taken as a reliable statistical parameter for the study of a large cohort.Combining state-of-art imaging technology and fundamental principle in Tissue Engineering,structure-based quantitation was recently initiated with a novel proof-of-concept tool,qFibrosis.qFibrosis showed not only the superior performance to CPA in accurately and reproducibly differentiating adjacent stages of fibrosis,but also the possibility for facilitating analysis of fibrotic regression and cirrhosis sub-staging.Conclusions:With input from multidisciplinary innovation,liver biopsy assessment as a new "gold standard" is anticipated to substantially support the accelerated progress of Hepatology medicine.

  3. Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF-β1.

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    Xiaobao Fan

    Full Text Available Transforming growth factor β1 (TGF-β1 is the pivotal pro-fibrogenic cytokine in hepatic fibrosis. Reducing the over-produced expression of TGF-β1 or blocking its signaling pathways is considered to be a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the feasibility of attenuating hepatic fibrosis by vaccination against TGF-β1 with TGF-β1 kinoids. Two TGF-β1 kinoid vaccines were prepared by cross-linking TGF-β1-derived polypeptides (TGF-β1(25-[41-65] and TGF-β1(30-[83-112] to keyhole limpet hemocyanin (KLH. Immunization with the two TGF-β1 kinoids efficiently elicited the production of high-levels of TGF-β1-specific antibodies against in BALB/c mice as tested by enzyme-linked immunosorbent assay (ELISA and Western blotting. The antisera neutralized TGF-β1-induced growth-inhibition on mink lung epithelial cells (Mv1Lu and attenuated TGF-β1-induced Smad2/3 phosphorylation, α-SMA, collagen type 1 alpha 2 (COL1A2, plasminogen activator inhibitor-1 (PAI-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1 expression in the rat hepatic stellate cell (HSC line, HSC-T6. Vaccination against TGF-β1 with the kinoids significantly suppressed CCl4-induced collagen deposition and the expression of α-SMA and desmin, attenuated hepatocyte apoptosis and accelerated hepatocyte proliferation in BALB/c mice. These results demonstrated that immunization with the TGF-β1 kinoids efficiently attenuated CCl4-induced hepatic fibrosis and liver injury. Our study suggests that vaccination against TGF-β1 might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.

  4. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    International Nuclear Information System (INIS)

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  5. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G. [Radiotherapy Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy); Castiglione, F. [Department of Human Pathology and Oncology, University of Florence, Firenze (Italy); Vanzi, E.; Bottoncetti, A.; Pupi, A. [Nuclear Medicine Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy)

    2011-10-15

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  6. Fibroscan ® : A noninvasive test of liver fibrosis assessment

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    Al-Ghamdi Abdullah

    2007-01-01

    Full Text Available Determination of the extent of progress of hepatic fibrosis is important in clinical practice, where it may reflect the severity of liver disease and predict response to treatment. Percutaneous liver biopsy is the gold standard for grading and staging of liver disease. However, liver biopsy is an invasive procedure with certain unavoidable risks and complications. Several methods have been studied in an attempt to reach a diagnosis of cirrhosis by noninvasive means. Fibroscan ® has been designed to quantify liver fibrosis by means of elastography and found to have reasonably good sensitivity and specificity patterns, especially in patients with advanced fibrosis and can be used as an alternative to liver biopsy.

  7. New Developments on the Treatment of Liver Fibrosis.

    Science.gov (United States)

    Koyama, Yukinori; Xu, Jun; Liu, Xiao; Brenner, David A

    2016-01-01

    Liver fibrosis results from many chronic injuries and often progresses to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Liver transplantation is the only treatment available for patients with advanced stages of liver fibrosis. Therefore, new strategies for anti-fibrotic therapy are required. Various kinds of hepatocyte damage result in inflammation, which leads to the activation of hepatic stellate cells (HSCs), which are the major source of myofibroblasts in the liver. Myofibroblasts proliferate in response to various kinds of cytokines, chemokines, and growth factors and produce extracellular matrix proteins, which forms the fibrous scar. Myofibroblasts undergo apoptosis and inactivation when the underlying causative etiologies are cleared. Here we describe our current knowledge of targeting the steps in HSC activation as therapeutic target for liver fibrosis. PMID:27332862

  8. Preventive effect of halofuginone on concanavalin A-induced liver fibrosis.

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    Jie Liang

    Full Text Available Halofuginone (HF is an active component of extracts derived from the plant alkaloid febrifugine and has shown therapeutic promise in animal models of fibrotic disease. Our main objectives were to clarify the suppressive effect of HF on concanavalin A (ConA-induced liver fibrosis. ConA injection into the tail vein caused a great increase in the serum aspartate aminotransferase (AST and alanine aminotransferase (ALT levels, while orally administration of HF significantly decreased the levels of the transaminases. In addition, the levels of hyaluronic acid (HA, procollagen III (PCIII and TGF-β1 in the serum and collagen I, α-SMA, tissue inhibitors of metalloproteinase 2 (TIMP2 and Smad3 in the liver tissue were significantly lowered with the treatment of HF. Histological examination also demonstrated that HF significantly reduced the severity of liver fibrosis. Since ConA-induced liver fibrosis is caused by the repeated activation of T cells, immunomodulatory substances might be responsible for the suppressive effect of HF. We found that the production of nuclear factor (NF-kB in the serum was increased in ConA-treated group, while decreased significantly with the treatment of HF. The changes of inflammatory cytokines tumor necrosis factor (TNF-α, IL-6 and IL-1β in the serum followed the same rhythm. All together, our findings indicate that orally administration HF (10ppm would attenuate the liver fibrosis by suppressing the synthesis of collagen I and inflammation-mediated liver injury.

  9. Collagen immunostains can distinguish capsular fibrous tissue from septal fibrosis and may help stage liver fibrosis.

    Science.gov (United States)

    Chen, Wei; Rock, Jonathan B; Yearsley, Martha M; Hanje, A James; Frankel, Wendy L

    2014-01-01

    Core-needle biopsy remains essential for diagnosis of cirrhosis; however, evaluation of fibrosis in such biopsies is often challenging due to the fragmented nature of cirrhotic liver specimens. It is also common to see portions of liver capsules present in the biopsy which adds to the diagnostic challenge. The distinction between capsular/subcapsular fibrous tissue and septal fibrosis is critical to avoid potential overstaging of liver fibrosis. We compared the differential immunostaining in liver capsular and septal areas for collagens III, IV, V, VI, vitronectin, laminin, Orcein, and Trichrome in 15 whole sections of explanted cirrhotic livers and 5 simulated liver biopsies. Collagens III, IV, V, VI, Trichrome, and Orcein show distinct staining patterns in capsular fibrous tissue and septal fibrosis. Collagen IV shows strong diffuse septal staining and consistently weak to negative capsular staining. Collagens III and VI stain similar to IV for septal fibrosis, whereas collagen V, Trichrome, and Orcein show strong staining in both areas. Collagen IV, possibly with III or VI in addition to the routine Trichrome and hematoxylin and eosin stain, is useful in differentiating capsular fibrous tissue from septal fibrosis on challenging and fragmented liver biopsies.

  10. CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis.

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    Po-Yin Chu

    Full Text Available Heart failure (HF is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice or type II diabetes (Israeli Sand-rats and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.

  11. Liver fibrosis in chronic viral hepatitis: An ultrasonographic study

    Institute of Scientific and Technical Information of China (English)

    Rong-Qin Zheng; Qing-Hui Wang; Ming-De Lu; Shi-Bin Xie; Jie Ren; Zhong-Zhen Su; Yin-Ke Cai; Ji-Lu Yao

    2003-01-01

    AIM: To select valuable ultrasonographic predictors for the evaluation of hepatic inflammation and fibrosis degree in chronic hepatitis, and to study the value of ultrasonography in the evaluation of liver fibrosis and compensated liver cirrhosis in comparison with serology and histology.METHODS: Forty-four ultrasonographic variables were analyzed and screened using color Doppler ultrasound system in 225 patients with chronic viral hepatitis and compensated liver cirrhosis. The valuable ultrasonographic predictors were selected on the basis of a comparison with histopathological findings. The value of ultrasonography and serology in the evaluation of liver fibrosis degree and the diagnosis of compensated liver cirrhosis was also studied and compared. Meanwhile, the influencing factors on ultrasonographic diagnosis of compensated liver cirrhosis were also analyzed.RESULTS: By statistical analysis, the maximum velocity of portal vein and the degree of gall-bladder wall smoothness were selected as the valuable predictors for the inflammation grade (G), while liver surface, hepatic parenchymal echo pattern, and the wall thickness of gall-bladder were selected as the valuable predictors for the fibrosis stage (S). Three S-related independent ultrasonographyic predictors and three routine serum fibrosis markers (HA, HPCIII and CIV) were used to discriminate variables for the comparison of ultrasonography with serology. The diagnostic accuracy of ultrasonography in moderate fibrosis was higher than that of serology (P<0.01), while there were no significant differences in the general diagnostic accuracy of fibrosis as well as between mild and severe fibrosis (P<0.05). There were no significant differences between ultrasonography and serology in the diagnosis of compensated liver cirrhosis.However, the diagnostic accuracy of ultrasonography was higher in inactive liver cirrhosis and lower in active cirrhosis than that of serology (both P<0.05). False positive and false

  12. Liver and spleen volume variations in patients with hepatic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Peng Liu; Peng Li; Wen He; Li-in Zhao

    2009-01-01

    AIM: To study the liver and spleen volume variations in hepatic fibrosis patients at different histopathological stages.METHODS: Multidetector computed tomography (MDCT) scan was performed in 85 hepatic fibrosis patients. Liver volume (LV) and spleen volume (SV) were measured. Fifteen healthy individuals served as a control group (S0). The patients were divided into stage 1 (S1) group ( n = 34), stage 2 (S2) group ( n = 25), stage 3 (S3) group ( n = 16), and stage 4 (S4)group ( n = 10) according to their histopathological stage of liver fibrosis.RESULTS: The LV and standard LV(SLV)had a tendency to increase with the severity of fibrosis, but no statistical difference was observed in the 5 groups (LV: F = 0.245, P = 0.912; SLV: F = 1.902,P = 0.116). The SV was gradually increased with the severity of fibrosis, and a statistically significant difference in SV was observed among the 5 groups( P < 0.01). The LV/SV ratio and SLV/SV ratio were gradually decreased with the aggravation of hepatic fibrosis, and statistically significant differences in both LV/SV and SLV/SV were found among the 5 groups ( P< 0.01).CONCLUSION: The absence of obvious LV reduction in patients with chronic liver disease may be a morphological index of patients without liver cirrhosis. The SV is related to the severity of fibrosis, and the spleen of patients with advanced fibrosis is enlarged evidently. The LV/SV ratio and SLV/SV ratio are of a significant clinical value in the diagnosis of advanced liver fibrosis.

  13. Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice.

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    Hyon-Seung Yi

    Full Text Available Accumulating evidence suggests that retinol and its metabolites are closely associated with liver fibrogenesis. Recently, we demonstrated that genetic ablation of alcohol dehydrogenase 3 (ADH3, a retinol metabolizing gene that is expressed in hepatic stellate cells (HSCs and natural killer (NK cells, attenuated liver fibrosis in mice. In the current study, we investigated whether pharmacological ablation of ADH3 has therapeutic effects on experimentally induced liver fibrosis in mice.Liver fibrosis was induced by intraperitoneal injections of carbon tetrachloride (CCl4 or bile duct ligation (BDL for two weeks. To inhibit ADH3-mediated retinol metabolism, 10 μg 4-methylpyrazole (4-MP/g of body weight was administered to mice treated with CCl4 or subjected to BDL. The mice were sacrificed at week 2 to evaluate the regression of liver fibrosis. Liver sections were stained for collagen and α-smooth muscle actin (α-SMA. In addition, HSCs and NK cells were isolated from control and treated mice livers for molecular and immunological studies.Treatment with 4-MP attenuated CCl4- and BDL-induced liver fibrosis in mice, without any adverse effects. HSCs from 4-MP treated mice depicted decreased levels of retinoic acids and increased retinol content than HSCs from control mice. In addition, the expression of α-SMA, transforming growth factor-β1 (TGF-β1, and type I collagen α1 was significantly reduced in the HSCs of 4-MP treated mice compared to the HSCs from control mice. Furthermore, inhibition of retinol metabolism by 4-MP increased interferon-γ production in NK cells, resulting in increased apoptosis of activated HSCs.Based on our data, we conclude that inhibition of retinol metabolism by 4-MP ameliorates liver fibrosis in mice through activation of NK cells and suppression of HSCs. Therefore, retinol and its metabolizing enzyme, ADH3, might be potential targets for therapeutic intervention of liver fibrosis.

  14. Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance.

    Science.gov (United States)

    Stål, Per

    2015-10-21

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD.

  15. Non-Invasive Evaluation of Cystic Fibrosis Related Liver Disease in Adults with ARFI, Transient Elastography and Different Fibrosis Scores

    OpenAIRE

    Karlas, Thomas; Neuschulz, Marie; Oltmanns, Annett; Güttler, Andrea; Petroff, David; Wirtz, Hubert; Mainz, Jochen G.; Mössner, Joachim; Berg, Thomas; Tröltzsch, Michael; Keim, Volker; Wiegand, Johannes

    2012-01-01

    Background Cystic fibrosis-related liver disease (CFLD) is present in up to 30% of cystic fibrosis patients and can result in progressive liver failure. Diagnosis of CFLD is challenging. Non-invasive methods for staging of liver fibrosis display an interesting diagnostic approach for CFLD detection. Aim We evaluated transient elastography (TE), acoustic radiation force impulse imaging (ARFI), and fibrosis indices for CFLD detection. Methods TE and ARFI were performed in 55 adult CF patients. ...

  16. Protection effect of kallistatin on carbon tetrachloride-induced liver fibrosis in rats via antioxidative stress.

    Directory of Open Access Journals (Sweden)

    Xiaoping Huang

    Full Text Available Prolonged inflammation and oxidative stress are emerging as key causes of pathological wound healing and the development of liver fibrosis. We have investigated the effects of recombinant human kallistatin, produced in Pichia. pastoris, on preventing carbon tetrachloride (CCl4-induced liver fibrosis in rats. Daily administration of kallistatin prevented development of CCl4-induced liver fibrosis, which was evidenced by histological study. In all kallistatin treated rats, activation of hepatic stellate cells (HSC as assessed by s-smooth muscle actin staining was attenuated, TGF- β1 expression was inhibited, class I serum biomarkers associated with the process of fibrogenesis, such as hyaluronic acid, laminin, and procollagen III, were lowered, compared with that in the model control group. Furthermore, residual hepatic functional reserve was improved by kallistatin treatment. CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters. We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line. Kallistatin scavenged H2O2-induced ROS in the LX-2 cells, and suppressed the activation of primary HSC. These results suggest recombinant human kallistatin might be a promising drug candidate for therapeutic intervention of liver fibrosis.

  17. Protection Effect of Kallistatin on Carbon Tetrachloride-Induced Liver Fibrosis in Rats via Antioxidative Stress

    Science.gov (United States)

    Huang, Xiaoping; Wang, Xiao; Lv, Yinghui; Xu, Luli; Lin, Junsheng; Diao, Yong

    2014-01-01

    Prolonged inflammation and oxidative stress are emerging as key causes of pathological wound healing and the development of liver fibrosis. We have investigated the effects of recombinant human kallistatin, produced in Pichia. pastoris, on preventing carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Daily administration of kallistatin prevented development of CCl4-induced liver fibrosis, which was evidenced by histological study. In all kallistatin treated rats, activation of hepatic stellate cells (HSC) as assessed by s-smooth muscle actin staining was attenuated, TGF- β1 expression was inhibited, class I serum biomarkers associated with the process of fibrogenesis, such as hyaluronic acid, laminin, and procollagen III, were lowered, compared with that in the model control group. Furthermore, residual hepatic functional reserve was improved by kallistatin treatment. CCl4 induced elevation of malondialdehyde level and reduced superoxide dismutase activity in the liver, while kallistatin reduced these oxidative parameters. We also investigated the effects of kallistatin on rat primary HSC and LX-2, the human HSC cell line. Kallistatin scavenged H2O2-induced ROS in the LX-2 cells, and suppressed the activation of primary HSC. These results suggest recombinant human kallistatin might be a promising drug candidate for therapeutic intervention of liver fibrosis. PMID:24558397

  18. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Hiroshi Sakugawa; Fukunori Kinjo; Atsushi Saito; Tomofumi Nakayoshi; Kasen Kobashigawa; Tsuyoshi Yamashiro; Tatsuji Maeshiro; Satoru Miyagi; Joji Shiroma; Akiyo Toyama; Tomokuni Nakayoshi

    2005-01-01

    AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease.However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type Ⅵ collagen 7S domain and hyaluronic acid.METHODS: One hundred and twelve patients with histologically proven NAFLD were studied.RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type Ⅵ collagen 7S domain ≥5.0 ng/mL, hyaluronic acid ≥43 ng/mL. Both markers had a high positive predictive value: type Ⅵ collagen 7S domain, 86% and hyaluronic acid,92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type Ⅵ collagen 7S domain (≥5.0 ng/mL),84% and hyaluronic acid (≥50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis.CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis.

  19. Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation

    Institute of Scientific and Technical Information of China (English)

    Wen-ying CHOU; Cheng-nan LU; Tsung-hsing LEE; Chia-ling WU; Kung-sheng HUNG; Allan M CONCEJERO; Bruno JAWAN; Cheng-haung WANG

    2006-01-01

    Aim:Liver fibrosis represents a process of healing and scarring in response to chronic liver injury.Effective therapies for liver fibrosis are lacking.Interleukin-10 (IL-10) is a cytokine that downregulates pro-inflammatory responses and has a modulatory effect on hepatic fibrogenesis.The aim of this study was to investigate whether electroporative IL-10 gene therapy has an hepatic fibrolytic effect on mice.Methods:Hepatic fibrosis was induced by administering carbon tetrachloride (CCl4) for 10 weeks in mice.The human IL-10 expression plasmid was delivered via electroporation after hepatic fibrosis was established.Histopathology,reverse transcription polymerase chain reaction (RT-PCR) ,immunoblotting,and gelatin zymography were used to investigate the possible mechanisms of action of IL-10.Results:Human IL-10 gene therapy reversed CCl4-induced liver fibrosis in mice.RT-PCR revealed that IL-10 gene therapy attenuated liver TGF-β1,collagen αl,fibronectin,and cell adhesion molecule mRNA upregulation.Following gene transfer,both the activation of α-smooth muscle actin and cyclooxygenase-2 were significantly attenuated.Furthermore.IL-10 significantly inhibited matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinase (TIMP) activation after CCl4 intoxication.Conclusions:We demonstrated that IL-10 gene therapy attenuated CCl4-induced liver fibrosis in mice.IL-10 prevented upregulated fibrogenic and pro-inflammatory gene responses.Its collagenolytic effect may be attributed to MMP and TIMP modulation.IL-10 gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

  20. New Effective Treatment of Liver Fibrosis by Chinese Herbal Medicine

    Institute of Scientific and Technical Information of China (English)

    张国梁

    2002-01-01

    @@ Liver fibrosis is an abnormal proliferation pathologic process of intrahepatic fibrous connective tissue that occurs after liver cells have been necrotized and stimulated by inflammatory factors. It is called fibrosis when the pathological change is mild, and liver cirrhosis when the change becomes so severe as to reconstruct the liver lobuli to form pseudolobuli and nodule(1). Liver fibrosis is an important pathological characteristic of chronic hepatopathy and the chief intermediate link to further develop of liver cirrhosis. No ideal remedy for treatment of chronic hepatitic cirrhosis has been found so far. Although some drugs, such as colchicine and penicillamine, had been reported to have the effect of fibrosis inhibition, their clinical application is still limited for the rather severe toxic-side effects. Certain progress have been made from the clinical and experimental studies on anti-fibrosis treatment by traditional Chinese medicine (TCM) carried out widely in China in recent ten years. And here is a general review of the drugs used.

  1. Utility of Noninvasive Markers of Fibrosis in Cholestatic Liver Diseases.

    Science.gov (United States)

    Corpechot, Christophe

    2016-02-01

    Methods of liver fibrosis assessment have changed considerably in the last 20 years, and noninvasive markers now have been recognized as major first-line tools in the management of patients with chronic viral hepatitis infection. But what about the efficiency and utility of these surrogate indices for the more uncommon chronic cholestatic liver diseases, namely primary biliary cirrhosis and primary sclerosing cholangitis? This article provides clinicians with a global overview of what is currently known in the field. Both diagnostic and prognostic aspects of noninvasive markers of fibrosis in cholestatic liver diseases are presented and discussed.

  2. Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation.

    Directory of Open Access Journals (Sweden)

    Tian Lan

    Full Text Available Reactive oxygen species (ROS produced by nicotinamide adenine dinucleotide phosphate oxidase (NOX play a key role in liver injury and fibrosis. Previous studies demonstrated that GKT137831, a dual NOX1/4 inhibitor, attenuated liver fibrosis in mice as well as pro-fibrotic genes in hepatic stellate cells (HSCs as well as hepatocyte apoptosis. The effect of NOX1 and NOX4 deficiency in liver fibrosis is unclear, and has never been directly compared. HSCs are the primary myofibroblasts in the pathogenesis of liver fibrosis. Therefore, we aimed to determine the role of NOX1 and NOX4 in liver fibrosis, and investigated whether NOX1 and NOX4 signaling mediates liver fibrosis by regulating HSC activation. Mice were treated with carbon tetrachloride (CCl4 to induce liver fibrosis. Deficiency of either NOX1 or NOX4 attenuates liver injury, inflammation, and fibrosis after CCl4 compared to wild-type mice. NOX1 or NOX4 deficiency reduced lipid peroxidation and ROS production in mice with liver fibrosis. NOX1 and NOX4 deficiency are approximately equally effective in preventing liver injury in the mice. The NOX1/4 dual inhibitor GKT137831 suppressed ROS production as well as inflammatory and proliferative genes induced by lipopolysaccharide (LPS, platelet-derived growth factor (PDGF, or sonic hedgehog (Shh in primary mouse HSCs. Furthermore, the mRNAs of proliferative and pro-fibrotic genes were downregulated in NOX1 and NOX4 knock-out activated HSCs (cultured on plastic for 5 days. Finally, NOX1 and NOX4 protein levels were increased in human livers with cirrhosis compared with normal controls. Thus, NOX1 and NOX4 signaling mediates the pathogenesis of liver fibrosis, including the direct activation of HSC.

  3. Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

    Science.gov (United States)

    Sivam, S; Al-Hindawi, Y; Di Michiel, J; Moriarty, C; Spratt, P; Jansz, P; Malouf, M; Plit, M; Pleass, H; Havryk, A; Bowen, D; Haber, P; Glanville, A R; Bye, P T P

    2016-07-01

    Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation. PMID:27405894

  4. Antifibrotic effect of heparin on liver fibrosis model in rats

    Institute of Scientific and Technical Information of China (English)

    Binita; Shah; Gaurang; Shah

    2012-01-01

    AIM: To evaluate the effect of chronic thrombin inhibition by heparin on experimentally induced chronic liver injury (liver fibrosis) in rats. METHODS: Chronic liver injury (liver fibrosis) was induced in Wistar rats by oral administration of carbon tetrachloride (CCl 4 ) for 7 wk, an animal model with persistent severe hepatic fibrosis. Intravenous administration of the thrombin antagonist (heparin) started 1 wk after the start of CCl 4 intoxication for 6 wk. After completion of treatment (7 wk), markers of hepatic dysfunction were measured and changes evaluated histopathologically. RESULTS: Higher serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total, direct and indirect bilirubin levels, as well as lower fibrinogen levels, were found in CCl 4 intoxicated rats. Heparin, silymarin and combination of drug (heparin and silymarin) treatment for 6 wk prevented a rise in SGOT, SGPT, ALP, total, direct and indirect bilirubin levels and improved fibrinogen levels. Deterioration in hepatic function determined by the fibrosis area was retarded, as evident from hepatic histopathology. Total protein levels were not changed in all groups.CONCLUSION: Heparin, a thrombin antagonist, preserved hepatic function and reduced severity of hepatic dysfunction/fibrogenesis. Combination of heparin and silymarin produced additional benefits on liver fibrosis.

  5. [Non-invasive evaluation of liver fibrosis in hepatitis C].

    Science.gov (United States)

    de Lédinghen, V; Poynard, T; Wartelle, C; Rosenthal, E

    2008-03-01

    In 2007, the recommended FibroScan, FibroTest or liver biopsy for the initial diagnosis of fibrosis in patients with hepatitis C without co morbidities. These methods have to be interpreted according to the clinical situation, keeping in mind negative and positive false results. For FibroTest, hemolysis, Gilbert syndrome or acute inflammation can modify the result. Pre-analytical and analytical conditions of FibroTest have to be respected according to manufactory recommendations. For FibroScan, the numbers of measurements, the rate of successful measurements, and the interquartile range have to be correct. In case of suspicious results, FibroTest or FibroScan have to be done again. The liver biopsy, FibroTest, and FibroScan are less relevant for the distinction of two adjacent stages of fibrosis. However, their performances are excellent for the diagnosis of severe fibrosis or cirrhosis compared to moderate fibrosis.

  6. Liver fibrosis in primary intestinal lymphangiectasia: An undervalued topic

    Institute of Scientific and Technical Information of China (English)

    Raffaele; Licinio; Mariabeatrice; Principi; Enzo; Ierardi; Alfredo; Di; Leo

    2014-01-01

    The relationship between primary intestinal lymphangiectasia(PIL) and liver fibrosis is an emerging topic with many obscure aspects due to the rarity of the disorder.A recent paper reported that a six-month lowfat diet improved liver fibrosis.We report the case of a 17-year-old girl affected by PIL whose hepatic fibrosis progressively worsened within one year,despite dietetic support.This and the previous case report describe extraordinary events,which do not allow clear-cut clinical aspects to be established.Nevertheless,both cases suggest that in patients with PIL,it is necessary to closely monitor liver morphology with in-depth investigations including not only ultrasonography,but also elastography.

  7. Simultaneous liver-pancreas transplantation for cystic fibrosis-related liver disease : A multicenter experience

    NARCIS (Netherlands)

    Bandsma, R. H. J.; Bozic, M. A.; Fridell, J. A.; Crull, M. H.; Molleston, J.; Avitzur, Y.; Mozer-Glassberg, Y.; Gonzalez-Peralta, R. P.; Hodik, M.; Fecteau, A.; de Angelis, M.; Durie, P.; Ng, V. L.

    2014-01-01

    Background: Diabetes is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). While liver transplantation is well established for CF-related liver disease (CFLD), the role of simultaneous liver pancreas transplantation is less understood. Methods: We polled 81 pedi

  8. Pioglitazone Attenuates Vascular Fibrosis in Spontaneously Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Dengfeng Gao

    2012-01-01

    Full Text Available Objective. We sought to investigate whether the peroxisome proliferator-activated receptor-γ (PPAR-γ ligand pioglitazone can attenuate vascular fibrosis in spontaneously hypertensive rats (SHRs and explore the possible molecular mechanisms. Methods. SHRs (8-week-old males were randomly divided into 3 groups (n=8 each for treatment: pioglitazone (10 mg/kg/day, hydralazine (25 mg/kg/day, or saline. Normal male Wistar Kyoto (WKY rats (n=8 served as normal controls. Twelve weeks later, we evaluated the effect of pioglitazone on vascular fibrosis by Masson’s trichrome and immunohistochemical staining of collagen III and real-time RT-PCR analysis of collagen I, III and fibronectin mRNA.Vascular expression of PPAR-γ and connective tissue growth factor (CTGF and transforming growth factor-β (TGF-β expression were evaluated by immunohistochemical staining, western blot analysis, and real-time RT-PCR. Results. Pioglitazone and hydralazine treatment significantly decreased systolic blood pressure in SHRs. Masson’s trichrome staining for collagen III and real-time RT-PCR analysis of collagen I, III and fibronectin mRNA indicated that pioglitazone significantly inhibited extracellular matrix production in the aorta. Compared with Wistar Kyoto rats, SHRs showed significantly increased vascular CTGF expression. Pioglitazone treatment significantly increased PPAR-γ expression and inhibited CTGF expression but had no effect on TGF-β expression. Conclusions. The results indicate that pioglitazone attenuated vascular fibrosis in SHRs by inhibiting CTGF expression in a TGF-β-independent mechanism.

  9. Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis

    OpenAIRE

    Canbay, Ali; Guicciardi, Maria Eugenia; Higuchi, Hajime; Feldstein, Ariel; Bronk, Steven F.; Rydzewski, Robert; Tanai, Makiko; Gores, Gregory J.

    2004-01-01

    Although a lysosomal, cathepsin B–dependent (Ctsb-dependent) pathway of apoptosis has been described, the contribution of this pathway to tissue damage remains unclear. Our aim was to ascertain if Ctsb inactivation attenuates liver injury, inflammation, and fibrogenesis after bile duct ligation (BDL). In 3-day BDL mice, hepatocyte apoptosis, mitochondrial cytochrome c release, and serum alanine aminotransferase (ALT) values were reduced in Ctsb–/– versus Ctsb+/+ animals. Likewise, R-3032 (a C...

  10. Advance in quantitatively diagnosing and staging liver fibrosis with magnetic resonance imaging

    International Nuclear Information System (INIS)

    Liver fibrosis is the common characteristic of all kinds of chronic liver diseases, and early quantitative diagnosis of the fibrosis is of great significance for the choice of therapeutic methods and the promotion of this disease inversion. Liver biopsy is the gold standard for the diagnosis of liver fibrosis, but it is limited in clinical application due to its invasive nature. As a non-invasive examination method, magnetic resonance quantitative technique has progressed greatly in assessment of liver fibrosis in recent years. We will review the progress in the study on quantitatively diagnosing and staging liver fibrosis with magnetic resonance imaging. (authors)

  11. Transplantation of fetal liver epithelial progenitor cells ameliorates experimental liver fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    Jin-Fang Zheng; Li-Jian Liang; Chang-Xiong Wu; Jin-Song Chen; Zhen-Sheng Zhang

    2006-01-01

    AIM: To investigate the effect of transplanted fetal liver epithelial progenitor (FLEP) cells on liver fibrosis in mice.METHODS: FLEP cells were isolated from embryonal day (ED) 14 BALB/c mice and transplanted into female syngenic BALB/c mice (n = 60). After partial hepatectomy (PH), diethylnitrosamine (DEN) was administered to induce liver fibrosis. Controls received FLEP cells and non-supplemented drinking water, the model group received DEN-spiked water, and the experimental group received FLEP cells and DEN.Mice were killed after 1, 2, and 3 mo, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), and laminin (LN) in serum,and hydroxyproline (Hyp) content in liver were assessed.Alpha-smooth muscle actin (α-SMA) of liver was tested by immunohistochemistry. Transplanted male mice FLEP cells were identified by immunocytochemistry for sry (sex determination region for Y chromosome) protein.RESULTS: Serum ALT, AST, HA, and LN were markedly reduced by transplanted FLEP cells. Liver Hyp content and α-SMA staining in mice receiving FLEP cells were lower than that of the model group, which was consistent with altered liver pathology. Transplanted cells proliferated and differentiated into hepatocytes and bile duct epithelial cells with 30%-50% repopulation in the liver fibrosis induced by DEN after 3 mo.CONCLUSION: Transplanted FLEP cells proliferate and differentiate into hepatocytes and bile duct epithelial cells with high repopulation capacity in the fiberized liver induced by DEN, which restores liver function and reduces liver fibrosis.

  12. Broad-spectrum matrix metalloproteinase inhibition curbs inflammation and liver injury but aggravates experimental liver fibrosis in mice.

    Directory of Open Access Journals (Sweden)

    Vincent E de Meijer

    Full Text Available BACKGROUND: Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs. The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF-alpha-converting enzyme (TACE. We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury. METHODOLOGY/PRINCIPAL FINDINGS: Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4 administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-alpha receptors. Liver injury was quantified by alanine aminotransferase (ALT levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-alpha receptors exhibited an 80% reduction of serum ALT

  13. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats.

    Directory of Open Access Journals (Sweden)

    Gang Tan

    Full Text Available BACKGROUND: Hydrogen sulfide (H(2S displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2S in carbon tetrachloride (CCl(4-induced hepatotoxicity, cirrhosis and portal hypertension. METHODS AND FINDINGS: Sodium hydrosulfide (NaHS, a donor of H(2S, and DL-propargylglycine (PAG, an irreversible inhibitor of cystathionine γ-lyase (CSE, were applied to the rats to investigate the effects of H(2S on CCl(4-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2S, hepatic H(2S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4 significantly reduced serum levels of H(2S, hepatic H(2S production and CSE expression. NaHS attenuated CCl(4-induced acute hepatotoxicity by supplementing exogenous H(2S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, hyaluronic acid (HA, albumin, tumor necrosis factor (TNF-α, interleukin (IL-1β, IL-6 and soluble intercellular adhesion molecule (ICAM-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA expression. PAG showed opposing effects to NaHS on most of the above parameters. CONCLUSIONS: Exogenous H(2S attenuates CCl(4-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2S may present a promising approach, particularly for its prophylactic effects, against liver

  14. Endothelial Dysfunction Correlates with Liver Fibrosis in Chronic HCV Infection

    Directory of Open Access Journals (Sweden)

    Michele Barone

    2015-01-01

    Full Text Available Background. Hepatitis C virus (HCV infection can exert proatherogenic activities due to its direct action on vessel walls and/or via the chronic inflammatory process involving the liver. Aims. To clarify the role of HCV in atherosclerosis development in monoinfected HCV patients at different degrees of liver fibrosis and with no risk factors for coronary artery disease. Methods. Forty-five patients were included. Clinical, serological, and anthropometric parameters, liver fibrosis (transient liver elastometry (fibroscan and aspartate aminotransferase to platelet ratio index (APRI, carotid intima-media thickness (c-IMT, and brachial artery flow-mediated vasodilatation (FMD were assessed. Patients were divided into 3 tertiles according to fibroscan values. Results. Patients in the third tertile (fibroscan value >11.5 KPa showed FMD values were significantly lower than second and first tertiles (4.7±1.7% versus 7.1±2.8%, p=0.03. FMD values were inversely related to liver elastomeric values. c-IMT values were normal. The risk for endothelial dysfunction development in the third tertile (p=0.02 was 6.9 higher than the first tertile. A fibroscan value >11.5 KPa had a positive predictive power equal to 79% for endothelial dysfunction. Conclusions. HCV advanced liver fibrosis promotes atherosclerosis by inducing endothelial dysfunction independently of common cardiovascular risk factors.

  15. Autophagy: A new therapeutic target for liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Hepatic fibrosis is a wound-healing response to liverinjury and the result of imbalance of extracellular matrix(ECM) accumulation and degradation. The relentless production and progressive accumulation of ECM canlead to end-stage liver disease. Although significantprogress has been achieved in elucidating the mechanismsof fibrogenesis, effective anti-fibrotic strategiesare still lacking. Autophagy is an intracellular process ofself-digestion of defective organelles to provide materialrecycling or energy for cell survival. Autophagy hasbeen implicated in the pathophysiology of many humandisorders including hepatic fibrosis. However, the exactrelationships between autophagy and hepatic fibrosisare not totally clear and need further investigations.A new therapeutic target for liver fibrosis could bedeveloped with a better understanding of autophagy.

  16. Renin-angiotensin system in the pathogenesis of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Regina Maria Pereira; Robson Augusto Souza dos Santos; Filipi Leles da Costa Dias; Mauro Martins Teixeira; Ana Cristina Sim(o)es e Silva

    2009-01-01

    Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system (RAS) have progressively assumed an important role. Angiotensin (Ang) Ⅱ acts as a profibrotic mediator and Ang-(1-7), the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis,focusing on the putative role of the ACE2-Ang-(1-7)-Mas receptor axis.

  17. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease.

    OpenAIRE

    Zeybel, Müjdat; Hardy, Timothy; Robinson, Stuart M.; Fox, Christopher; Anstee, Quentin M.; Ness, Thomas; Masson, Steven; Masson, Steven; French, Jeremy; White, Steve; Mann, Jelena

    2015-01-01

    Background: Chronic liver injury can lead to the development of liver fibrosis and cirrhosis but only in a minority of patients. Currently, it is not clear which factors determine progression to fibrosis. We investigated whether DNA\\methylation profile as determined by pyrosequencing can distinguish patients with mild from those with advanced/severe fibrosis in non-alcoholic liver disease (NAFLD) and alcoholic liver disease (ALD). To this end, paraffin-embedded liverbiopsies were collected fr...

  18. Color correction for automatic fibrosis quantification in liver biopsy specimens

    Directory of Open Access Journals (Sweden)

    Yuri Murakami

    2013-01-01

    Full Text Available Context: For a precise and objective quantification of liver fibrosis, quantitative evaluations through image analysis have been utilized. However, manual operations are required in most cases for extracting fiber areas because of color variation included in digital pathology images. Aims: The purpose of this research is to propose a color correction method for whole slide images (WSIs of Elastica van Gieson (EVG stained liver biopsy tissue specimens and to realize automated operation of image analysis for fibrosis quantification. Materials and Methods: Our experimental dataset consisted of 38 WSIs of liver biopsy specimens collected from 38 chronic viral hepatitis patients from multiple medical facilities, stained with EVG and scanned at ×20 using a Nano Zoomer 2.0 HT (Hamamatsu Photonics K.K., Hamamatsu, Japan. Color correction was performed by modifying the color distribution of a target WSI so as to fit to the reference, where the color distribution was modeled by a set of two triangle pyramids. Using color corrected WSIs; fibrosis quantification was performed based on tissue classification analysis. Statistical Analysis Used: Spearman′s rank correlation coefficients were calculated between liver stiffness measured by transient elastography and median area ratio of collagen fibers calculated based on tissue classification results. Results: Statistical analysis results showed a significant correlation r = 0.61-0.68 even when tissue classifiers were trained by using a subset of WSIs, while the correlation coefficients were reduced to r = 0.40-0.50 without color correction. Conclusions: Fibrosis quantification accompanied with the proposed color correction method could provide an objective evaluation tool for liver fibrosis, which complements semi-quantitative histologic evaluation systems.

  19. Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease

    Science.gov (United States)

    Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Kumagai, Erina; Sugiyama, Masaya; Korenaga, Masaaki; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aikata, Hiroshi; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Nozaki, Yuichi; Kawaguchi, Takumi; Torimura, Takuji; Abe, Masanori; Hiasa, Yoichi; Fukai, Moto; Kamiyama, Toshiya; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)–1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients. PMID:27363523

  20. Staging of liver fibrosis or cirrhosis: The role of hepaticvenous pressure gradient measurement

    Institute of Scientific and Technical Information of China (English)

    Ki Tae Suk; Dong Joon Kim

    2015-01-01

    Liver fibrosis is a common histological change ofchronic liver injury and it is closely related with portalhypertension which is hemodynamic complication ofchronic liver disease. Currently, liver fibrosis has beenknown as a reversible dynamic process in previousliteratures. Although liver biopsy is a gold standardfor assessing the stage of liver fibrosis, it may notcompletely represent the stage of liver fibrosis becauseof sampling error or semi-quantative measurement.Recent evidences suggested that histologic, clinical,hemodynamic, and biologic features are closelyassociated in patients with chronic liver disease. Hepaticvenous pressure gradient (HVPG) measurement has beenknown as a modality to evaluate the portal pressure.The HVPG measurement has been used clinicallyfor fibrosis diagnosis, risk stratification, preoperativescreening for liver resection, monitoring the efficacy ofmedical treatments, and assessing the prognosis of liverfibrosis. Therefore, the HVPG measurement can be usedto monitor areas the chronic liver disease but also otherimportant areas of chronic liver disease.

  1. Dihydroartemisinin alleviates bile duct ligation-induced liver fibrosis and hepatic stellate cell activation by interfering with the PDGF-βR/ERK signaling pathway.

    Science.gov (United States)

    Chen, Qin; Chen, Lianyun; Kong, Desong; Shao, Jiangjuan; Wu, Li; Zheng, Shizhong

    2016-05-01

    Liver fibrosis represents a frequent event following chronic insult to trigger wound healing responses in the liver. Activation of hepatic stellate cells (HSCs), which is a pivotal event during liver fibrogenesis, is accompanied by enhanced expressions of a series of marker proteins and pro-fibrogenic signaling molecules. Artemisinin, a powerful antimalarial medicine, is extracted from the Chinese herb Artemisia annua L., and can inhibit the proliferation of cancer cells. Dihydroartemisinin (DHA), the major active metabolite of artemisinin, is able to attenuate lung injury and fibrosis. However, the effect of DHA on liver fibrosis remains unclear. The aim of this study was to investigate the effect of DHA on bile duct ligation-induced injury and fibrosis in rats. DHA improved the liver histological architecture and attenuated collagen deposition in the fibrotic rat liver. Experiments in vitro showed that DHA inhibited the proliferation of HSCs and arrested the cell cycle at the S checkpoint by altering several cell-cycle regulatory proteins. Moreover, DHA reduced the protein expressions of a-SMA, α1 (I) collagen and fibronectin, being associated with interference of the platelet-derived growth factor β receptor (PDGF-βR)-mediated ERK pathway. These data collectively revealed that DHA relieved liver fibrosis possibly by targeting HSCs via the PDGF-βR/ERK pathway. DHA may be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis. PMID:27038258

  2. Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis.

    Science.gov (United States)

    Ippolito, Danielle L; AbdulHameed, Mohamed Diwan M; Tawa, Gregory J; Baer, Christine E; Permenter, Matthew G; McDyre, Bonna C; Dennis, William E; Boyle, Molly H; Hobbs, Cheryl A; Streicker, Michael A; Snowden, Bobbi S; Lewis, John A; Wallqvist, Anders; Stallings, Jonathan D

    2016-01-01

    Toxic industrial chemicals induce liver injury, which is difficult to diagnose without invasive procedures. Identifying indicators of end organ injury can complement exposure-based assays and improve predictive power. A multiplexed approach was used to experimentally evaluate a panel of 67 genes predicted to be associated with the fibrosis pathology by computationally mining DrugMatrix, a publicly available repository of gene microarray data. Five-day oral gavage studies in male Sprague Dawley rats dosed with varying concentrations of 3 fibrogenic compounds (allyl alcohol, carbon tetrachloride, and 4,4'-methylenedianiline) and 2 nonfibrogenic compounds (bromobenzene and dexamethasone) were conducted. Fibrosis was definitively diagnosed by histopathology. The 67-plex gene panel accurately diagnosed fibrosis in both microarray and multiplexed-gene expression assays. Necrosis and inflammatory infiltration were comorbid with fibrosis. ANOVA with contrasts identified that 51 of the 67 predicted genes were significantly associated with the fibrosis phenotype, with 24 of these specific to fibrosis alone. The protein product of the gene most strongly correlated with the fibrosis phenotype PCOLCE (Procollagen C-Endopeptidase Enhancer) was dose-dependently elevated in plasma from animals administered fibrogenic chemicals (P < .05). Semiquantitative global mass spectrometry analysis of the plasma identified an additional 5 protein products of the gene panel which increased after fibrogenic toxicant administration: fibronectin, ceruloplasmin, vitronectin, insulin-like growth factor binding protein, and α2-macroglobulin. These results support the data mining approach for identifying gene and/or protein panels for assessing liver injury and may suggest bridging biomarkers for molecular mediators linked to histopathology.

  3. Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model.

    Science.gov (United States)

    Abe, Hiroyuki; Kamimura, Kenya; Kobayashi, Yuji; Ohtsuka, Masato; Miura, Hiromi; Ohashi, Riuko; Yokoo, Takeshi; Kanefuji, Tsutomu; Suda, Takeshi; Tsuchida, Masanori; Aoyagi, Yutaka; Zhang, Guisheng; Liu, Dexi; Terai, Shuji

    2016-01-01

    Liver fibrosis is the final stage of liver diseases that lead to liver failure and cancer. While various diagnostic methods, including the use of serum marker, have been established, no standard therapy has been developed. The objective of this study was to assess the approach of overexpressing matrix metalloproteinase-13 gene (MMP13) in rat liver to prevent liver fibrosis progression. A rat liver fibrosis model was established by ligating the bile duct, followed by liver-targeted hydrodynamic gene delivery of a MMP13 expression vector, containing a CAG promoter-MMP13-IRES-tdTomato-polyA cassette. After 14 days, the serum level of MMP13 peaked at 71.7 pg/ml in MMP13-treated group, whereas the nontreated group only showed a level of ~5 pg/ml (P sirius red showed a statistically larger volume of fibrotic tissue in the nontreated group compared to that of MMP13-treated rats (P < 0.05). These results suggest that the liver-targeted hydrodynamic delivery of MMP13 gene could be effective in the prevention of liver fibrosis. PMID:26730813

  4. A liver fibrosis cocktail? Psoriasis, methotrexate and genetic hemochromatosis

    Directory of Open Access Journals (Sweden)

    Morley Nick

    2005-11-01

    Full Text Available Abstract Background Pathologists are often faced with the dilemma of whether to recommend continuation of methotrexate therapy for psoriasis within the context of an existing pro-fibrogenic risk factor, in this instance, patients with genetic hemochromatosis. Case presentations We describe our experience with two male psoriatic patients (A and B on long term methotrexate therapy (cumulative dose A = 1.56 gms and B = 7.88 gms with hetero- (A and homozygous (B genetic hemochromatosis. These patients liver function were monitored with routine biochemical profiling; apart from mild perivenular fibrosis in one patient (B, significant liver fibrosis was not identified in either patient with multiple interval percutaneous liver biopsies; in the latter instance this patient (B had an additional risk factor of partiality to alcohol. Conclusion We conclude that methotrexate therapy is relatively safe in patients with genetic hemochromatosis, with no other risk factor, but caution that the risk of fibrosis be monitored, preferably by non-invasive techniques, or by liver biopsy.

  5. Non-invasive assessment of liver fibrosis in chronic liver diseases: Implementation in clinical practice and decisional algorithms

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani

    2009-01-01

    Chronic hepatitis B and C together with alcoholic and non-alcoholic fatty liver diseases represent the major causes of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications, including decompensation, bleeding and liver cancer. Formation and accumulation of fibrosis in the liver is the common pathway that leads to an evolutive liver disease. Precise definition of liver fibrosis stage is essential for management of the patient in clinical practice since the presence of bridging fibrosis represents a strong indication for antiviral therapy for chronic viral hepatitis, while cirrhosis requires a specific follow-up including screening for esophageal varices and hepatocellular carcinoma. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis but it has some limitations being invasive, costly and prone to sampling errors. Recently, blood markers and instrumental methods have been proposed for the non-invasive assessment of liver fibrosis. However, there are still some doubts as to their implementation in clinical practice and a real consensus on how and when to use them is not still available. This is due to an unsatisfactory accuracy for some of them, and to an incomplete validation for others. Some studies suggest that performance of non-invasive methods for liver fibrosis assessment may increase when they re combined. Combination algorithms of non-invasive methods for assessing liver fibrosis may represent a rational and reliable approach to implement noninvasive assessment of liver fibrosis in clinical practice and to reduce rather than abolish liver biopsies.

  6. Colchicine for alcoholic and non-alcoholic liver fibrosis or cirrhosis

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2001-01-01

    Colchicine is an anti-inflammatory and anti-fibrotic drug. Several randomized clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic as well as non-alcoholic fibrosis and cirrhosis. The objectives were to assess the efficacy of colchicine...... evaluated in randomized trials on mortality, liver related mortality, liver related complications, liver fibrosis markers, liver histology, alcohol consumption, quality of life, and health economics in patients with alcoholic and non-alcoholic fibrosis or cirrhosis....

  7. Liver fibrosis can be assessed by non-invasive ultrasound elastography

    DEFF Research Database (Denmark)

    Thielsen, Peter; Wilkens, Rune; Rafaelsen, Søren Rafael;

    2014-01-01

    Diagnosis and assessment of liver fibrosis is of great importance for initiating treatment and starting hepatocellular carcinoma surveillance in patients with established cirrhosis. Liver biopsy is still considered the gold standard for liver fibrosis staging, however; it is far from perfect. Non......-invasive assessment of liver fibrosis is becoming more available and is well tolerated. This review describes the feasibility and reliability of two elastography methods: transient elastography and Acoustic Radiation Force Impulse-elastography....

  8. Nitric oxide in liver fibrosis: The role of inducible nitric oxide synthase.

    Science.gov (United States)

    Iwakiri, Yasuko

    2015-12-01

    The inducible form of nitric oxide synthase (iNOS) is expressed in hepatic cells in pathological conditions. Its induction is involved in the development of liver fibrosis, and thus iNOS could be a therapeutic target for liver fibrosis. This review summarizes the role of iNOS in liver fibrosis, focusing on 1) iNOS biology, 2) iNOS-expressing liver cells, 3) iNOS-related therapeutic strategies, and 4) future directions.

  9. Molecular Cues Guiding Matrix Stiffness in Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Takaoki Saneyasu

    2016-01-01

    Full Text Available Tissue and matrix stiffness affect cell properties during morphogenesis, cell growth, differentiation, and migration and are altered in the tissue remodeling following injury and the pathological progression. However, detailed molecular mechanisms underlying alterations of stiffness in vivo are still poorly understood. Recent engineering technologies have developed powerful techniques to characterize the mechanical properties of cell and matrix at nanoscale levels. Extracellular matrix (ECM influences mechanical tension and activation of pathogenic signaling during the development of chronic fibrotic diseases. In this short review, we will focus on the present knowledge of the mechanisms of how ECM stiffness is regulated during the development of liver fibrosis and the molecules involved in ECM stiffness as a potential therapeutic target for liver fibrosis.

  10. Molecular Cues Guiding Matrix Stiffness in Liver Fibrosis

    Science.gov (United States)

    Saneyasu, Takaoki; Akhtar, Riaz

    2016-01-01

    Tissue and matrix stiffness affect cell properties during morphogenesis, cell growth, differentiation, and migration and are altered in the tissue remodeling following injury and the pathological progression. However, detailed molecular mechanisms underlying alterations of stiffness in vivo are still poorly understood. Recent engineering technologies have developed powerful techniques to characterize the mechanical properties of cell and matrix at nanoscale levels. Extracellular matrix (ECM) influences mechanical tension and activation of pathogenic signaling during the development of chronic fibrotic diseases. In this short review, we will focus on the present knowledge of the mechanisms of how ECM stiffness is regulated during the development of liver fibrosis and the molecules involved in ECM stiffness as a potential therapeutic target for liver fibrosis. PMID:27800489

  11. The Dimethylnitrosamine Induced Liver Fibrosis Model in the Rat.

    Science.gov (United States)

    Chooi, Kum Fai; Kuppan Rajendran, Dinesh Babu; Phang, Siew Siang Gary; Toh, Han Hui Alden

    2016-01-01

    Four to six week old, male Wistar rats were used to produce animal models of liver fibrosis. The process requires four weeks of administration of 10 mg/kg dimethylnitrosamine (DMN), given intraperitoneally for three consecutive days per week. Intraperitoneal injections were performed in the fume hood as DMN is a known hepatoxin and carcinogen. The model has several advantages. Firstly, liver changes can be studied sequentially or at particular stages of interest. Secondly, the stage of liver disease can be monitored by measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes. Thirdly, the severity of liver damage at different stages can be confirmed by sacrifice of animals at designated time points, followed by histological examination of Masson's Trichome stained liver tissues. After four weeks of DMN dosing, the typical fibrosis score is 5 to 6 on the Ishak scale. The model can be reproduced consistently and has been widely used to assess the efficacy of potential anti-fibrotic agents. PMID:27340889

  12. Zingiber officinale acts as a nutraceutical agent against liver fibrosis

    Directory of Open Access Journals (Sweden)

    Hashem Reem M

    2011-06-01

    Full Text Available Abstract Background/objective Zingiber officinale Roscoe (ginger (Zingiberaceae has been cultivated for thousands of years both as a spice and for medicinal purposes. Ginger rhizomes successive extracts (petroleum ether, chloroform and ethanol were examined against liver fibrosis induced by carbon tetrachloride in rats. Results The evaluation was done through measuring antioxidant parameters; glutathione (GSH, total superoxide dismutase (SOD and malondialdehyde (MDA. Liver marker enzymes; succinate and lactate dehydrogenases (SDH and LDH, glucose-6-phosphatase (G-6-Pase, acid phosphatase (AP, 5'- nucleotidase (5'NT and liver function enzymes; aspartate and alanine aminotransferases (AST and ALT as well as cholestatic markers; alkaline phosphatase (ALP, gamma glutamyl transferase (GGT, total bilirubin were estimated. Liver histopathological analysis and collagen content were also evaluated. Treatments with the selected extracts significantly increased GSH, SOD, SDH, LDH, G-6-Pase, AP and 5'NT. However, MDA, AST, ALT ALP, GGT and total bilirubin were significantly decreased. Conclusions Extracts of ginger, particularly the ethanol one resulted in an attractive candidate for the treatment of liver fibrosis induced by CCl4. Further studies are required in order to identify the molecules responsible of the pharmacological activity.

  13. Pentoxifylline inhibits liver fibrosis via hedgehog signaling pathway.

    Science.gov (United States)

    Li, Hui; Hua, Juan; Guo, Chun-Xia; Wang, Wei-Xian; Wang, Bao-Ju; Yang, Dong-Liang; Wei, Ping; Lu, Yin-Ping

    2016-06-01

    Infection of schistosomiasis japonica may eventually lead to liver fibrosis, and no effective antifibrotic therapies are available but liver transplantation. Hedgehog (HH) signaling pathway has been involved in the process and is a promising target for treating liver fibrosis. This study aimed to explore the effects of pentoxifylline (PTX) on liver fibrosis induced by schistosoma japonicum infection by inhibiting the HH signaling pathway. Phorbol12-myristate13-acetate (PMA) was used to induce human acute mononuclear leukemia cells THP-1 to differentiate into macrophages. The THP-1-derived macrophages were stimulated by soluble egg antigen (SEA), and the culture supernatants were collected for detection of activation of macrophages. Cell Counting Kit-8 (CCK-8) was used to detect the cytotoxicity of the culture supernatant and PTX on the LX-2 cells. The LX-2 cells were administered with activated culture supernatant from macrophages and(or) PTX to detect the transforming growth factor-β gene expression. The mRNA expression of shh and gli-1, key parts in HH signaling pathway, was detected. The mRNA expression of shh and gli-1 was increased in LX-2 cells treated with activated macrophages-derived culture supernatant, suggesting HH signaling pathway may play a key role in the activation process of hepatic stellate cells (HSCs). The expression of these genes decreased in LX-2 cells co-cultured with both activated macrophages-derived culture supernatant and PTX, indicating PTX could suppress the activation process of HSCs. In conclusion, these data provide evidence that PTX prevents liver fibrogenesis in vitro by the suppression of HH signaling pathway. PMID:27376806

  14. Loss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis

    International Nuclear Information System (INIS)

    Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results: We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.

  15. Systems level analysis and identification of pathways and networks associated with liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Mohamed Diwan M AbdulHameed

    Full Text Available Toxic liver injury causes necrosis and fibrosis, which may lead to cirrhosis and liver failure. Despite recent progress in understanding the mechanism of liver fibrosis, our knowledge of the molecular-level details of this disease is still incomplete. The elucidation of networks and pathways associated with liver fibrosis can provide insight into the underlying molecular mechanisms of the disease, as well as identify potential diagnostic or prognostic biomarkers. Towards this end, we analyzed rat gene expression data from a range of chemical exposures that produced observable periportal liver fibrosis as documented in DrugMatrix, a publicly available toxicogenomics database. We identified genes relevant to liver fibrosis using standard differential expression and co-expression analyses, and then used these genes in pathway enrichment and protein-protein interaction (PPI network analyses. We identified a PPI network module associated with liver fibrosis that includes known liver fibrosis-relevant genes, such as tissue inhibitor of metalloproteinase-1, galectin-3, connective tissue growth factor, and lipocalin-2. We also identified several new genes, such as perilipin-3, legumain, and myocilin, which were associated with liver fibrosis. We further analyzed the expression pattern of the genes in the PPI network module across a wide range of 640 chemical exposure conditions in DrugMatrix and identified early indications of liver fibrosis for carbon tetrachloride and lipopolysaccharide exposures. Although it is well known that carbon tetrachloride and lipopolysaccharide can cause liver fibrosis, our network analysis was able to link these compounds to potential fibrotic damage before histopathological changes associated with liver fibrosis appeared. These results demonstrated that our approach is capable of identifying early-stage indicators of liver fibrosis and underscore its potential to aid in predictive toxicity, biomarker identification, and to

  16. Systems Level Analysis and Identification of Pathways and Networks Associated with Liver Fibrosis

    Science.gov (United States)

    AbdulHameed, Mohamed Diwan M.; Tawa, Gregory J.; Kumar, Kamal; Ippolito, Danielle L.; Lewis, John A.; Stallings, Jonathan D.; Wallqvist, Anders

    2014-01-01

    Toxic liver injury causes necrosis and fibrosis, which may lead to cirrhosis and liver failure. Despite recent progress in understanding the mechanism of liver fibrosis, our knowledge of the molecular-level details of this disease is still incomplete. The elucidation of networks and pathways associated with liver fibrosis can provide insight into the underlying molecular mechanisms of the disease, as well as identify potential diagnostic or prognostic biomarkers. Towards this end, we analyzed rat gene expression data from a range of chemical exposures that produced observable periportal liver fibrosis as documented in DrugMatrix, a publicly available toxicogenomics database. We identified genes relevant to liver fibrosis using standard differential expression and co-expression analyses, and then used these genes in pathway enrichment and protein-protein interaction (PPI) network analyses. We identified a PPI network module associated with liver fibrosis that includes known liver fibrosis-relevant genes, such as tissue inhibitor of metalloproteinase-1, galectin-3, connective tissue growth factor, and lipocalin-2. We also identified several new genes, such as perilipin-3, legumain, and myocilin, which were associated with liver fibrosis. We further analyzed the expression pattern of the genes in the PPI network module across a wide range of 640 chemical exposure conditions in DrugMatrix and identified early indications of liver fibrosis for carbon tetrachloride and lipopolysaccharide exposures. Although it is well known that carbon tetrachloride and lipopolysaccharide can cause liver fibrosis, our network analysis was able to link these compounds to potential fibrotic damage before histopathological changes associated with liver fibrosis appeared. These results demonstrated that our approach is capable of identifying early-stage indicators of liver fibrosis and underscore its potential to aid in predictive toxicity, biomarker identification, and to generally identify

  17. A comparison of MR elastography and 31P MR spectroscopy with histological staging of liver fibrosis

    International Nuclear Information System (INIS)

    Conventional imaging techniques are insensitive to liver fibrosis. This study assesses the diagnostic accuracy of MR elastography (MRE) stiffness values and the ratio of phosphomonoesters (PME)/phosphodiesters (PDE) measured using 31P spectroscopy against histological fibrosis staging. The local research ethics committee approved this prospective, blinded study. A total of 77 consecutive patients (55 male, aged 49 ± 11.5 years) with a clinical suspicion of liver fibrosis underwent an MR examination with a liver biopsy later the same day. Patients underwent MRE and 31P spectroscopy on a 1.5 T whole body system. The liver biopsies were staged using an Ishak score for chronic hepatitis or a modified NAS fibrosis score for fatty liver disease. MRE increased with and was positively associated with fibrosis stage (Spearman's rank = 0.622, P 31P MR spectroscopy and fibrosis stage. circle Magnetic resonance elastography (MRE) and MR spectroscopy can both assess the liver. (orig.)

  18. Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease.

    Science.gov (United States)

    Lombardi, Rosa; Buzzetti, Elena; Roccarina, Davide; Tsochatzis, Emmanuel A

    2015-10-21

    Alcoholic liver disease (ALD) consists of a broad spectrum of disorders, ranging from simple steatosis to alcoholic steatohepatitis and cirrhosis. Fatty liver develops in more than 90% of heavy drinkers, however only 30%-35% of them develop more advanced forms of ALD. Therefore, even if the current "gold standard" for the assessment of the stage of alcohol-related liver injury is histology, liver biopsy is not reasonable in all patients who present with ALD. Currently, although several non-invasive fibrosis markers have been suggested as alternatives to liver biopsy in patients with ALD, none has been sufficiently validated. As described in other liver disease, the diagnostic accuracy of such tests in ALD is acceptable for the diagnosis of significant fibrosis or cirrhosis but not for lesser fibrosis stages. Existing data suggest that the use of non-invasive tests could be tailored to first tier screening of patients at risk, in order to diagnose early patients with progressive liver disease and offer targeted interventions for the prevention of decompensation. We review these tests and critically appraise the existing evidence.

  19. Attenuation of carbon tetrachloride-induced hepatic fibrosis by glycine, vitamin E and vitamin C

    Directory of Open Access Journals (Sweden)

    Aziza A. Saad

    2014-09-01

    Conclusion: The results of this study confirmed the ameliorative effects of vitamin E plus C combination and glycine supplements against liver fibrosis in rats induced by CCl4 [J Exp Integr Med 2014; 4(3.000: 180-186

  20. Chloroquine improved carbon tetrachloride-induced liver fibrosis through its inhibition of the activation of hepatic stellate cells: role of autophagy.

    Science.gov (United States)

    He, Wei; Wang, Bin; Yang, Jing; Zhuang, Yun; Wang, Liangzhi; Huang, Xiaodan; Chen, Jianping

    2014-01-01

    Autophagy is involved in the activation of hepatic stellate cells (HSCs), which is the key process of liver fibrosis. We reasoned that chloroquine, based on its ability to inhibit autophagy, might exert beneficial effects in liver fibrosis. Liver fibrosis in rats was induced by carbon tetrachloride (CCl4). Rats were divided into three groups, a normal control group (N group), model group (M group), and chloroquine group (CQ group). Liver fibrosis in the rats was evaluated by hematoxyline-eosin (H&E) and Masson staining. The activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) were determined using an automated biochemistry analyzer. Total hepatic hydroxyproline levels were determined with a kit. The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) were detected by immunofluorescence staining, and the expressions of LC3-II and p62 were determined by Western blotting. Compared with N group, M group showed impaired liver function, liver fibrosis, increased hydroxyproline content, up-regulated expressions of α-SMA and TGF-β1, which have been reported to be pro-fibrogenic genes in vivo, and increased autophagy flux as indicated by the accumulation of LC3-II and degradation of p62. These changes were attenuated by chloroquine treatment. Chloroquine exerts beneficial effects in CCl4-induced liver fibrosis. The mechanism of action includes inhibition of autophagy pathways and inhibition of activation of HSCs. PMID:25177034

  1. Cystic fibrosis-related liver disease: a single-center experience

    OpenAIRE

    Paula Catarino Costa; Celeste Canha Barreto; Luisa Pereira; Maria Luisa Lobo; Maria Adília Costa; Ana Isabel Gouveia Lopes

    2011-01-01

    Prospective studies concerning liver disease in pediatric cystic fibrosis patients are scarce. The present study aimed to describe the prevalence and clinical expression of cystic fibrosis - related liver disease, in a cohort of 62 pediatric patients. Descriptive study, resulting from the prospective evaluation, between 1994 and 2009, of 62 pediatric patients (age <18 years) with cystic fibrosis. The follow-up protocol included a clinical assessment every 2 months, liver function tests eve...

  2. Tetrathiomolybdate protects against bile duct ligation-induced cholestatic liver injury and fibrosis.

    Science.gov (United States)

    Song, Ming; Song, Zhenyuan; Barve, Shirish; Zhang, Jingwen; Chen, Theresa; Liu, Marcia; Arteel, Gavin E; Brewer, George J; McClain, Craig J

    2008-05-01

    Tetrathiomolybdate (TM), a potent copper-chelating drug, was initially developed for the treatment of Wilson's disease. Our working hypothesis is that the fibrotic pathway is copper-dependent. Because biliary excretion is the major pathway for copper elimination, a bile duct ligation (BDL) mouse model was used to test the potential protective effects of TM. TM was given in a daily dose of 0.9 mg/mouse by means of intragastric gavage 5 days before BDL. All the animals were killed 5 days after surgery. Plasma liver enzymes and total bilirubin were markedly decreased in TM-treated BDL mice. TM also inhibited the increase in plasma levels of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 seen in BDL mice. Cholestatic liver injury was markedly attenuated by TM treatment as shown by histology. Hepatic collagen deposition was significantly decreased, and it was paralleled by a significant suppression of hepatic smooth muscle alpha-actin and fibrogenic gene expression in TM-treated BDL mice. Although the endogenous antioxidant ability was enhanced, oxidative stress as shown by malondialdehyde and 4-hydroxyalkenals, hepatic glutathione/oxidized glutathione ratio, was not attenuated by TM treatment, suggesting the protective mechanism of TM may be independent of oxidative stress. In summary, TM attenuated BDL-induced cholestatic liver injury and fibrosis in mice, in part by inhibiting TNF-alpha and TGF-beta1 secretion. The protective mechanism seems to be independent of oxidative stress. Our data provide further evidence that TM might be a potential therapy for hepatic fibrosis.

  3. Severe liver dysfunction in an infant with cystic fibrosis masquerading as metabolic liver disease

    Directory of Open Access Journals (Sweden)

    K P Srikanth

    2016-01-01

    Full Text Available We present a rare presentation of cystic fibrosis with neonatal cholestasis. Histological features of mucoviscidosis were present in liver involving the biliary tract, intestinal mucosa, pancreas, and lung. Besides, there was a rare association with autosomal dominant type of polycystic renal disease.

  4. FEASIBILITY OF DIAGNOSING AND STAGING LIVER FIBROSIS WITH DIFFUSION WEIGHTED IMAGING

    Institute of Scientific and Technical Information of China (English)

    Nai-yi Zhu; Ke-min Chen; Wei-min Chai; Wei-xia Li; Lian-jun Du

    2008-01-01

    Objective To assess the clinical feasibility of diagnosing and staging liver fibrosis by apparent diffusion coefficient (ADC). Methods Totally, 43 patients (mean age 29.3 years) with chronic hepatitis by liver biopsy and 7 healthy controls (mean age 39.9 years) underwent liver diffusion weighted imaging (DWI) with four b values: 0, 200, 500, and 1000 s/mm2 respectively. The liver fibrosis was staged according to Ishak fibrosis stage. The ADC value of liver fibrosis patients and healthy controls was compared. The correlation of ADC value and liver fibrosis staging was analyzed.Result The histological staging showed 8 stage 1 patients, 10 stage 2 patients, 6 stage 3 patients, 9 stage 4 patients, 8 stage 5 patients and 2 stage 6 patients. The mean ADC value of liver fibrosis patients was significantly lower than that of healthy controls except for stage 1 group (P < 0.05). There was a negative correlation between liver fibrosis staging and ADC value (r = -0.697 with b=500 s/mm2, P < 0.01). Receiver operating characteristic (ROC) curve of ADC value of advanced liver fibrosis (Ishak stage F3 and higher) showed that area under curve = 0.913, 0.825, and 0.794 with b=500, 1000, and 200 s/mm2, respectively (95% confidence interval: 83.6%-99.0%, 70.7%-94.3%, 66.50%-92.4%; P < 0.05). When b value was 500 s/mm2, the sensitivity (84%) and specificity (800%) of DWI for diagnosis of advanced liver fibrosis were the highest.Conclusion DWI is proved to be a useful clinical tool in the quantitative evaluation of liver fibrosis and in the prediction of the process of liver fibrosis with the recommendable b value (500 s/mm2).

  5. Gefitinib attenuates murine pulmonary fibrosis induced by bleomycin

    Institute of Scientific and Technical Information of China (English)

    WANG Ping; TIAN Qing; LIANG Zhi-xin; YANG Zhen; XU Shu-feng; SUN Ji-ping; CHEN Liang-an

    2010-01-01

    Background Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is an effective treatment for epithelial tumors, including non-small cell lung cancer (NSCLC), and is generally well tolerated.However, some clinical trials revealed that gefitinib exposure caused lung fibrosis, a severe adverse reaction.This study investigated the effect of gefitinib on lung fibrosis in mice.Methods We generated a mouse model of lung fibrosis induced by bleomycin to investigate the fibrotic effect of gefitinib.C57BL/6 mice were injected intratracheally with bleomycin or saline, with intragastric administration of gefitinib or saline.Lung tissues were harvested on day 14 or 21 for histology and genetic analysis.Results The histological results showed that bleomycin successfully induced lung fibrosis in mice, and gefitinib prevented lung fibrosis and suppressed the proliferation of S100A4-positive fibroblast cells.In addition, Western blotting analysis revealed that gefitinib decreased the expression of phosphorylated EGFR (p-EGFR).Furthermore, quantitative real-time PCR (qRT-PCR) demonstrated that gefitinib inhibited the accumulation of collagens Ⅰ and Ⅲ.Conclusions These results reveal that gefitinib reduces pulmonary fibrosis induced by bleomycin in mice and suggest that administration of small molecule EGFR tyrosine kinase inhibitors has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that targeting tyrosine kinase receptors might be useful for the treatment of pulmonary fibrosis in humans.

  6. Correlation between ultrasound imaging and serum markers of liver fibrosis in patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Jian-Xia Liu

    2016-01-01

    Objective:To investigate the clinical value of ultrasonic imaging in the assessment of liver fibrosis in patients with chronic hepatitis B. Methods:A total of 20 cases of liver biopsy in chronic hepatitis B, according to the degree of hepatic fibrosis were divided into mild hepatic fibrosis group, moderate fibrosis group, severe fibrosis group, the other selected healthy volunteers as control group, using color Doppler ultrasound, the use of imaging technology and automatic tracking. Strengthen the quantitative analysis, using the second generation microbubble contrast agent SonoVue contrast analysis, contrast agent reach the portal time (PVAT), hepatic artery time (HAAT), hepatic vein (HVVT), the calculation time of hepatic arteriovenous transit time (VAT) and hepatic portal vein transit time (VVT), using chemiluminescence detection of serum liver fiber hyaluronic acid (HA), laminin (LN) and collagen type IV (CIV) index. Results:there was no significant difference in HAAT, PVAT, VAT, VVT and HVAT in all groups, and there was no significant difference, mild, moderate and severe liver fibrosis group, and HA, LN and C levels were significantly higher than those in control group. Conclusion:serum liver fibrosis indexes can guide the degree of liver fibrosis. The ultrasound contrast can reflect the changes of liver blood flow dynamics, and it has a certain guiding significance to the assessment of the degree of liver fibrosis, the monitoring of the disease and the clinical treatment.

  7. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.

    Directory of Open Access Journals (Sweden)

    George M Philips

    Full Text Available OBJECTIVE: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3 develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/- mice to investigate the hypothesis that activation of the hedgehog (Hh signaling pathway promotes development of both liver fibrosis and HCC. METHODS: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/- mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. RESULTS: Unlike controls, Mdr2(-/- mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. CONCLUSIONS: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.

  8. Losartan attenuates renal interstitial fibrosis and tubular cell apoptosis in a rat model of obstructive nephropathy.

    Science.gov (United States)

    He, Ping; Li, Detian; Zhang, Beiru

    2014-08-01

    Ureteral obstruction leads to renal injury and progresses to irreversible renal fibrosis, with tubular cell atrophy and apoptosis. There is conflicting evidence concerning whether losartan (an angiotensin II type I receptor antagonist) mitigates renal interstitial fibrosis and renal tubular epithelial cell apoptosis following unilateral ureteral obstruction (UUO) in animal models. The aim of this study was to investigate the effect and mechanism of losartan on renal tubular cell apoptosis and renal fibrosis in a rat model of UUO. The rats were subjected to UUO by ureteral ligation and were treated with dimethyl sulfoxide (control) or losartan. The controls underwent sham surgery. The renal tissues were collected 3, 5, 7 and 14 days after surgery for measurement of various indicators of renal fibrosis. UUO increased the expression levels of α‑smooth muscle actin and collagen I, and the extent of renal tubular fibrosis and apoptosis in a time‑dependent manner. Losartan treatment partially attenuated these responses. Progression of renal interstitial fibrosis was accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3) and altered the expression levels of two apoptosis‑related proteins (Bax and Bcl2). Losartan treatment also partially attenuated these responses. The results indicated that losartan attenuated renal fibrosis and renal tubular cell apoptosis in a rat model of UUO. This effect appeared to be mediated by partial blockage of STAT3 phosphorylation.

  9. Hepatocellular carcinoma complicating cystic fibrosis related liver disease.

    LENUS (Irish Health Repository)

    O'Donnell, D H

    2012-02-01

    Early diagnosis and treatment of the respiratory and gastrointestinal complications of cystic fibrosis (CF) have led to improved survival with many patients living beyond the fourth decade. Along with this increased life expectancy is the risk of further disease associated with the chronic manifestations of their condition. We report a patient with documented CF related liver disease for which he was under routine surveillance that presented with histologically proven hepatocellular carcinoma (HCC). It is important that physicians are aware of this association as increased vigilance may lead to earlier diagnosis and perhaps, a better outcome.

  10. Long non-coding RNA APTR promotes the activation of hepatic stellate cells and the progression of liver fibrosis

    International Nuclear Information System (INIS)

    In this study, we aimed at assessing a role of Alu-mediated p21 transcriptional regulator (APTR) in hepatofibrogenesis. APTR was upregulated in fibrotic liver samples and activated hepatic stellate cells (HSCs). Knockdown of APTR inhibited the activation of HSCs in vitro and mitigated the accumulation of collagen in vivo. Importantly, APTR silencing could abrogate TGF-β1-induced upregulation of α-SMA in HSCs. In addition, inhibition of cell cycle and cell proliferation by APTR knockdown was attenuated by p21 siRNA1 in primary HSCs. Finally, serum APTR levels were increased in patients with liver cirrhosis, indicating a potential biomarker for liver cirrhosis. Collectively, evidence is proposed for a new biological role of APTR in hepatofibrogenesis. - Highlights: • APTR is upregulated in fibrotic liver tissues and activated HSCs. • APTR silencing inhibits HSC activation and the progression of liver fibrosis. • Antifibrotic effect of APTR silencing is achieved by increasing p21

  11. The role of relaxin in the regulation of human liver and kidney fibrosis

    OpenAIRE

    Hayden, Annette Louise

    2009-01-01

    Liver fibrosis has a range of aetiologies and is a global cause of mortality. A critical effect of liver fibrosis which also increases mortality is portal hypertension. The hepatic stellate cell is accepted as a major progenitor of liver myofibroblasts, which have been shown to be a major source of collagen and extracellular matrix proteins that disrupt liver architecture and function. Relaxin is a hormone involved in remodelling of extracellular matrix in the uterus and cer...

  12. Signal Transduction of Platelet-Induced Liver Regeneration and Decrease of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Soichiro Murata

    2014-03-01

    Full Text Available Platelets contain three types of granules: alpha granules, dense granules, and lysosomal granules. Each granule contains various growth factors, cytokines, and other physiological substances. Platelets trigger many kinds of biological responses, such as hemostasis, wound healing, and tissue regeneration. This review presents experimental evidence of platelets in accelerating liver regeneration and improving liver fibrosis. The regenerative effect of liver by platelets consists of three mechanisms; i.e., the direct effect on hepatocytes, the cooperative effect with liver sinusoidal endothelial cells, and the collaborative effect with Kupffer cells. Many signal transduction pathways are involved in hepatocyte proliferation. One is activation of Akt and extracellular signal-regulated kinase (ERK1/2, which are derived from direct stimulation from growth factors in platelets. The other is signal transducer and activator of transcription-3 (STAT3 activation by interleukin (IL-6 derived from liver sinusoidal endothelial cells and Kupffer cells, which are stimulated by contact with platelets during liver regeneration. Platelets also improve liver fibrosis in rodent models by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cyclic adenosine monophosphate (cyclic AMP is increased by adenosine through its receptors on hepatic stellate cells, resulting in inactivation of these cells. Adenosine is produced by the degradation of adenine nucleotides such as adenosine diphosphate (ADP and adenosine tri-phosphate (ATP, which are stored in abundance within the dense granules of platelets.

  13. Liver Hemangioma Might Lead to overestimation of Liver Fibrosis by Fibroscan; A Missed Issue in Two Cases

    Directory of Open Access Journals (Sweden)

    Seyed Hossein Aalaei-Andabili

    2012-06-01

    Full Text Available Background: The assessment of liver fibrosis is an important way for prediction of liver disease progression and patient’s prognosis. Liver stiffness measurement (LSM is strongly associated with stage of liver diseases. Overestimation of liver fibrosis in heart failure has been reported. We would like to introduce a new leading cause of liver fibrosis overestimation by presentation of two cases.Case Presentation: One case with right lobe hemangioma has an overestimation of liver fibrosis. The result completely changed when Fibroscan was performed in patient’s left lobe. Interestingly, another case with left lobe hemangioma had overestimation of fibrosis in her left lobe but, right lob Fibroscan was normal.Conclusions: We found that liver hemangioma may leads to overestimation of liver stiffness and the correct inspection of liver echogenicity before any interpretation of high liver stiffness is recommended. We suggest that patient with higher level of Fibroscan score repeat it in other sides of the liver. Also, they should be evaluated by sonography for ruling out of possible confounders such as hepatic hemangioma..

  14. Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis.

    NARCIS (Netherlands)

    Berends, M.A.M.; Snoek, J.; Jong, E.M.G.J. de; Krieken, J.H.J.M. van; Knegt, R.J. de; Oijen, M.G.H. van; Kerkhof, P.C.M. van de; Drenth, J.P.H.

    2007-01-01

    BACKGROUND: Methotrexate (MTX) use is associated with hepatic fibrosis in psoriasis patients. To monitor this serial liver biopsies were performed. The Fibroscan and the Fibrotest are two novel, non-invasive methods that might be able to assess MTX-induced hepatic fibrosis. AIM: Evaluating the accur

  15. Effects of glycyrrhetinic acid on collagen metabolism of hepatic stellate cells at different stages of liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Ji Yao Wang; Qi Sheng Zhang; Ji Sheng Guo; Mei Yu Hu

    2001-01-01

    @@ INTRODUCTIONLiver fibrosis is a dynamic course leading tocirrhosis from a various chronic liver diseases. Thepathological basis of fibrosis is the disturbance ofproduction and degradation of the extracellularmatrix (ECM), which causes accumulation of ECMin the liver[1,2].

  16. Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis.

    Science.gov (United States)

    Li, Xing; Wu, Xiao-Qin; Xu, Tao; Li, Xiao-Feng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun

    2016-09-01

    Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 was maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis. PMID:27396813

  17. The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies.

    Directory of Open Access Journals (Sweden)

    Jun eXu

    2014-07-01

    Full Text Available Liver fibrosis results from dysregulation of normal wound healing, inflammation, activation of myofibroblasts and deposition of extracellular matrix (ECM. Chronic liver injury causes death of hepatocytes and formation of apoptotic bodies, which in turn, release factors that recruit inflammatory cells (neutrophils, monocytes, macrophages, and lymphocytes to the injured liver. Hepatic macrophages (Kupffer cells produce TGF1 and other inflammatory cytokines that activate Collagen Type I producing myofibroblasts, which are not present in the normal liver. Secretion of TGF1 and activation of myofibroblasts play a critical role in the pathogenesis of liver fibrosis of different etiologies. Although the composition of fibrogenic myofibroblasts varies dependent on etiology of liver injury, liver resident Hepatic Stellate Cells (HSCs and Portal Fibroblasts (PFs are the major source of myofibroblasts in fibrotic liver in both experimental models of liver fibrosis and in patients with liver disease. Several studies have demonstrated that hepatic fibrosis can reverse upon cessation of liver injury. Regression of liver fibrosis is accompanied by the disappearance of fibrogenic myofibroblasts followed by resorption of the fibrous scar. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g. stop collagen production and partially restore expression of lypogenic genes. Resolution of liver fibrosis is associated with recruitment of macrophages that secrete matrix-degrading enzymes (matrix metalloproteinase, collagenases and are responsible for fibrosis resolution. However, prolonged/repeated liver injury may cause irreversible crosslinking of ECM and formation of uncleavable collagen fibers. Advanced fibrosis progresses to cirrhosis and hepatocellular carcinoma (HCC. The current review will summarize the role and contribution of different cell types to populations of fibrogenic myofibroblasts in fibrotic liver.

  18. The pattern of fibrosis in the acinar zone 3 areas in early alcoholic liver disease

    DEFF Research Database (Denmark)

    Junge, Jette; Horn, T; Vyberg, M;

    1991-01-01

    The degree of fibrosis and the pattern of collagen distribution in the acinar zone 3, as well as the thickness of the terminal hepatic vein walls (THV) were analyzed in 48 consecutive liver needle biopsies from 48 alcoholics with preserved liver architecture. The fibrosis occurred to more or less...

  19. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2001-01-01

    The majority of liver fibrosis and liver cirrhosis cases in the Western World is caused by alcohol and hepatotoxic viruses. Colchicine is an anti-inflammatory and anti-fibrotic medication. Several randomised clinical trials have addressed the question whether colchicine has any efficacy in patients...... with alcoholic as well as non-alcoholic fibrosis and cirrhosis....

  20. Baseline prevalence and predictors of liver fibrosis among HIV-positive individuals

    DEFF Research Database (Denmark)

    Matthews, G V; Neuhaus, J; Bhagani, S;

    2015-01-01

    deferred antiretroviral therapy (ART) on liver fibrosis progression. METHODS: Sites in the Strategic Timing of AntiRetroviral Treatment (START) study with access to FibroScan® were invited to participate in the Liver Fibrosis Progression Substudy. All substudy participants underwent FibroScan® at baseline...

  1. Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells

    Directory of Open Access Journals (Sweden)

    Xiang Y. Kong

    2014-03-01

    Full Text Available Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1gt/gt mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1gt/gt liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1gt/gt Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1gt/gt mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.

  2. Lack of hepcidin expression attenuates steatosis and causesfibrosis in the liver

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    AIM To investigate the role of key iron-regulatoryprotein, hepcidin in non-alcoholic fatty liver disease(NAFLD).METHODS: Hepcidin (Hamp1 ) knockout and floxedcontrol mice were administered a high fat and highsucrose (HFS) or a regular control diet for 3 or 7 mo.Steatosis, triglycerides, fibrosis, protein and gene expressionin mice livers were determined by histologicaland biochemical techniques, western blotting and realtimepolymerase chain reaction.RESULTS: Knockout mice exhibited hepatic ironaccumulation. Despite similar weight gains, HFS feedinginduced hepatomegaly in floxed, but not knockout,mice. The livers of floxed mice exhibited higher levelsof steatosis, triglycerides and c-Jun N-terminal kinase(JNK) phosphorylation than knockout mice. In contrast,a significant increase in fibrosis was observed inknockout mice livers within 3 mo of HFS administration.The hepatic gene expression levels of sterol regulatory element-binding protein-1c and fat-specific protein-27,but not peroxisome proliferator-activated receptoralphaor microsomal triglyceride transfer protein, wereattenuated in HFS-fed knockout mice. Knockout micefed with regular diet displayed increased carnitinepalmitoyltransferase-1a and phosphoenolpyruvatecarboxykinase-1 but decreased glucose-6-phosphataseexpression in the liver. In summary, attenuated steatosiscorrelated with decreased expression of lipogenic andlipid storage genes, and JNK phosphorylation. Deletionof Hamp1 alleles per se modulated hepatic expressionof beta-oxidation and gluconeogenic genes.CONCLUSION: Lack of hepcidin expression inhibitshepatic lipid accumulation and induces early developmentof fibrosis following high fat intake. Hepcidinand iron may play a role in the regulation of metabolicpathways in the liver, which has implications for NAFLDpathogenesis.

  3. Plasma biomarker screening for liver fibrosis with the N-terminal isotope tagging strategy.

    Science.gov (United States)

    Li, ShuLong; Liu, Xin; Wei, Lai; Wang, HuiFen; Zhang, JiYang; Wei, HanDong; Qian, XiaoHong; Jiang, Ying; He, FuChu

    2011-05-01

    A non-invasive diagnostic approach is crucial for the evaluation of severity of liver disease, treatment decisions, and assessing drug efficacy. This study evaluated plasma proteomic profiling via an N-terminal isotope tagging strategy coupled with liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometry measurement to detect liver fibrosis staging. Pooled plasma from different liver fibrosis stages, which were assessed in advance by the current gold-standard of liver biopsy, was quantitatively analyzed. A total of 72 plasma proteins were found to be dysregulated during the fibrogenesis process, and this finding constituted a valuable candidate plasma biomarker bank for follow-up analysis. Validation results of fibronectin by Western blotting reconfirmed the mass-based data. Ingenuity Pathways Analysis showed four types of metabolic networks for the functional effect of liver fibrosis disease in chronic hepatitis B patients. Consequently, quantitative proteomics via the N-terminal acetyl isotope labeling technique provides an effective and useful tool for screening plasma candidate biomarkers for liver fibrosis. We quantitatively monitored the fibrogenesis process in CHB patients. We discovered many new valuable candidate biomarkers for the diagnosis of liver fibrosis and also partly identified the mechanism involved in liver fibrosis disease. These results provide a clearer understanding of liver fibrosis pathophysiology and will also hopefully lead to improvement of clinical diagnosis and treatment.

  4. Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice

    Energy Technology Data Exchange (ETDEWEB)

    Harris, Todd R. [Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 (United States); Bettaieb, Ahmed [Department of Nutrition, University of California, Davis, CA 95616 (United States); Kodani, Sean; Dong, Hua [Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 (United States); Myers, Richard; Chiamvimonvat, Nipavan [Department of Internal Medicine: Cardiovascular, University of California, Davis, CA 95616 (United States); Haj, Fawaz G. [Department of Nutrition, University of California, Davis, CA 95616 (United States); Department of Internal Medicine: Endocrinology, Diabetes and Metabolism, University of California, Davis, CA 95616 (United States); Hammock, Bruce D., E-mail: bdhammock@ucdavis.edu [Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616 (United States)

    2015-07-15

    Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl{sub 4})-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl{sub 4}-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl{sub 4}-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl{sub 4}-treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-(4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy)-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl{sub 4}, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress. - Highlights: • We administer an inhibitor of sEH in a CCl4 murine model. • sEH inhibition reduces liver collagen deposition and pro-fibrotic gene expression. • sEH inhibition induces MMP-1a activity.

  5. Viscoelasticity-based magnetic resonance elastography for the assessment of liver fibrosis in hepatitis C patients after liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Kamphues, C.; Bova, R.; Yahyazadeh, A.; Bahra, M.; Neuhaus, P. [Charite, Campus Virchow Klinikum, Berlin (Germany). Klinik fuer Allgemein-, Viszeral- und Transplantationschirurgie; Klatt, D.; Braun, J.; Sack, I.; Asbach, P. [Charite - Universitaetsmedizin, Berlin (Germany). Klinik fuer Radiologie; Klauschen, F. [Charite - Universitaetsmedizin, Berlin (Germany). Inst. fuer Pathologie

    2012-11-15

    Purpose: Despite advantages in antiviral therapy of hepatitis C (HCV) in recent years, progressing liver fibrosis remains a major problem for patients suffering from hepatitis C after liver transplantation. Therefore, effective non-invasive methods for the assessment of liver fibrosis are needed in order to guide treatment decisions and predict prognosis in these patients. The aim of this study was to prospectively assess the diagnostic accuracy of viscoelasticity-based magnetic resonance (MR) elastography for the assessment of liver fibrosis in HCV patients after liver transplantation. Materials and Methods: After IRB approval, a total of 25 patients, who had received a liver graft due to chronic hepatitis C underwent both liver biopsy and MR elastography. Two viscoelastic constants, the shear elasticity {mu} and the powerlaw exponent {alpha} were calculated by fitting the frequency function of the complex shear modulus with the viscoelastic springpot-model. Results: A strong positive correlation between shear elasticity {mu} and the stage of fibrosis could be found (R = 0.486, p = 0.0136). The area under the receiver operating curve (AUROC) of MR elastography based on {mu} for diagnosis of severe fibrosis (F {>=} 3) was 0.87 and 0.65 for diagnosis of significant fibrosis (F {>=} 2). The powerlaw exponent {alpha} did not correlate with the stage of fibrosis. Conclusion: MR elastography represents a promising non-invasive procedure for the assessment of higher grades of fibrosis in HCV patients after liver transplantation. The poor correlation for lower grades of fibrosis suggests unknown mechanical interactions in the transplanted liver. (orig.)

  6. Viscoelasticity-based magnetic resonance elastography for the assessment of liver fibrosis in hepatitis C patients after liver transplantation

    International Nuclear Information System (INIS)

    Purpose: Despite advantages in antiviral therapy of hepatitis C (HCV) in recent years, progressing liver fibrosis remains a major problem for patients suffering from hepatitis C after liver transplantation. Therefore, effective non-invasive methods for the assessment of liver fibrosis are needed in order to guide treatment decisions and predict prognosis in these patients. The aim of this study was to prospectively assess the diagnostic accuracy of viscoelasticity-based magnetic resonance (MR) elastography for the assessment of liver fibrosis in HCV patients after liver transplantation. Materials and Methods: After IRB approval, a total of 25 patients, who had received a liver graft due to chronic hepatitis C underwent both liver biopsy and MR elastography. Two viscoelastic constants, the shear elasticity μ and the powerlaw exponent α were calculated by fitting the frequency function of the complex shear modulus with the viscoelastic springpot-model. Results: A strong positive correlation between shear elasticity μ and the stage of fibrosis could be found (R = 0.486, p = 0.0136). The area under the receiver operating curve (AUROC) of MR elastography based on μ for diagnosis of severe fibrosis (F ≥ 3) was 0.87 and 0.65 for diagnosis of significant fibrosis (F ≥ 2). The powerlaw exponent α did not correlate with the stage of fibrosis. Conclusion: MR elastography represents a promising non-invasive procedure for the assessment of higher grades of fibrosis in HCV patients after liver transplantation. The poor correlation for lower grades of fibrosis suggests unknown mechanical interactions in the transplanted liver. (orig.)

  7. Losartan attenuates paraquat-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Guo, F; Sun, Y B; Su, L; Li, S; Liu, Z F; Li, J; Hu, X T; Li, J

    2015-05-01

    Paraquat (PQ) is one of the most widely used herbicides in the world and can cause pulmonary fibrosis in the cases with intoxication. Losartan, an angiotensin II type 1 receptor antagonist, has beneficial effects on the treatment of fibrosis. The aim of this study was to examine the effect of losartan on pulmonary fibrosis in PQ-intoxicated rats. Adult male Sprague Dawley rats (n = 32, 180-220 g) were randomly assigned to four groups: (i) control group; (ii) PQ group; (iii) PQ + losartan 7d group; and (iv) PQ + losartan 14d group. Losartan treatment (intragastrically (i.g.), 10 mg/kg) was performed for 7 and 14 days after a single i.g. dose of 40 mg/kg PQ. All rats were killed on the 16th day, and hematoxylin-eosin and Masson's trichrome staining were used to examine lung injury and fibrosis. The levels of hydroxyproline and transforming growth factor β1 (TGF-β1), matrix metallopeptidase 9 (Mmp9), and tissue inhibitor of metalloproteinase 1 (TIMP-1) messenger RNA (mRNA) expression and relative expression levels of collagen type I and III were also detected. PQ caused a significant increase in hydroxyproline content, mRNA expression of TGF-β1, Mmp9, and TIMP-1, and relative expression levels of collagen type I and III ( p losartan significantly decreased the amount of hydroxyproline and downregulated TGF-β1, Mmp9, and TIMP-1 mRNA and collagen type I and III expressions ( p losartan could markedly reduce such damage and prevent pulmonary fibrosis. The results of this study indicated that losartan could reduce lung damage and prevent pulmonary fibrosis induced by PQ.

  8. The Role of Butylidenephthalide in Targeting Microenvironment Contributes to the Ameliorate of Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Hong-Meng eChuang

    2016-04-01

    Full Text Available The treatment of liver fibrosis has clinical limitations because of its multiple etiologies, such as epithelial–mesenchymal transition (EMT promotion, cell regeneration and remodeling dysfunction, inflammatory cell activation, and scar tissue deposition. These factors might be considered as a new target for the fibrotic microenvironment, leading to increased fibrogenesis and liver fibrosis. Here, we investigate a small molecule named butylidenephthalide (BP and its multiple effects on liver fibrosis treatment. Thioacetamide was used in vivo to induce chronic liver fibrosis. BP was administered orally in rats for a period of 2 weeks and 4 weeks, which resulted in a significantly reduced fibrosis score (p<0.05 and (p<0.001, respectively. The inflammatory reaction of macrophage infiltration were reduced in the administration of BP, which led to the decrease in the transaminase levels. Moreover, we also found liver functions recovering (due to the increased serum albumin and reduced prothrombin time where liver cells regenerated, which can be seen in the increase of Ki-67 on Oval cell. In addition, the fibrotic scar was also reduced, along with the expression of matrix metalloprotease by hepatic stellate cell. Furthermore, regarding the mechanism/study of EMT reduced by BP, the knockdown of BMP-7, which could reduce α-SMA expression, was mediated by the regulation of TGF-β, which implies its major role on EMT. Finally, in the in vivo study, BP treatment of liver fibrosis was reduced by Bmp7 knockdown in zebrafish, suggesting that BP leads to the reduction of liver fibrosis, which also depends on BMP-7 induction. These results suggest that BP had multiple targets for treating liver fibrosis in the following ways: reduction of EMT, decreasing inflammatory reaction, and liver cell proliferation. This multiple targets approach provided a new mechanism to treat liver injury and fibrosis.

  9. Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani; Alfredo Alberti

    2006-01-01

    Chronic liver diseases are very common worldwide,particularly those linked to viral hepatitis and to alcoholic and non-alcoholic fatty liver. Their natural history is variable and long-term evolution differs in individual patients. Optimised clinical management of compensated chronic liver diseases requires precise definition of the stage of liver fibrosis, the main determinant of prognosis and of most therapeutic decisions. Liver biopsy is the gold standard for assessment of hepatic fibrosis.However, it is invasive with possible complications,costly and prone to sampling errors. Many non-invasive markers of liver fibrosis have been recently proposed and assessed in the clinical setting as surrogates of liver biopsy. Direct markers are based on biochemical parameters directly linked to fibrogenesis while indirect markers use simple or more sophisticated parameters that correlate with liver fibrosis stages. Non-invasive markers of liver fibrosis have been tested in different forms of chronic liver disease and showed variable diagnostic performance, but accuracy rarely was above 75%-80%. Better results were obtained when markers were combined. On this line, we have recently proposed a set of algorithms that combine sequentially indirectnon-invasive markers of liver fibrosis, reaching 90%-95%diagnostic accuracy with significant reduction in the need for liver biopsy. Based on available evidence, it can be anticipated that non-invasive markers of liver fibrosis and their combined use will soon become a most useful tool in the clinical management of many forms of chronic liver disease. However, their implementation is expected to reduce, but not to completely eliminate, the need for liver biopsy.

  10. Increased liver stiffness in alcoholic liver disease:Differentiating fibrosis from steatohepatitis

    Institute of Scientific and Technical Information of China (English)

    Sebastian; Mueller; Gunda; Millonig; Lucie; Sarovska; Stefanie; Friedrich; Frank; M; Reimann; Maria; Pritsch; Silke; Eisele; Felix; Stickel; Thomas; Longerich; Peter; Schirmacher; Helmut; Karl; Seitz

    2010-01-01

    AIM:To test if inflammation also interferes with liver stiffness (LS) assessment in alcoholic liver disease (ALD) and to provide a clinical algorithm for reliable fibrosis assessment in ALD by FibroScan (FS).METHODS:We first performed sequential LS analysis before and after normalization of serum transaminases in a learning cohort of 50 patients with ALD admitted for alcohol detoxification. LS decreased in almost all patients within a mean observation interval of 5.3 d. Six patients (12%) would have been m...

  11. Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores.

    Directory of Open Access Journals (Sweden)

    Thomas Karlas

    Full Text Available BACKGROUND: Cystic fibrosis-related liver disease (CFLD is present in up to 30% of cystic fibrosis patients and can result in progressive liver failure. Diagnosis of CFLD is challenging. Non-invasive methods for staging of liver fibrosis display an interesting diagnostic approach for CFLD detection. AIM: We evaluated transient elastography (TE, acoustic radiation force impulse imaging (ARFI, and fibrosis indices for CFLD detection. METHODS: TE and ARFI were performed in 55 adult CF patients. In addition, AST/Platelets-Ratio-Index (APRI, and Forns' score were calculated. Healthy probands and patients with alcoholic liver cirrhosis served as controls. RESULTS: Fourteen CF patients met CFLD criteria, six had liver cirrhosis. Elastography acquisition was successful in >89% of cases. Non-cirrhotic CFLD individuals showed elastography values similar to CF patients without liver involvement. Cases with liver cirrhosis differed significantly from other CFLD patients (ARFI: 1.49 vs. 1.13 m/s; p = 0.031; TE: 7.95 vs. 4.16 kPa; p = 0.020 and had significantly lower results than individuals with alcoholic liver cirrhosis (ARFI: 1.49 vs. 2.99 m/s; p = 0.002. APRI showed the best diagnostic performance for CFLD detection (AUROC 0.815; sensitivity 85.7%, specificity 70.7%. CONCLUSIONS: ARFI, TE, and laboratory based fibrosis indices correlate with each other and reliably detect CFLD related liver cirrhosis in adult CF patients. CF specific cut-off values for cirrhosis in adults are lower than in alcoholic cirrhosis.

  12. Liver fibrosis and regeneration in dogs and cats : An immunohistochemical approach

    OpenAIRE

    Ijzer, J

    2008-01-01

    In this thesis we focus on liver tissue repair processes in canine and feline hepatitis, on formalin fixed paraffin embedded archival liver specimens. Hepatitis was diagnosed using histological standard criteria, and always includes hepatocellular cell death and an inflammatory infiltrate. Subsequently, the liver may react with regeneration and fibrosis (a detectable deposit of extracellular matrix). Fibrosis can develop into cirrhosis, which has a poor prognosis. Based on a better understand...

  13. Decorin prevents the development of CCl4-induced liver fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    Ma Rui; He Shilin; Liang Xiao; Yu Hong; Liang Yuelong; Cai Xiujun

    2014-01-01

    Background Liver fibrosis normally progresses to cirrhosis and destroys the normal architecture of the liver,resulting in liver dysfunction and irreversible cirrhosis.The aim of this study was to investigate the anti-fibrosis effect and the possible underlying mechanisms of decorin.Methods The mice model of liver fibrosis was induced by intraperitoneal injection of 50% (v/v) of carbon tetrachloride (CCl4) diluted in olive oil (1 ml/kg body weight) once every 2 days for 5 weeks.Three weeks after injecting CCl4 intraperitoneally,mice were randomly divided into normal control with vehicles only (olive oil),mouse model given CCl4 only,and CCl4 plus decorin (DCN,250 μg/kg).Two weeks later,all the mice were sacrificed and their liver tissues were analyzed for the expressions of genes related to liver fibrosis and under hematoxylin-eosin staining,Masson staining,and immunohistochemical staining of all groups.Aspartate transaminase,alanine transaminase,and total bilirubin of the serum were determined for evaluation of the liver function.Results Exogenous protein decorin could reduce liver fibrosis induced by CCl4 in mice.The degree of fibrosis in the experimental group was alleviated,and the contents of collagen fibers were lower in the experimental group than those of the control group.In addition,expressions of transforming growth factor β1 and α-smooth muscle actin decreased in the experimental group.Conclusions Taking liver fibrosis model of mouse as the experimental target and by injecting exogenous protein decorin into the model,we confirmed that decorin could inhibit the expression of proteins related to fibrosis and reduce the formation of liver fibrosis in mice.

  14. Noninvasive models for assessment of liver fibrosis in patients with chronic hepatitis B virus infection.

    Science.gov (United States)

    Zeng, Da-Wu; Dong, Jing; Liu, Yu-Rui; Jiang, Jia-Ji; Zhu, Yue-Yong

    2016-08-01

    There are approximately 240 million patients with chronic hepatitis B virus (HBV) infection worldwide. Up to 40% of HBV-infected patients can progress to liver cirrhosis, hepatocellular carcinoma or chronic end-stage liver disease during their lifetime. This, in turn, is responsible for around 650000 deaths annually worldwide. Repeated hepatitis flares may increase the progression of liver fibrosis, making the accurate diagnosis of the stage of liver fibrosis critical in order to make antiviral therapeutic decisions for HBV-infected patients. Liver biopsy remains the "gold standard" for diagnosing liver fibrosis. However, this technique has recently been challenged by the development of several novel noninvasive tests to evaluate liver fibrosis, including serum markers, combined models and imaging techniques. In addition, the cost and accessibility of imaging techniques have been suggested as additional limitations for invasive assessment of liver fibrosis in developing countries. Therefore, a noninvasive assessment model has been suggested to evaluate liver fibrosis, specifically in HBV-infected patients, owing to its high applicability, inter-laboratory reproducibility, wide availability for repeated assays and reasonable cost. The current review aims to present the status of knowledge in this new and exciting field, and to highlight the key points in HBV-infected patients for clinicians. PMID:27547009

  15. Effect of Fuzheng Huayu formula and its actions against liver fibrosis

    Directory of Open Access Journals (Sweden)

    Xu Lieming

    2009-06-01

    Full Text Available Abstract Liver fibrosis is a common histological process to develop into cirrhosis in various chronic liver diseases including chronic hepatitis and fatty liver. Therefore anti-liver fibrosis is very important strategy to treat chronic liver diseases. Fuzheng Huayu (FZHY, a preparation containing herbs such as Radix Salvia Miltiorrhizae, Cordyceps, Semen Persicae, was formulated on the basis of Chinese medicine theory in treating liver fibrosis and was approved. Pharmacological studies and clinical trials demonstrate that FZHY has a significant effect against liver fibrosis and that many of the pharmacological actions are attributable to the effect. This article reviews the effects and actions of FZHY, in particular the effects observed from clinical trials in treating liver fibrosis caused by chronic hepatitis B and the actions on inhibition of hepatic stellate cell activation, protection of hepatocytes and inhibition of hepatic sinusoidal capillarization. This article also reviews the coordinated effects of the constituent herbs of FZHY and the actions of their active compounds such as salvianonic acid B (SA-B on liver fibrosis.

  16. Acoustic radiation force imaging sonoelastography for noninvasive staging of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Carmen Fierbinteanu-Braticevici; Dan Andronescu; Radu Usvat; Dragos Cretoiu; Cristian Baicus; Gabriela Marinoschi

    2009-01-01

    AIM: To investigate the diagnostic accuracy of acoustic radiation force impulse (ARFI) imaging as a noninvasive method for the assessment of liver fibrosis in chronic hepatitis C (CHC) patients.METHODS: We performed a prospective blind comparison of ARFI elastography, APRI index and FibroMax in a consecutive series of patients who underwent liver biopsy for CHC in University Hospital Bucharest. Histopathological staging of liver fibrosis according to the METAVIR scoring system served as the reference. A total of 74 patients underwent ARFI elastography, APRI index, FibroMax and successful liver biopsy.RESULTS: The noninvasive tests had a good correlation with the liver biopsy results. The most powerful test in predicting fibrosis was ARFI elastography. The diagnostic accuracy of ARFI elastography, expressed as area under receiver operating characteristic curve (AUROC) had a validity of 90.2% (95% CI AUROC =0.831-0.972, P < 0.001) for the diagnosis of significant fibrosis (F ≥ 2). ARFI sonoelastography predicted even better F3 or F4 fibrosis (AUROC = 0.993, 95% CI =0.979-1).CONCLUSION: ARFI elastography had very good accuracy for the assessment of liver fibrosis and was superior to other noninvasive methods (APRI Index,FibroMax) for staging liver fibrosis.

  17. Effects of Guiyuanfang and autologous transplantation of bone marrow stem cells on rats with liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Li-Mao Wu; Lian-Da Li; Hong Liu; Ke-Yong Ning; Yi-Kui Li

    2005-01-01

    AIM: To investigate the therapeutic effects of Guiyuanfang and bone marrow stem cells (BMSCs) on rats with liver fibrosis.METHODS: Liver fibrosis model was induced by carbon tetrachloride, ethanol, high lipid and assessed biochemically and histologically. Liver function and hydroxyproline contents of liver tissue were determined.Serum hyaluronic acid (HA) level and procollagen Ⅲ level were performed by radioimmunoassay. The VG staining was used to evaluate the collagen deposit in the liver.Immunohistochemical SABC methods were used to detect transplanted BMSCs and expression of urokinase plasminogen activator (uPA).RESULTS: Serum transaminase level and liver fibrosis in rats were markedly reduced by Guiyuanfang and BMSCs. HA level and procollagen Ⅲ level were also reduced obviously,compared to model rats (HA: 47.18±10.97 ng/mL,48.96±14.79 ng/mL; PCⅢ: 22.48±5.46 ng/mL, 26.90±3.35ng/mL; P<0.05).Hydroxyproline contents of liver tissue in both BMSCs group and Guiyuanfang group were far lower than that of model group (1 227.2±43.1 μg/g liver tissue, 1390.8±156.3 μg/g liver tissue; P<0.01). After treatment fibrosis scores were also reduced. Both Guiyuanfang and BMSCs could increase the expression of uPA. The transplanted BMSCs could engraft, survive, and proliferate in the liver.CONCLUSION: Guiyuanfang protects against liver fibrosis.Transplanted BMSCs may engraft, survive, and proliferate in the fibrosis livers indefinitely. Guiyuanfang may synergize with BMSCs to improve recovery from liver fibrosis.

  18. Prevention of Liver Fibrosis by Triple Helix-Forming Oligodeoxyribonucleotides Targeted to the Promoter Region of Type I Collagen Gene

    OpenAIRE

    Koilan, Subramaniyan; Hamilton, David; Baburyan, Narina; Padala, Mythili K.; Weber, Karl T.; Guntaka, Ramareddy V.

    2010-01-01

    Hepatic fibrosis leading to cirrhosis remains a global health problem. The most common etiologies are alcoholism and viral infections. Liver fibrosis is associated with major changes in both quantity and composition of extracellular matix and leads to disorganization of the liver architecture and irreversible damage to the liver function. As of now there is no effective therapy to control fibrosis. The end product of fibrosis is abnormal synthesis and accumulation of type I collagen in the ex...

  19. Liver fibrosis grading using multiresolution histogram information in real-time elastography

    Science.gov (United States)

    Albouy-Kissi, A.; Sarry, L.; Massoulier, S.; Bonny, C.; Randl, K.; Abergel, A.

    2010-03-01

    Despites many limitations, liver biopsy remains the gold standard method for grading and staging liver biopsy. Several modalities have been developed for a non invasive assessment of liver diseases. Real-time elastography may constitute a true alternative to liver biopsy by providing an image of tissular elasticity distribution correlated to the fibrosis grade. In this paper, we investigate a new approach for the assessment of liver fibrosis by the classification of fibrosis morphometry. Multiresolution histogram, based on a combination of intensity and texture features, has been tested as feature space. Thus, the ability of such multiresolution histograms to discriminate fibrosis grade has been proven. The results have been tested on seventeen patients that underwent a real time elastography and FibroScan examination.

  20. MR elastography of the liver at 3.0 T in diagnosing liver fibrosis grades; preliminary clinical experience

    Energy Technology Data Exchange (ETDEWEB)

    Yoshimitsu, Kengo; Mitsufuji, Toshimichi; Shinagawa, Yoshinobu; Fujimitsu, Ritsuko; Morita, Ayako; Urakawa, Hiroshi; Takano, Koichi [Fukuoka University, Department of Radiology, Fukuoka (Japan); Hayashi, Hiroyuki [Fukuoka University, Department of Pathology, Faculty of Medicine, Fukuoka (Japan)

    2016-03-15

    To clarify the usefulness of 3.0-T MR elastography (MRE) in diagnosing the histological grades of liver fibrosis using preliminary clinical data. Between November 2012 and March 2014, MRE was applied to all patients who underwent liver MR study at a 3.0-T clinical unit. Among them, those who had pathological evaluation of liver tissue within 3 months from MR examinations were retrospectively recruited, and the liver stiffness measured by MRE was correlated with histological results. Institutional review board approved this study, waiving informed consent. There were 70 patients who met the inclusion criteria. Liver stiffness showed significant correlation with the pathological grades of liver fibrosis (rho = 0.89, p < 0.0001, Spearman's rank correlation). Areas under the receiver operating characteristic curve were 0.93, 0.95, 0.99 and 0.95 for fibrosis score greater than or equal to F1, F2, F3 and F4, with cut-off values of 3.13, 3.85, 4.28 and 5.38 kPa, respectively. Multivariate analysis suggested that grades of necroinflammation also affected liver stiffness, but to a significantly lesser degree as compared to fibrosis. 3.0-T clinical MRE was suggested to be sufficiently useful in assessing the grades of liver fibrosis. (orig.)

  1. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease

    OpenAIRE

    Zeybel, Müjdat; Hardy, Timothy; Robinson, Stuart M.; Fox, Christopher; Anstee, Quentin M.; Ness, Thomas; Masson, Steven; Masson, Steven; French, Jeremy; White, Steve; Mann, Jelena

    2015-01-01

    RESEARCH Open Access Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease Müjdat Zeybel1, Timothy Hardy1, Stuart M Robinson1, Christopher Fox1, Quentin M Anstee1, Thomas Ness2, Steven Masson1, John C Mathers1, Jeremy French1, Steve White1 and Jelena Mann1* Abstract Background: Chronic liver injury can lead to the development of liver fibrosis and cirrhosis but only in a minority of patie...

  2. The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference.

    Science.gov (United States)

    Hong, Feng; Si, Chuanping; Gao, Pengfei; Cederbaum, Arthur I; Xiong, Huabao; Lu, Yongke

    2016-01-01

    Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild-type (WT) mice and CYP2A5 knockout (cyp2a5 (-/-) ) mice as well as in CYP2E1 knockout (cyp2e1 (-/-) ) mice as a comparison. Acute and subchronic liver injuries including fibrosis were induced by CCL4 and TAA in WT mice but not in cyp2e1 (-/-) mice, confirming the indispensable role of CYP2E1 in CCL4 and TAA hepatotoxicity. WT mice and cyp2a5 (-/-) mice developed comparable acute liver injury induced by a single injection of CCL4 as well as subchronic liver injury including fibrosis induced by 1 month of repeated administration of CCL4, suggesting that CYP2A5 does not affect CCL4-induced liver injury and fibrosis. However, while 200 mg/kg TAA-induced acute liver injury was comparable in WT mice and cyp2a5 (-/-) mice, 75 and 100 mg/kg TAA-induced liver injury were more severe in cyp2a5 (-/-) mice than those found in WT mice. After multiple injections with 200 mg/kg TAA for 1 month, while subchronic liver injury as indicated by serum aminotransferases was comparable in WT mice and cyp2a5 (-/-) mice, liver fibrosis was more severe in cyp2a5 (-/-) mice than that found in WT mice. These results suggest that while both CCL4- and TAA-induced liver injuries and fibrosis are CYP2E1 dependent, under some conditions, CYP2A5 may protect against TAA-induced liver injury and fibrosis, but it does not affect CCL4 hepatotoxicity.

  3. Effect of Sea buckthorn on liver fibrosis: A clinical study

    Institute of Scientific and Technical Information of China (English)

    Ze-Li Gao; Xiao-Hong Gu; Feng-Tao Cheng; Fo-Hu Jiang

    2003-01-01

    AIM: To appraise the effect of sea buckthorn (Hippophae rhamnoides) on cirrhotic patients.METHODS: Fifty cirrhotic patients of Child-Pugh grade A and B were randomly divided into two groups: Group A as the treated group (n=30), taking orally the sea buckthom extract, 15 g 3 times a day for 6 months. Group B as the control group (n=18), taking vitamin B complex one tablet,3 times a day for 6 months. The following tests were performed before and after the treatment in both groups to determine LN, HA, collagens types Ⅲ and IV, cytokines IL6 and TNFα, liver serum albumin, total bile acid, ALT, AST and prothrombin time.RESULTS: The serum levels of TNFα, IL-6, laminin and type IV collagen in group A were significantly higher than those in the control group. After a course of sea buckthorn treatment, the serum levels of LN, HA, collagen types Ⅲand IV, total bile acid (TBA) decreased significantly as compared with those before and after treatment in the control group. The sea buckthorn notably shortened the duration for normalization of aminotransferases.CONCLUSION: Sea buckthom may be a hopeful drug for prevention and treatment of liver fibrosis.

  4. Adenovirus-mediated over-expression of Septin4 ameliorates hepatic fibrosis in mouse livers infected with Schistosoma japonicum.

    Science.gov (United States)

    He, Xue; Bao, Jing; Chen, Jinling; Sun, Xiaolei; Wang, Jianxin; Zhu, Dandan; Song, Ke; Peng, Wenxia; Xu, Tianhua; Duan, Yinong

    2015-12-01

    Septin4 (Sept4) belongs to Septin family and may be involved in apoptosis, vesicle trafficking and other cell processes. In this study, we attempted to investigate the effect of Sept4 in hepatic fibrosis induced by Schistosoma japonicum. ICR mice infected with S. japonicum for 12weeks were treated with PBS, Ad-ctr and Ad-Sept4, respectively. All mice were killed at 2weeks after injection, and the changes in the fibrotic livers were detected via H&E staining, Sirius red staining, qRT-PCR, western blot and TUNEL analysis. In addition, pcDNA3.1-Sept4 plasmid was transfected into LX-2 cells to observe the effect of Sept4 on apoptosis of HSCs in vitro. Ad-Sept4 could ameliorate liver fibrosis, as detected by H&E staining and Sirius red staining. The number of TUNEL-positive cells was increased in the Ad-Sept4 treated group. The expression of Sept4 and cleaved-caspase-3 were all augmented, while the expression of α-SMA, Col1α1 and IL-13 were reduced in the Ad-Sept4 treated group, compared with that expressed in the Ad-ctr group. Over-expression of Sept4 in LX-2 cells could promote apoptosis of LX-2 cells in vitro. In conclusion, Ad-Sept4 can attenuate the development of liver fibrosis induced by S. japonicum through apoptosis. PMID:26190030

  5. Usefulness of non-invasive serum markers for predicting liver fibrosis in Egyptian patients with chronic HCV infection.

    Science.gov (United States)

    El Guesiry, Dalal; Moez, Pacinte; Hossam, Nermine; Kassem, Mohamed

    2011-01-01

    Accurate monitoring of liver fibrosis changes in patients with hepatitis C virus (HCV) infection would be helpful in defining the need to intervene, implement the appropriate response in treatment and to minimize the use of liver biopsy. We aimed to evaluate the diagnostic utility of the different serum markers and indices in detecting liver fibrosis in study patients. Initial liver biopsy, routine liver function tests, estimation of hyaluronic acid, MMP-1, and PIIINP levels was performed for 30 Egyptian patients with HCV and 15 controls. Marker algorithms based on common laboratory such APRI score, Fibrotest and Actitest. PIIINP and MMP-1 serum markers were combined and entered into a stepwise logistic regression analysis with formulation of a score equation for fibrosis staging. Combined PIIINP and MMP-1 yielded different cut off scores to estimate two clinically relevant fibrosis stages: "significant fibrosis" versus "extensive fibrosis. Apri score also showed AUC of 1.0 with 100 % sensitivity and specificity to exclude the presence of cirrhosis and was significantly correlated to Metavair fibrosis stage in early fibrosis. On the other hand, PIIINP, Fibrotest and acti test were significantly correlated to Metavair fibrosis stage in both early and late fibrosis. In conclusion, integrating PIIINP/MMP-1 score was able to provide reliable information about the degree of liver fibrosis in chronic hepatitis C patients using different cut-offs values. A combination of liver markers as well as its related indices is an emerging tool to differentiate early from advanced liver fibrosis in HCV patients. PMID:23082465

  6. State-of-the-art imaging of liver fibrosis and cirrhosis: A comprehensive review of current applications and future perspectives

    Directory of Open Access Journals (Sweden)

    Adrian Huber

    2015-01-01

    Conclusion: MR elastography (MRE appears to be the most reliable method for grading liver fibrosis, although the CT fibrosis score derived from the combination of caudate-to-right-lobe ratio and the diameters of the liver veins significantly correlates with the stage of fibrosis.

  7. Biochemical and radio-immunological studies on HCV-induced liver fibrosis

    International Nuclear Information System (INIS)

    Hepatitis C virus infection is now becoming a common health problem in Egypt. Liver biopsy is the gold standard for this diagnosis. However, liver biopsy is invasive and is associated with complications with chronic hepatitis C patients. There is a clinical need for noninvasive measurement of liver fibrosis. Noninvasive bio markers such as Collagen III was identified in serum samples of patients with HCV induced liver fibrosis at 70 kDa using SDS-PAGE and western blot, measured by ELISA and purified using electro elution . Hyaluronic acid also can be used to differentiate between liver fibrosis patients and healthy individuals using radioimmunoassay .we have developed noninvasive diagnosis that can be applied to patients who either have contraindications or refuse liver biopsy for the management of their HCV infection.

  8. Transient elastography compared to liver biopsy and morphometry for predicting fibrosis in pediatric chronic liver disease: Does etiology matter?

    Science.gov (United States)

    Behairy, Behairy El-Sayed; Sira, Mostafa Mohamed; Zalata, Khaled Refat; Salama, El-Sayed Ebrahem; Abd-Allah, Mohamed Ahmed

    2016-01-01

    AIM: To evaluate transient elastography (TE) as a noninvasive tool in staging liver fibrosis compared with liver biopsy and morphometry in children with different chronic liver diseases. METHODS: A total of 90 children [50 with chronic hepatitis C virus (HCV), 20 with autoimmune hepatitis (AIH) and 20 with Wilson disease] were included in the study and underwent liver stiffness measurement (LSM) using TE. Liver biopsies were evaluated for fibrosis, qualitatively, by Ishak score and quantitatively by fibrosis area fraction (FAF) using digital image analysis (morphometry). LSM was correlated with fibrosis and other studied variables using spearman correlation. A stepwise multiple regression analysis was also performed to examine independent factors associated with LSM. Different cut-off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. Cut-off values with optimal clinical performance (optimal sensitivity and specificity simultaneously) were selected. RESULTS: The majority of HCV group had minimal activity (80%) and no/mild fibrosis (72%). On the other hand, the majority of AIH group had mild to moderate activity (70%) and moderate to severe fibrosis (95%) and all Wilson disease group had mild to moderate activity (100%) and moderate to severe fibrosis (100%). LSM correlated significantly with both FAF and Ishak scores and the correlation appeared better with the latter (r = 0.839 vs 0.879, P < 0.0001 for both). LSM discriminated individual stages of fibrosis with high performance. Sensitivity ranged from 81.4% to 100% and specificity ranged from 75.0% to 97.2%. When we compared LSM values for the same stage of fibrosis, they varied according to the different etiologies. Higher values were in AIH (16.15 ± 7.23 kPa) compared to Wilson disease (8.30 ± 0.84 kPa) and HCV groups (7.43 ± 1.73 kPa). Multiple regression analysis revealed that Ishak fibrosis stage was the only independent variable

  9. Influence of heme oxygenase-1 expression on immune liver fibrosis induced by cobalt protoporphyrin in rats

    Institute of Scientific and Technical Information of China (English)

    Fei Wang; Zhi-Jun Duan; Ying-Jie Sun

    2009-01-01

    AIM: To investigate the effect of heme oxygenase-1 (HO-1) expression on immune liver fibrosis induced by cobalt protoporphyrin (CoPP) in rats. METHODS: An immune liver fibrosis model of rat was established by administering human serum albumin (HSA). The rats were divided into CoPP, liver fibrosis and normal control groups. Rats in the CoPP group received intraperitoneal CoPP concurrently with HSA. Expression of HO-1 protein was observed by Western blotting and immunohistochemistry. Hematoxylin and eosin (HE) staining was performed to assess fibrosis proliferation and distribution, proliferation extent of fibroblasts, and alterations in hepatocytes and inflammatory cells. Type Ⅰ and Ⅲ collagens were detected with Van Gieson's (VG) staining and Foot's reticular fiber staining, respectively. In addition, spindle-shaped cells existing at perisinusoidal locations beyond portal and septa areas were investigated with HE staining.RESULTS: Western blotting and immunohistochemistry showed that the expression of HO-1 protein was higher in the CoPP group than in the liver fibrosis group (P < 0.05). Compared with the liver fibrosis group, the serological index of hepatic fibrosis in the CoPP group decreased significantly (P < 0.05). HE, VG and Foot's staining revealed that administration of CoPP reduced the extent of hepatic fibrosis. The levels of serological indicators and the number of spindle-shaped cells at perisinuous locations beyond the portal and septa areas were reduced in the CoPP group. Only a few inflammatory cells were seen around the portal areas and central veins in the CoPP group. CONCLUSION: Increased endogenous HO-1 may suppress liver fibrosis by protecting liver cells,inhibiting inflammatory cell infiltration and hepatic stellate cell transformation.

  10. Diffusion-Weighted MRI for the Assessment of Liver Fibrosis: Principles and Applications

    Science.gov (United States)

    Attinà, Giancarlo; Fuccio Sanzà, Giovanni; Foti, Pietro Valerio; Ettorre, Giovanni Carlo; Milone, Pietro

    2015-01-01

    The importance of an early identification of hepatic fibrosis has been emphasized, in order to start therapy and obtain fibrosis regression. Biopsy is the gold-standard method for the assessment of liver fibrosis in chronic liver diseases, but it is limited by complications, interobserver variability, and sampling errors. Several noninvasive methods have been recently introduced into clinical routine, in order to detect liver fibrosis early. One of the most diffuse approaches is represented by diffusion-weighted liver MRI. In this review, the main technical principles are briefly reported in order to explain the rationale for clinical applications. In addition, roles of apparent diffusion coefficient, intravoxel incoherent motion, and relative apparent diffusion coefficient are also reported, showing their advantages and limits. PMID:25866819

  11. Diffusion-Weighted MRI for the Assessment of Liver Fibrosis: Principles and Applications

    Directory of Open Access Journals (Sweden)

    Stefano Palmucci

    2015-01-01

    Full Text Available The importance of an early identification of hepatic fibrosis has been emphasized, in order to start therapy and obtain fibrosis regression. Biopsy is the gold-standard method for the assessment of liver fibrosis in chronic liver diseases, but it is limited by complications, interobserver variability, and sampling errors. Several noninvasive methods have been recently introduced into clinical routine, in order to detect liver fibrosis early. One of the most diffuse approaches is represented by diffusion-weighted liver MRI. In this review, the main technical principles are briefly reported in order to explain the rationale for clinical applications. In addition, roles of apparent diffusion coefficient, intravoxel incoherent motion, and relative apparent diffusion coefficient are also reported, showing their advantages and limits.

  12. [Clinical Application of Non-invasive Diagnostic Tests for Liver Fibrosis].

    Science.gov (United States)

    Shin, Jung Woo; Park, Neung Hwa

    2016-07-25

    The diagnostic assessment of liver fibrosis is an important step in the management of patients with chronic liver diseases. Liver biopsy is considered the gold standard to assess necroinflammation and fibrosis. However, recent technical advances have introduced numerous serum biomarkers and imaging tools using elastography as noninvasive alternatives to biopsy. Serum markers can be direct or indirect markers of the fibrosis process. The elastography-based studies include transient elastography, acoustic radiation force imaging, supersonic shear wave imaging and magnetic resonance elastography. As accumulation of clinical data shows that noninvasive tests provide prognostic information of clinical relevance, non-invasive diagnostic tools have been incorporated into clinical guidelines and practice. Here, the authors review noninvasive tests for the diagnosis of liver fibrosis. PMID:27443617

  13. Antifibrotic effects of green tea on in vitro and in vivo models of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Hye Kyung Kim; Taik-Hoon Yang; Hong-Yon Cho

    2009-01-01

    AIM: To examine the protective effect of green tea extract (GT) on hepatic fibrosis in vitro and in vivo in dimethylnitrosamine (DMN)-induced rats. METHODS: HSC-T6, a rat hepatic stellate cell line, was used as an in vitro assay system. Cell proliferation,collagen content, and type 1 collagen expression were examined in activated HSC-T6 cells. Collagen was determined by estimating the hydroxyproline content.In rats with DMN-induced hepatic fibrosis, serum aspartate aminotransferase and alanine aminotransferase concentrations, liver hydroxyproline and lipid peroxides were determined. Pathologic changes were examined by hematoxylin & eosin staining.RESULTS: GT administration prevented the development of hepatic fibrosis in the rat model of DMN-induced liver fibrosis. These results were confirmed both by liver histology and by quantitative measurement of hepatic hydroxyproline content, a marker of liver collagen deposition. Accordingly, inhibition of proliferation, reduced collagen deposition, and type 1 collagen expression were observed in activated HSC-T6 cells following GT treatment. These results imply that GT reduced the proliferation of activated HSC and down regulated the collagen content and expression of collagen type 1, thereby ameliorating hepatic fibrosis. tea administration can effectively improve liver fibrosis caused by DMN, and may be used as a therapeutic option and preventive measure against hepatic fibrosis.

  14. Heme oxygenase-1 prevents liver fibrosis in rats by regulating the expression of PPARγ and NF-κB

    Institute of Scientific and Technical Information of China (English)

    Hui Yang; Long-Feng Zhao; Zhong-Fu Zhao; Yan Wang; JingJing Zhao; Li Zhang

    2012-01-01

    AIM:To investigate the effects of heme oxygenase (HO)-1 on liver fibrosis and the expression of peroxisome proliferator-activated receptor gamma (PPARγ)and nuclear factor-kappa B (NF-κB) in rats.METHODS:Sixty Wistar rats were used to construct liver fibrosis models and were randomly divided into 5 groups:group A (normal,untreated),group B (model for 4 wk,untreated),group C (model for 6 wk,untreated),group D [model for 6 wk,treated with zinc protoporphyrin Ⅸ (ZnPP-Ⅸ) from week 4 to week 6],group E (model for 6 wk,treated with hemin from week 4 to week 6).Next,liver injury was assessed by measuring serum alanine aminotransferase (ALT),aspartate aminotransferase (AST) and albumin levels.The degree of hepatic fibrosis was evaluated by measuring serum hyaluronate acid (HA),type Ⅳ collagen (IV-C) and by histological examination.Hydroxyproline (Hyp) content in the liver homogenate was determined.The expression levels of alpha-smooth muscle actin (α-SMA) in liver tissue were measured by real-time quantitative polymerase chain reaction (RT-PCR).The expression levels of PPARγ,and NF-KB were determined by RT-PCR and Western blotting.RESULTS:The expression of HO-1 increased with the development of fibrosis.Induction of HO-1 by hemin significantly attenuated the severity of liver injury and the levels of liver fibrosis as compared with inhibition of HO-1 by ZnPP-Ⅸ.The concentrations of serum ALT,AST,HA and IV-C in group E decreased compared with group C and group D (P < 0.01).Amount of Hyp and α-SMA in the liver tissues in group E decreased compared with group C (0.62 ± 0.14 vs 0.84 ± 0.07,1.42 ±0.17 vs 1.84 ± 0.17,respectively,P < 0.01) and group D (0.62-0.14 vs 1.11 ± 0.16,1.42 ± 0.17 vs 2.56 ±0.37,respectively,P < 0.01).The expression of PPARγ at levels of transcription and translation decreased with the development of fibrosis especially in group D; and it increased in group E compared with groups C and D (0.88 ± 0.15 vs 0.56 ± 0.19,0.88 ± 0

  15. Human precision-cut liver slices as a model to test antifibrotic drugs in the early onset of liver fibrosis

    NARCIS (Netherlands)

    Westra, Inge M; Mutsaers, Henricus A M; Luangmonkong, Theerut; Hadi, Mackenzie; Oosterhuis, Dorenda; de Jong, Koert P; Groothuis, Geny M M; Olinga, Peter

    2016-01-01

    Liver fibrosis is the progressive accumulation of connective tissue ultimately resulting in loss of organ function. Currently, no effective antifibrotics are available due to a lack of reliable human models. Here we investigated the fibrotic process in human precision-cut liver slices (PCLS) and stu

  16. Umbilical cord-derived mesenchymal stem cells alleviate liver fibrosis in rats

    Science.gov (United States)

    Chai, Ning-Li; Zhang, Xiao-Bin; Chen, Si-Wen; Fan, Ke-Xing; Linghu, En-Qiang

    2016-01-01

    AIM: To evaluate the efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation in the treatment of liver fibrosis. METHODS: Cultured human UC-MSCs were isolated and transfused into rats with liver fibrosis induced by dimethylnitrosamine (DMN). The effects of UC-MSCs transfusion on liver fibrosis were then evaluated by histopathology; serum interleukin (IL)-4 and IL-10 levels were also measured. Furthermore, Kupffer cells (KCs) in fibrotic livers were isolated and cultured to analyze their phenotype. Moreover, UC-MSCs were co-cultured with KCs in vitro to assess the effects of UC-MSCs on KCs’ phenotype, and IL-4 and IL-10 levels were measured in cell culture supernatants. Finally, UC-MSCs and KCs were cultured in the presence of IL-4 antibodies to block the effects of this cytokine, followed by phenotypical analysis of KCs. RESULTS: UC-MSCs transfused into rats were recruited by the injured liver and alleviated liver fibrosis, increasing serum IL-4 and IL-10 levels. Interestingly, UC-MSCs promoted mobilization of KCs not only in fibrotic livers, but also in vitro. Co-culture of UC-MSCs with KCs resulted in increased production of IL-4 and IL-10. The addition of IL-4 antibodies into the co-culture system resulted in decreased KC mobilization. CONCLUSION: UC-MSCs could increase IL-4 and promote mobilization of KCs both in vitro and in vivo, subsequently alleviating the liver fibrosis induced by DMN.

  17. Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

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    Shu Li

    2012-01-01

    Full Text Available The renin-angiotensin system (RAS plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B, one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN- induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I and α-smooth muscle actin (α-SMA production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β, and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation.

  18. Liver fibrosis progression in HIV/hepatitis C virus coinfected patients with normal aminotransferases levels

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    Fábio Heleno de Lima Pace

    2012-08-01

    Full Text Available INTRODUCTION: Approximately 30% of hepatitis C virus (HCV monoinfected patients present persistently normal alanine aminotransferase (ALT levels. Most of these patients have a slow progression of liver fibrosis. Studies have demonstrated the rate of liver fibrosis progression in hepatitis C virus-human immunodeficiency virus (HCV-HIV coinfected patients is faster than in patients infected only by HCV. Few studies have evaluated the histological features of chronic hepatitis C in HIV-infected patients with normal ALT levels. METHODS: HCV-HIV coinfected patients (HCV-RNA and anti-HIV positive with known time of HCV infection (intravenous drugs users were selected. Patients with hepatitis B surface antigen (HBsAg positive or hepatitis C treatment before liver biopsy were excluded. Patients were considered to have a normal ALT levels if they had at least 3 normal determinations in the previous 6 months prior to liver biopsy. All patients were submitted to liver biopsy and METAVIR scale was used. RESULTS: Of 50 studied patients 40 (80% were males. All patients were treated with antiretroviral therapy. The ALT levels were normal in 13 (26% patients. HCV-HIV co-infected patients with normal ALT levels had presented means of the liver fibrosis stages (0.77±0.44 versus 1.86±1.38; p<0.001 periportal inflammatory activity (0.62±0.77 versus 2.24±1.35; p<0.001 and liver fibrosis progression rate (0.058±0.043 fibrosis unit/year versus 0.118±0.102 fibrosis unit/year significantly lower as compared to those with elevated ALT. CONCLUSIONS: HCV-HIV coinfected patients with persistently normal ALTs showed slower progression of liver fibrosis. In these patients the development of liver cirrhosis is improbable.

  19. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis.

    OpenAIRE

    Elena Turola; Salvatore Petta; Ester Vanni; Fabiola Milosa; Luca Valenti; Rosina Critelli; Luca Miele; Livia Maccio; Vincenza Calvaruso; Fracanzani, Anna L.; Marcello Bianchini; Nazarena Raos; Elisabetta Bugianesi; Serena Mercorella; Marisa Di Giovanni

    2015-01-01

    ABSTRACT Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and m...

  20. Cystic fibrosis-related liver disease: a single-center experience

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    Paula Catarino Costa

    2011-10-01

    Full Text Available Prospective studies concerning liver disease in pediatric cystic fibrosis patients are scarce. The present study aimed to describe the prevalence and clinical expression of cystic fibrosis - related liver disease, in a cohort of 62 pediatric patients. Descriptive study, resulting from the prospective evaluation, between 1994 and 2009, of 62 pediatric patients (age <18 years with cystic fibrosis. The follow-up protocol included a clinical assessment every 2 months, liver function tests every 6 months and annual liver ultrasonography. The cumulative prevalence of liver disease was 11.2% (7/62 cases. All patients had ΔF508 mutation and pancreatic insufficiency, none had meconium ileus. The liver involvement became clinically evident at a mean age of 8 years (3-15 years, revealed by hepatomegaly or hepatosplenomegaly (3 cases and/ or abnormalities of liver function tests (3 cases changes of liver ultrasound (7 cases with evidence of portal hypertension (2 cases. Four patients were submitted to liver biopsy; biliary fibrosis was documented in one case, focal biliary cirrhosis in 2 cases and multilobular cirrhosis in another case. Within a median 11.6 years follow-up period (all patients under UDCA therapy after liver disease diagnosis, progression of liver disease was observed in 2 patients; one patient developed refractory variceal bleeding and progressive hepatic failure, requiring liver transplant. The results of the present study agree with those of previous pediatric studies, further documenting clinical expression of liver disease in CF patients, which is usually detected in the first decade of life and emphasize the contribution of ultrasound to early diagnosis of liver involvement. Moreover, although advanced liver disease is a relatively rare event, early isolated liver transplantation may have to be considered at this age group.

  1. Validity of Autotaxin as a Novel Diagnostic Marker for Liver Fibrosis in Egyptian Chronic HCV Patients

    OpenAIRE

    Ezzat, Wafaa M.; Halla M. Ragab; Nabila Abd El Maksoud; Nour A. Abdulla; Yasser A. Elhosary

    2013-01-01

    We aimed to detect the validity of serum ATX as a diagnostic marker for liver fibrosis. Forty-eight males and 16 females were enrolled in the current study. Their ages ranged from 29-57 years with mean of 45.09, all were chronically HCV infected. Laboratory assessment was done for all subjects in form of complete blood picture; liver function test; lipid profile and serum detection of ATX. Patients were grouped according to the stage of fibrosis into group 1: fibrosis score 0, 1, 2, 3; group ...

  2. FibroMeters: a family of blood tests for liver fibrosis.

    Science.gov (United States)

    Calès, P; Boursier, J; Oberti, F; Hubert, I; Gallois, Y; Rousselet, M-C; Dib, N; Moal, V; Macchi, L; Chevailler, A; Michalak, S; Hunault, G; Chaigneau, J; Sawadogo, A; Lunel, F

    2008-09-01

    FibroMeters are blood tests for liver fibrosis with several specificities: two main diagnostic targets (fibrosis stage and area of fibrosis); adaptation to specific causes; and results confirmed by an expert system. Thus, FibroMeters comprise six different tests: one for staging and one for quantitation of liver fibrosis in each of the three main causes of chronic liver disease-chronic viral hepatitis, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FibroMeters display a high overall diagnostic accuracy and are the only tests to correctly classify 100% of HCV patients without fibrosis or with cirrhosis. They have 90% predictive values in a higher proportion of patients than with other usual blood tests. A 90% correct classification is available in 100% of HCV patients with the following reliable diagnostic intervals: F0/1, F1/2, F2+/-1, F3+/-1. In real-life conditions, the reproducibility of FibroMeters is higher than that of liver biopsy or ultrasonographic elastometry. FibroMeters are robust tests with the most stable diagnostic performance across different centers. Optional tests are also available, such as a specific one for cirrhosis, which has a diagnostic accuracy of 93.0% (AUROC: 0.92) and a 100% positive predictive value for diagnosis of HCV cirrhosis. Determination by FibroMeters of the area of fibrosis - the only direct, non-invasive, quantitative measurement of liver fibrosis - are especially useful for following-up cirrhosis as it correlates well with clinical events. FibroMeters are also very accurate in HVB or HIV-HCV co-infected patients. The tests specific for ALD and NAFLD also have a high diagnostic accuracy (AUROCs: 0.96 and 0.94, respectively, for significant fibrosis). PMID:18973845

  3. Gene expression profiles of hepatic cell-type specific marker genes in progression of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Yoshiyuki Takahara; Mitsuo Takahashi; Hiroki Wagatsuma; Fumihiko Yokoya; Qing-Wei Zhang; Mutsuyo Yamaguchi; Hiroyuki Aburatani; Norifumi Kawada

    2006-01-01

    AIM: To determine the gene expression profile data for the whole liver during development of dimethylnitrosamine (DMN)-induced hepatic fibrosis.METHODS: Marker genes were identified for different types of hepatic cells, including hepatic stellate cells (HSCs), Kupffer cells (including other inflammatory cells),and hepatocytes, using independent temporal DNA microarray data obtained from isolated hepatic cells.RESULTS: The cell-type analysis of gene expression gave several key results and led to formation of three hypotheses: (1) changes in the expression of HSCspecific marker genes during fibrosis were similar to gene expression data in in vitro cultured HSCs, suggesting a major role of the self-activating characteristics of HSCs in formation of fibrosis; (2) expression of mast cell-specific marker genes reached a peak during liver fibrosis,suggesting a possible role of mast cells in formation of fibrosis; and (3) abnormal expression of hepatocytespecific marker genes was found across several metabolic pathways during fibrosis, including sulfur-containing amino acid metabolism, fatty acid metabolism, and drug metabolism, suggesting a mechanistic relationship between these abnormalities and symptoms of liver fibrosis.CONCLUSION: Analysis of marker genes for specific hepatic cell types can identify the key aspects of fibrogenesis. Sequential activation of inflammatory cells and the self-supporting properties of HSCs play an important role in development of fibrosis.

  4. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis

    Science.gov (United States)

    Dadrich, Monika; Nicolay, Nils H.; Flechsig, Paul; Bickelhaupt, Sebastian; Hoeltgen, Line; Roeder, Falk; Hauser, Kai; Tietz, Alexandra; Jenne, Jürgen; Lopez, Ramon; Roehrich, Manuel; Wirkner, Ute; Lahn, Michael; Huber, Peter E.

    2016-01-01

    ABSTRACT Background: Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods: C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results: Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion: Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement: RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined

  5. Liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfection: Diagnostic methods and clinical impact

    Institute of Scientific and Technical Information of China (English)

    Caterina; Sagnelli; Salvatore; Martini; Mariantonietta; Pisaturo; Giuseppe; Pasquale; Margherita; Macera; Rosa; Zampino; Nicola; Coppola; Evangelista; Sagnelli

    2015-01-01

    Several non-invasive surrogate methods have recently challenged the main role of liver biopsy in assessing liver fibrosis in hepatitis C virus(HCV)-monoinfected and human immunodeficiency virus(HIV)/HCV-coinfected patients, applied to avoid the well-known side effects of liver puncture. Serological tests involve the determination of biochemical markers of synthesis or degradation of fibrosis, tests not readily available in clinical practice, or combinations of routine tests used in chronic hepatitis and HIV/HCV coinfection. Several radiologic techniques have also been proposed, some of which commonly used in clinical practice. The studies performed to compare the prognostic value of noninvasive surrogate methods with that of the degree of liver fibrosis assessed on liver tissue have not as yet provided conclusive results. Each surrogate technique has shown some limitations, including the risk of over- or under-estimating the extent of liver fibrosis. The current knowledge on liver fibrosis in HIV/HCVcoinfected patients will be summarized in this review article, which is addressed in particular to physicians involved in this setting in their clinical practice.

  6. Bone marrow cells ameliorate liver fibrosis and express albumin after transplantation in CCl 4 -induced fibrotic liver

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    Gibran Ali

    2012-01-01

    Full Text Available Background/Aim: We investigated the effect of bone marrow-derived stem cell (BMSC transplantation on carbon tetrachloride (CCl 4 -induced liver fibrosis. Patients and Methods: BMSCs of green fluorescent protein (GFP mice were transplanted into 4-week CCl 4 -treated C57BL/6 mice directly to the liver, and the mice were treated for 4 more weeks with CCl 4 (total, 8 weeks. After sacrificing the animals, quantitative data of percentage fibrosis area and the number of cells expressing albumin was obtained. One-way analysis of variance was applied to calculate the significance of the data. Results: GFP expressing cells clearly indicated migrated BMSCs with strong expression of albumin after 28 days post-transplantation shown by anti-albumin antibody. Double fluorescent immunohistochemistry showed reduced expression of αSMA on GFP-positive cells. Four weeks after BMSC transplantation, mice had significantly reduced liver fibrosis as compared with that of mice treated with CCl 4 assessed by Sirius red staining. Conclusion: Mice with BMSC transplantation with continuous CCl 4 injection had reduced liver fibrosis and a significantly improved expression of albumin compared with mice treated with CCl 4 alone. These findings strengthen the concept of cellular therapy in liver fibrosis.

  7. Progress of Targeting Transforming Growth Factor-β1 Small Interfering RNA in Liver Fibrosis

    Institute of Scientific and Technical Information of China (English)

    Xuan Zhou; Xue-feng Yang

    2014-01-01

    Liver fibrosis is a common pathological consequence of a variety of chronic stimuli, including viral, autoimmune, drug-induced, cholestatic and metabolic diseases. Fibrosis is driven by a dynamic process involving increased synthesis of matrix components and a failure of physiological mechanisms of matrix turnover. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis. HSCs are the main source of extracellular matrix (ECM). Transforming growth factor-beta (TGF-β), which is the fibrogenic master cytokine, can induce the activation of HSCs to produce a large amount of ECM, and is capable of inducing apoptosis of liver cells. RNA interference (RNAi) is a novel gene disruption technology. Studies have shown that small interfering RNA (siRNA) targeting TGF-β1 may inhibit the activation and proliferation of HSCs, suppress ECM synthesis and block liver fibrosis. TGF-β1 siRNA-mediated gene silencing therapy provides a new avenue for liver fibrosis. This review summarizes recent progresses in research on HSCs, TGF-β1 and TGF-β1 siRNA in liver fibrosis.

  8. Unani Treatment Decreased Fibrosis and Improved Liver Functions in Decompensated Cirrhosis of Liver: A Case Series

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    Akhtar Siddiqui

    2016-03-01

    Full Text Available At present, liver transplantation remains the only curative option for the patients with cirrhosis and end-stage liver diseases. The survival rate and recurrent diseases remain the major issues in the patient post-transplantation. Unani medicine is one of the oldest traditional systems of medicine which has been treating chronic liver diseases and cirrhosis (Talayyaful-Kabid for centuries. The current study aimed to assess the impact of Unani treatment on decompensated cirrhosis and collect data to warrant further clinical trials. Authors conducted a case series on five patients with decompensated cirrhosis and portal hypertension. The disease was confirmed through FibroScan and ultrasound and treated with Unani treatment orally for seven months. Results were evaluated based on FibroScan, liver function test (LFT, EuroQol-5D (EQ5D, Child-Pugh and TTO-TIME (trade-off question. Significant improvements in LFT, fibrosis and quality of life were achieved in the studied patients. The literature related to the herbal constituents of chief medicines used to treat in this case was reviewed. The herbs proved their potential anti-oxidative, anti-inflammatory, hepato-protective, immuno-modulator and antiviral activities, suggesting plausible mechanisms of action in the cases. The preliminary findings indicated the potential therapeutic role of Unani treatment in decompensated cirrhosis. Clinical trials should be conducted to explore further therapeutic potential of Unani treatment in decompensated cirrhosis.

  9. Evaluation of liver fibrosis in patients with thalassemia: the important role of hyaluronic acid.

    Science.gov (United States)

    Papastamataki, Maria; Delaporta, Polyxeni; Premetis, Evangelos; Kattamis, Antonios; Ladis, Vassilios; Papassotiriou, Ioannis

    2010-10-15

    Patients with transfusion-dependent thalassemia major often develop liver fibrosis due to liver iron overload and/or hepatitis virus C (HCV) infection. Hyaluronic acid (HA) plays a prominent role in the pathogenesis of liver fibrosis and the elevation of serum HA concentration is due to either increased synthesis by inflammatory cells and hepatic stellate cells or impaired degradation by sinusoidal endothelial cells (SECs) and thus is proposed as a non-invasive biomarker of liver fibrosis either by itself and/or included in the Hepascore formula. In this study we evaluated prospectively a screening of liver fibrosis in 201 adult patients aged 19-54 years with transfusion-dependent thalassemia major, based on HA measurements. 41/201 patients were HCV-RNA (+). HA was measured with a turbidimetric assay applied on a clinical chemistry analyzer. The Hepascore was computed from the results by using the model previously published. The main results of the study showed that: a) HA levels were increased in 110/201 (55%) thalassemia patients 85.0 ± 10.3 ng/ml, ranged from 15.0 to 1495.0 μg/l, compared to 20.8 ± 7.4 μg/l reference laboratory values, p0.324 and p>0.270, respectively). Our findings indicate that hyaluronic acid measurements contribute to the assessment of liver fibrosis in patients with thalassemia and might be helpful for further evaluation of patients with liver biopsy if this is truly needed. Furthermore, liver fibrosis in thalassemia seems to be independent from liver siderosis.

  10. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study

    OpenAIRE

    Ryder, S. D.

    2004-01-01

    Background: The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data concerning rates of progression are from studies using estimated dates of infection and single liver biopsy scores. We prospectively studied the rate of progression of fibrosis in HCV infected patients by repeat liver biopsies without intervening treatment.

  11. Prediction of liver-related events using fibroscan in chronic hepatitis B patients showing advanced liver fibrosis.

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    Seung Up Kim

    Full Text Available Liver stiffness measurement (LSM using transient elastography (FibroScan® can assess liver fibrosis noninvasively. This study investigated whether LSM can predict the development of liver-related events (LREs in chronic hepatitis B (CHB patients showing histologically advanced liver fibrosis.Between March 2006 and April 2010, 128 CHB patients with who underwent LSM and liver biopsy (LB before starting nucleot(side analogues and showed histologically advanced fibrosis (≥F3 with a high viral loads [HBV DNA ≥2,000 IU/mL] were enrolled. All patients were followed regularly to detect LRE development, including hepatic decompensation (variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome and hepatocellular carcinoma (HCC.The mean age of the patient (72 men, 56 women was 52.2 years. During the median follow-up period [median 27.8 (12.6-61.6 months], LREs developed in 19 (14.8% patients (five with hepatic decompensation, 13 with HCC, one with both. Together with age, multivariate analysis identified LSM as an independent predictor of LRE development [P19 kPa were at significantly greater risk than those with LSM≤19 kPa for LRE development (HR, 7.176; 95% CI, 2.257-22.812; P = 0.001.LSM can be a useful predictor of LRE development in CHB patients showing histologically advanced liver fibrosis.

  12. Effect of Chinese herbal compound on liver fibrosis in rabbits with schistosomiasis by B-ultrasound

    Institute of Scientific and Technical Information of China (English)

    Xiao-Lu Liang; Jia-Ying Yuan

    2013-01-01

    Objective:To explore the value of B-ultrasound on the evaluation of the effects of traditional Chinese medicine compound of Radix astragali, Salvia miltiorrhiza and Angelica sinensis, and TCM +praziquantel on liver fibrosis in rabbits with schistosomiasis. Methods: The hepatic fibrosis model in rabbits with schistosomiasis was established. The experimental animals (24 rabbits) were randomly divided into four groups (group A, B, C and D, n=6). Group A (control group) was only treated by praziquantel; Group B was treated by mixture of Radix astragali and Salvia miltiorrhiza +praziquantel; Group C was treated by mixture of Radix astragali and Angelica sinensis +praziquantel; Group D was treated by mixture of Radix astragali, Salvia miltiorrhiza and Angelica sinensis +praziquantel. Then B-ultrasonogram was used to evaluate the effects. Results: Each group showed certain curative effect on liver fibrosis in rabbits with schistosomiasis. The efficacy of group B, C and D was better than group A, and that of group D was the best. The differences in long diameter, thickness diameter, transverse diameter and portal vein inner diameter of liver before and after treatment were statistically significant (P<0.05). The liver function indexes and liver fibrosis indexes were significantly improved after treatment (P<0.05). Conclusions:The mixture of Radix astragali, Salvia miltiorrhiza and Angelica sinensis combined with Western medicine treatment can obviously improve the efficacy on liver fibrosis of schistosomiasis.

  13. Ginkgo biloba extract reverses CCl4-induced liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Yan-Jun Luo; Jie-Ping Yu; Zhao-Hong Shi; Li Wang

    2004-01-01

    AIM: To study the reversing effect of Ginkgo biloba extract (GbE) on established liver fibrosis in rats.METHODS: Following confirmation of CCl4-induced liver fibrosis, GbE or saline was administrated to the rats for 4 weeks. The remaining rats received neither CCl4 nor GbE as normal control. The four groups were compared in terms of serum enzymes, tissue damage, expression of αSMA and tissue inhibitor-1 of metalloproteinase (TIMP-1) and metalloproteinase-1 (MMP-1).RESULTS: Compared with saline-treated group, liver fibrosis rats treated with GbE had decreased serum total bilirubin (P<0.01) and aminotransferase levels (P<0.01) and increased levels of serum albumin (P<0.01). Microscopic studies revealed that the livers of rats receiving GbE showed allieviation in fibrosis (P<0.05) as well as expression of αSMA (P<0.01). The liver collagen and reticulum contents were lower in rats treated with GbE than saline-treated group (P<0.01). RT-PCR revealed that the level of TIMP-1 decreased while the level of MMP-1 increased in GbE group.CONCLUSION: Administration of GbE improved CCl4-induced liver fibrosis. It is possibly attributed to its effect of inhibiting the expression of TIMP-1 and promoting the apoptosis of hepatic stellate cells.

  14. Garlic attenuates histological and histochemical alterations in livers of Schistosoma mansoni infected mice.

    Science.gov (United States)

    Mahmoud, Y I; Riad, N H; Taha, H

    2016-08-01

    Interest in screening for new anti-schistosomal agents is growing because of increased concerns about resistance to and safety of praziquantel. We investigated the anti-schistosomal action of prophylactic and therapeutic doses of garlic on the histological and histochemical alterations caused by Schistosoma mansoni infection. Livers of infected mice were characterized by granulomas, periportal inflammation and fibrosis, hepatocyte vacuolation, fatty degeneration and necrosis, and hypertrophy and pigmentation of Kupffer cells. Significant depletion of carbohydrates and increased lipid vacuoles also were observed. All garlic regimens caused suppression of granuloma formation and amelioration of histological and histochemical changes; the continuous treatment protocol produced the best results. Garlic appears to be a safe and economical anti-schistosomal adjuvant for attenuating the pathogenicity of schistosomiasis. PMID:27045197

  15. The application of artificial neural network model in the non-invasive diagnosis of liver fibrosis

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    Bo LI

    2012-12-01

    Full Text Available Objective  To construct and evaluate an artificial neural network (ANN model as a new non-invasive diagnostic method for clinical assessment of liver fibrosis at early stage. Methods  The model was set up and tested among 683 chronic hepatitis B (CHB patients, with authentic positive clinical biopsy results, proved to have liver fibrosis or cirrhosis, admitted to 302 Hospital of PLA from May 2008 to March 2011. Among 683 samples, 504 samples were diagnosed as cirrhosis as a result of CHB, and 179 liver fibrosis due to other liver diseases. 134 out of 683 patients were included in training group by stratified sampling, and the others for verification. Six items (age, AST, PTS, PLT, GGT and DBil were selected as input layer indexes to set up the model for evaluation. Results  The ANN model for diagnosis of liver fibrosis was set up. The diagnostic accuracy was 77.4%, sensitivity was 76.8%, and specificity was 77.8%. Its Kappa concordance tests showed the diagnosis result of the model was consistent with biopsy result (Kappa index=0.534. The accuracy, sensitivity and specificity of CHB patients were 80.4%, 79.9% and 80.7% (Kappa index=0.598 respectively, and those for other liver diseases were 67.9%, 64.3% and 69.7% (Kappa index=0.316. Conclusion  The artificial neural network model established by the authors demonstrates its high sensitivity and specificity as a new non-invasive diagnostic method for liver fibrosis induced by HBV infection. However, it shows limited diagnostic reliability to fibrosis as a result of other liver diseases.

  16. A multiscale agent-based in silico model of liver fibrosis progression

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    Joyeeta eDutta-Moscato

    2014-05-01

    Full Text Available Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM of liver tissue in order to computationally examine the consequence of liver inflammation. Our Liver Fibrosis ABM (LFABM is comprised of literature-derived rules describing molecular and histopathologic aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern (DAMP molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathologic features observed in liver sections from rats treated with carbon tetrachloride (CCl4. An in silico tension test for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing TNF-a vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathologic and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into live fibrosis.

  17. Correlation between ultrasonographic and pathologic diagnosis of liver fibrosis due to chronic virus hepatitis

    Institute of Scientific and Technical Information of China (English)

    Lei Shen; Ji-Qiang Li; Min-De Zeng; Lun-Gen Lu; Si-Tao Fan; Han Bao

    2006-01-01

    AIM: To evaluate the validity of ultrasonographic and pathologic diagnosis of liver fibrosis in patients with chronic viral hepatitis.METHODS: The liver fibrosis status in 324 patients was evaluated by both needle biopsy and ultrasonography.Liver fibrosis was divided into S0 -S4 stages. S4 stage was designated as definite cirrhosis. The ultrasonographic examination included qualitative variables, description of liver surface and parenchyma, and quantitative parameters, such as diameter of vessels, blood flow velocity and spleen size.RESULTS: Ultrasonographic qualitative description of liver surface and parenchyma was related with the severity of fibrosis. Among the quantitative ultrasonographic parameters, cut-off value of spleen length (12.1 cm) had a sensitivity of 0.600 and a specificity of 0.753 for diagnosis of liver cirrhosis. The diameters of spleen (8 mm) and portal vein (12 mm) had a diagnostic sensitivity of 0.600and 0.767, and a diagnostic specificity of 0.781 and 0.446,respectively. The diagnostic accuracy for liver cirrhosis was moderately satisfactory, and the negative predictive values of these parameters reached near 0.95.CONCLUSION: Ultrasonography can predict the degree of liver fibrosis or cirrhosis. A single ultrasonographic parameter is limited in sensitivity and specificity for the diagnosis of early cirrhosis. The presence or absence of liver cirrhosis in patients with chronic virus hepatitis can be detected using 2 or 3 quantitative and qualitative parameters, especially the length of spleen, the diameter of spleen vein and echo pattern of liver surface.

  18. ACOUSTIC RADIATION FORCE IMPULSE IS EQUIVALENT TO LIVER BIOPSY TO EVALUATE LIVER FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS C AND NONALCOHOLIC FATTY LIVER DISEASE

    Directory of Open Access Journals (Sweden)

    Juliana Ayres de Alencar Arrais GUERRA

    2015-09-01

    Full Text Available BackgroundLiver biopsy is recommended as the gold standard method for assessing the stage of liver fibrosis in patients with chronic liver disease. However, it is invasive, with potential risks and complications. Elastography is an ultrasound technique that provides information of changes in the liver tissue, evaluating tissue elasticity and acoustic radiation force impulse is one of the available techniques.ObjectiveThe main objective of this study was to evaluate the sensitivity and specificity of acoustic radiation force impulse comparing to liver biopsy to evaluate fibrosis in patients with chronic hepatitis C virus and nonalcoholic fatty liver disease.MethodsTwenty four patients were included, everyone underwent liver biopsy and acoustic radiation force impulse, and the results were compared with values described in the literature by several authors.ResultsIn the population of patients with chronic hepatitis C, our data were better correlated with data published by Carmen Fierbinteanu-Braticevici et al., with an accuracy of 82.4%, sensitivity of 71.4% and specificity of 90%. For nonalcoholic fatty liver disease, our data were better correlated with data published by Masato Yoneda et al., with an accuracy of 85.7%, sensitivity 80% and specificity of 100%.ConclusionAcoustic radiation force impulse is a method with good accuracy to distinguish initial fibrosis from advanced fibrosis in hepatitis C virus and nonalcoholic fatty liver disease and can replace biopsy in most cases.

  19. Clusterin/apolipoprotein J attenuates angiotensin II-induced renal fibrosis.

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    Gwon-Soo Jung

    Full Text Available The blockade of angiotensin II (Ang II is a major therapeutic strategy for diabetic nephropathy. The main roles of Ang II in renal disease are mediated via the Ang type 1 receptor (AT1R. Upregulation of clusterin/apolipoprotein J has been reported in nephropathy models, suggesting it has a protective role in nephropathogenesis. Here, we studied how clusterin acts against Ang II-induced renal fibrosis. Levels of AT1R and fibrotic markers in clusterin-/- mice and Ang II infused rats transfected with an adenovirus encoding clusterin were evaluated by immunoblot analysis, real time RT-PCR, and immunohistochemical staining. The effect of clusterin on renal fibrosis was evaluated in NRK-52E cells, a cultured renal tubular epithelial cell line, using immunoblot analysis and real time RT-PCR. Nuclear localization of NF-κB was evaluated using immunofluorecence and co-immunoprecipitation. Renal fibrosis and expression of AT1R was higher in the kidneys of clusterin-/- mice than in those of wild-type mice. Furthermore, loss of clusterin accelerated Ang II-stimulated renal fibrosis and AT1R expression. Overexpression of clusterin in proximal tubular epithelial cells decreased the levels of Ang II-stimulated fibrotic markers and AT1R. Moreover, intrarenal delivery of clusterin attenuated Ang II-mediated expression of fibrotic markers and AT1R in rats. Fluorescence microscopy and co-immunoprecipitation in conjunction with western blot revealed that clusterin inhibited Ang II-stimulated nuclear localization of p-NF-κB via a direct physical interaction and subsequently decreased the AT1R level in proximal tubular epithelial cells. These data suggest that clusterin attenuates Ang II-induced renal fibrosis by inhibition of NF-κB activation and subsequent downregulation of AT1R. This study raises the possibility that clusterin could be used as a therapeutic target for Ang II-induced renal diseases.

  20. Effect of Anluohuaxian Tablet Combined with y-IFN on Schistosomal Liver Fibrosis

    Institute of Scientific and Technical Information of China (English)

    Jiaquan HUANG; Haiyan HUANG; Yuntao JIAO; Guo AI; Tiejun HUANG; Lan LI; Haijing YU; Ke MA; Fei XLAO

    2009-01-01

    The therapeutic effects of anluohuaxian tablet combined with γ-IFN on schistosomal liver fibrosis and its mechanism were studied in a murine model and clinical cases of schistosomal liver fibrosis.Fifty Kunming mice were randomly divided into 5 groups:normal control group,infection control group,anluohuaxian tablet-treated group,γ-IFN-treated group and combined treatment (anluohuaian tablet+γ-IFN) group.Pathologic changes in liver,including hepatic pigmentation and the size of schistosomal egg granuloma,were observed by HE staining after treatment for 8 weeks.The expression of the type Ⅰ and Ⅲ collagen,and TIMP-1 was detected by immunohistochemistry.TGF-β1 mRNA expression was examined by real-time fluorescent quantitative PCR.Sixty patients with schistosomal liver fibrosis were divided into treatment group and control group.The patients in treatment group were treated with anluohuaxian tablet in combination with γ-IFN for 6 months.Be-fore and after treatment,the changes of symptoms and signs,liver function,serum liver fibrosis in-dexes and imaging indexes were observed.The results showed that as compared with infection con-trol group,all forms of treatments relieved the hepatic pathological injury with apparently diminished size of schistosomal egg nodules and decreased percentage of pigmentation (P<0.05).Furthermore,the expression of collagen Ⅰ and Ⅲ,TIMP-Ⅰ,and TGF-β1 mRNA in combined treatment group was significantly decreased as compared with anluohuaxian tablet-treated and γ-IFN-treated groups (P<0.05).In the clinical observation,the serum liver fibrosis indexes,the portal vein width as well as the spleen thickness was significantly reduced in treatment group as compared with control group (P<0.05).It was concluded that the combined use of anluohuaxian tablet with γ-IFN in schistosomal liver fibrosis could protect liver function,alleviate liver fibrosis,and could be used as a choice in treating patients with schiatosomal liver fibrosis.

  1. Serum Liver Fibrosis Markers in the Prognosis of Liver Cirrhosis: A Prospective Observational Study.

    Science.gov (United States)

    Qi, Xingshun; Liu, Xu; Zhang, Yongguo; Hou, Yue; Ren, Linan; Wu, Chunyan; Chen, Jiang; Xia, Chunlian; Zhao, Jiajun; Wang, Di; Zhang, Yanlin; Zhang, Xia; Lin, Hao; Wang, Hezhi; Wang, Jinling; Cui, Zhongmin; Li, Xueyan; Deng, Han; Hou, Feifei; Peng, Ying; Wang, Xueying; Shao, Xiaodong; Li, Hongyu; Guo, Xiaozhong

    2016-01-01

    BACKGROUND The prognostic role of serum liver fibrosis markers in cirrhotic patients remains unclear. We performed a prospective observational study to evaluate the effect of amino-terminal pro-peptide of type III pro-collagen (PIIINP), collagen IV (CIV), laminin (LN), and hyaluronic acid (HA) on the prognosis of liver cirrhosis. MATERIAL AND METHODS All patients who were diagnosed with liver cirrhosis and admitted to our department were prospectively enrolled. PIIINP, CIV, LN, and HA levels were tested. RESULTS Overall, 108 cirrhotic patients were included. Correlation analysis demonstrated that CIV (coefficient r: 0.658, p<0.001; coefficient r: 0.368, p<0.001), LN (coefficient r: 0.450, p<0.001; coefficient r: 0.343, p<0.001), and HA (coefficient r: 0.325, p=0.001; coefficient r: 0.282, p=0.004) levels, but not PIIINP level (coefficient r: 0.081, p=0.414; coefficient r: 0.090, p=0.363), significantly correlated with Child-Pugh and MELD scores. Logistic regression analysis demonstrated that HA (odds ratio=1.00003, 95% confidence interval [CI]=1.000004-1.000056, p=0.022) was significantly associated with the 6-month mortality. Receiver operating characteristics analysis demonstrated that the area under the curve (AUC) of HA for predicting the 6-month mortality was 0.612 (95%CI=0.508-0.709, p=0.1531). CONCLUSIONS CIV, LN, and HA levels were significantly associated with the severity of liver dysfunction, but might be inappropriate for the prognostic assessment of liver cirrhosis. PMID:27480906

  2. Association of Fasciola hepatica Infection with Liver Fibrosis, Cirrhosis, and Cancer: A Systematic Review

    Science.gov (United States)

    Machicado, Claudia; Machicado, Jorge D.; Maco, Vicente; Terashima, Angelica; Marcos, Luis A.

    2016-01-01

    Background Fascioliasis has been sporadically associated with chronic liver disease on previous studies. In order to describe the current evidence, we carried out a systematic review to assess the association between fascioliasis with liver fibrosis, cirrhosis and cancer. Methodology and Principal Findings A systematic search of electronic databases (PubMed, LILACS, Scopus, Embase, Cochrane, and Scielo) was conducted from June to July 2015 and yielded 1,557 published studies. Among 21 studies that met inclusion and exclusion criteria, 12 studies explored the association of F. hepatica with liver fibrosis, 4 with liver cirrhosis, and 5 with cancer. Globally these studies suggested the ability of F. hepatica to promote liver fibrosis and cirrhosis. The role of F. hepatica in cancer is unknown. Given the heterogeneity of the studies, a meta-analysis could not be performed. Conclusions Future high-quality studies are needed to determine the role of F. hepatica on the development of liver fibrosis, liver cirrhosis, and cancer in humans. PMID:27681524

  3. Regulatory T Cells Prevent Liver Fibrosis During HIV Type 1 Infection in a Humanized Mouse Model

    OpenAIRE

    Nunoya, Jun-ichi; Washburn, Michael L.; Kovalev, Grigoriy I; Su, Lishan

    2013-01-01

    Human immunodeficiency virus type 1 (HIV-1) disease is associated with aberrant immune activation, and coinfection with hepatitis C virus (HCV) exacerbates hepatic inflammation and fibrosis. However, the role of HIV-1 infection or host immune modulation in liver pathogenesis is not clearly defined. Here, we report that regulatory T (Treg) cells prevent liver immunopathogenesis during HIV-1 infection in a humanized mouse model. In the absence of Treg cells, HIV-1 infection induced liver fibros...

  4. Validation of hepascore as a predictor of liver fibrosis in patients with chronic hepatitis C infection.

    Science.gov (United States)

    Kalantari, Hamid; Hoseini, Hannan; Babak, Anahita; Yaran, Majid

    2011-01-01

    Introduction. Liver biopsy is an invasive determinator for hepatic fibrosis. Serum biomarkers can probably be used as an alternative to liver biopsy in assessment of the degree of fibrosis in patients with chronic Hepatitis C. Method. Eighty patients with chronic Hepatitis C were included in the study using simple nonrandom sampeling metod. After fulfillment of liver biopsy, the patients were categorized according to the METAVIR Scoring system. The Hepascore algorithm is computed based on age, sex, and the serum levels of total bilirubin, δ-glutamyl transferase, α2-Macroglobulin, and hyaluronic acid. The spearman and ROC tests were used. Results. According to the liver biopsy results, 12, 25, 20, 7 and 16 patients had F0, F1, F2, F3, and F4, respectively. With regard to the 0.34 cut-off point Hepascore had 67%, 56%, 64%, and 56% sensitivity, specificity, respectively, positive prediction value (PPV), and negative prediction value (NPV), respectively, for diagnosis of significant fibrosis. For a Hepascore cut-off point 0.61, sensitivity, specificity, respectively, PPV and NPB 82%, 86%, 70%, and 92% in diagnosis of severe fibrosis. For a Hepascore cut-off point 0.84, sensitivity, specificity, PPV and NPB were respectively 100%, 97%, 89%, and 100% for diagnosis of cirrhosis. Conclusion. Hepascore has a high value in diagnosis of the level of fibrosis, particularly cirrhosis. Therefore, it can be used for primary screening of patients to determine the need for liver biopsy.

  5. Liver shear-wave velocity and serum fibrosis markers to diagnose hepatic fibrosis in patients with chronic viral hepatitis B

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jian Xue; Ji, Yong Hao; Zhao Junzhi; Zhang, Yao Ren; Dun, Guo Liang; Ning, Bo [Dept. of Ultrasonography, Baoji Central Hospital, Baoji (China); Ai, Hong [Dept. of Ultrasonography, The First Affiliated Hospital of Medical College, Xi' an Jiaotong University, Xi' an (China)

    2016-06-15

    To compare several noninvasive indices of fibrosis in chronic viral hepatitis B, including liver shear-wave velocity (SWV), hyaluronic acid (HA), collagen type IV (CIV), procollagen type III (PCIII), and laminin (LN). Acoustic radiation force impulse (ARFI) was performed in 157 patients with chronic viral hepatitis B and in 30 healthy volunteers to measure hepatic SWV (m/s) in a prospective study. Serum markers were acquired on the morning of the same day of the ARFI evaluation. Receiver operating characteristic (ROC) analysis was performed to evaluate and compare the accuracies of SWV and serum markers using METAVIR scoring from liver biopsy as a reference standard. The most accurate test for diagnosing fibrosis F ≥ 1 was SWV with the area under the ROC curve (AUC) of 0.913, followed by LN (0.744), HA (0.701), CIV (0.690), and PCIII (0.524). The best test for diagnosing F ≥ 2 was SWV (AUC of 0.851), followed by CIV (0.671), HA (0.668), LN (0.562), and PCIII (0.550). The best test for diagnosing F ≥ 3 was SWV (0.854), followed by CIV (0.693), HA (0.675), PCIII (0.591), and LN (0.548). The best test for diagnosing F = 4 was SWV (0.965), followed by CIV (0.804), PCIII (0.752), HA (0.744), and LN (0.662). SWV combined with HA and CIV did not improve diagnostic accuracy (AUC = 0.931 for F ≥ 1, 0.863 for F ≥ 2, 0.855 for F ≥ 3, 0.960 for F = 4). The performance of SWV in diagnosing liver fibrosis is superior to that of serum markers. However, the combination of SWV, HA, and CIV does not increase the accuracy of diagnosing liver fibrosis and cirrhosis.

  6. Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis.

    Science.gov (United States)

    Shimbori, Chiko; Bellaye, Pierre-Simon; Xia, Jiaji; Gauldie, Jack; Ask, Kjetil; Ramos, Carlos; Becerril, Carina; Pardo, Annie; Selman, Moises; Kolb, Martin

    2016-10-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibroblast and myofibroblast proliferation, and extensive deposition of extracellular matrix (ECM). Fibroblast growth factor-1 (FGF-1) belongs to the FGF family and has been shown to inhibit fibroblast collagen production and differentiation into myofibroblasts, and revert epithelial-mesenchymal transition by inhibiting TGF-β1 signalling pathways. However, the precise role of FGF-1 in pulmonary fibrosis has not yet been elucidated. In this study, we explore the mechanisms underlying the anti-fibrogenic effect of FGF-1 in pulmonary fibrosis in vitro and in vivo by prolonged transient overexpression of FGF-1 (AdFGF-1) and TGF-β1 (AdTGF-β1) using adenoviral vectors. In vivo, FGF-1 overexpression markedly attenuated TGF-β1-induced pulmonary fibrosis in rat lungs when given both concomitantly, or delayed, by enhancing proliferation and hyperplasia of alveolar epithelial cells (AECs). AdFGF-1 also attenuated the TGF-β1 signalling pathway and induced FGFR1 expression in AECs. In vitro, AdFGF-1 prevented the increase in α-SMA and the decrease in E-cadherin induced by AdTGF-β1 in normal human lung fibroblasts, primary human pulmonary AECs, and A549 cells. Concomitantly, AdTGF-β1-induced Smad2 phosphorylation was significantly reduced by AdFGF-1 in both cell types. AdFGF-1 also attenuated the increase in TGFβR1 protein and mRNA levels in fibroblasts. In AECs, AdFGF-1 decreased TGFβR1 protein by favouring TGFβR1 degradation through the caveolin-1/proteasome pathway. Furthermore, FGFR1 expression was increased in AECs, whereas it was decreased in fibroblasts. In serum of IPF patients, FGF-1 levels were increased compared to controls. Interestingly, FGF-1 expression was restricted to areas of AEC hyperplasia, but not α-SMA-positive areas in IPF lung tissue. Our results demonstrate that FGF-1 may have preventative and therapeutic effects on TGF-β1-driven pulmonary fibrosis via inhibiting

  7. Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat.

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    Wei Luo

    Full Text Available OBJECTIVE: Aldosterone, one of the main peptides in renin angiotensin aldosterone system (RAAS, has been suggested to mediate liver fibrosis and portal hypertension. Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice. However, the mechanisms remain unclear. The present study aimed to investigate the role of spionolactone on liver cirrhosis and portal hypertension. METHODS: Liver cirrhosis was induced by bile duct ligation (BDL. Spironolactone was administered orally (20 mg/kg/d after bile duct ligation was performed. Liver fibrosis was assessed by histology, Masson's trichrome staining, and the measurement of hydroxyproline and type I collagen content. The activation of HSC was determined by analysis of alpha smooth muscle actin (α-SMA expression. Protein expressions and protein phosphorylation were determined by immunohistochemical staining and Western blot analysis, Messenger RNA levels by quantitative real time polymerase chain reaction (Q-PCR. Portal pressure and intrahepatic resistance were examined in vivo. RESULTS: Treatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of HSC activation. In BDL rat liver, spironolactone suppressed up-regulation of proinflammatory cytokines (TNFα and IL-6. Additionally, spironolactone significantly decreased ROCK-2 activity without affecting expression of RhoA and Ras. Moreover, spironolactone markedly increased the levels of endothelial nitric oxide synthase (eNOS, phosphorylated eNOS and the activity of NO effector-protein kinase G (PKG in the liver. CONCLUSION: Spironolactone lowers portal hypertension by improvement of liver fibrosis and inhibition of intrahepatic vasoconstriction via down-regulating ROCK-2 activity and activating NO/PKG pathway. Thus, early spironolactone therapy might be the optional therapy in cirrhosis and

  8. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis

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    Elena Turola

    2015-09-01

    Full Text Available Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD. Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported; liver biopsy was scored according to ‘The Pathology Committee of the NASH Clinical Research Network’. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI, histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR: 1.408, 95% confidence interval (95% CI: 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06. In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04 was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males, whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis.

  9. Ovarian senescence increases liver fibrosis in humans and zebrafish with steatosis

    Science.gov (United States)

    Turola, Elena; Petta, Salvatore; Vanni, Ester; Milosa, Fabiola; Valenti, Luca; Critelli, Rosina; Miele, Luca; Maccio, Livia; Calvaruso, Vincenza; Fracanzani, Anna L.; Bianchini, Marcello; Raos, Nazarena; Bugianesi, Elisabetta; Mercorella, Serena; Di Giovanni, Marisa; Craxì, Antonio; Fargion, Silvia; Grieco, Antonio; Cammà, Calogero; Cotelli, Franco; Villa, Erica

    2015-01-01

    ABSTRACT Contrasting data exist on the effect of gender and menopause on the susceptibility, development and liver damage progression in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether menopause is associated with the severity of liver fibrosis in individuals with NAFLD and to explore the issue of ovarian senescence in experimental liver steatosis in zebrafish. In 244 females and age-matched males with biopsy-proven NAFLD, we assessed anthropometric, biochemical and metabolic features, including menopausal status (self-reported); liver biopsy was scored according to ‘The Pathology Committee of the NASH Clinical Research Network’. Young and old male and female zebrafish were fed for 24 weeks with a high-calorie diet. Weekly body mass index (BMI), histopathological examination and quantitative real-time PCR analysis on genes involved in lipid metabolism, inflammation and fibrosis were performed. In the entire cohort, at multivariate logistic regression, male gender [odds ratio (OR): 1.408, 95% confidence interval (95% CI): 0.779-2.542, P=0.25] vs women at reproductive age was not associated with F2-F4 fibrosis, whereas a trend was observed for menopause (OR: 1.752, 95% CI: 0.956-3.208, P=0.06). In women, menopause (OR: 2.717, 95% CI: 1.020-7.237, P=0.04) was independently associated with F2-F4 fibrosis. Similarly, in overfed zebrafish, old female fish with failing ovarian function [as demonstrated by extremely low circulating estradiol levels (1.4±0.1 pg/µl) and prevailing presence of atretic follicles in the ovaries] developed massive steatosis and substantial fibrosis (comparable with that occurring in males), whereas young female fish developed less steatosis and were totally protected from the development of fibrosis. Ovarian senescence significantly increases the risk of fibrosis severity both in humans with NAFLD and in zebrafish with experimental steatosis. PMID:26183212

  10. Supersonic shearwave elastography in the assessment of liver fibrosis for postoperative patients with biliary atresia

    Science.gov (United States)

    Chen, Shuling; Liao, Bing; Zhong, Zhihai; Zheng, Yanling; Liu, Baoxian; Shan, Quanyuan; Xie, Xiaoyan; Zhou, Luyao

    2016-01-01

    To explore an effective noninvasive tool for monitoring liver fibrosis of children with biliary atresia (BA) is important but evidences are limited. This study is to investigate the predictive accuracy of supersonic shearwave elastography (SSWE) in liver fibrosis for postoperative patients with BA and to compare it with aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4). 24 patients with BA received SSWE and laboratory tests before scheduled for liver biopsy. Spearman rank coefficient and receiver operating characteristic (ROC) were used to analyze data. Metavir scores were F0 in 3, F1 in 2, F2 in 4, F3 in 7 and F4 in 8 patients. FIB-4 failed to correlate with fibrosis stage. The areas under the ROC curves of SSWE, APRI and their combination were 0.79, 0.65 and 0.78 for significant fibrosis, 0.81, 0.64 and 0.76 for advanced fibrosis, 0.82, 0.56 and 0.84 for cirrhosis. SSWE values at biopsy was correlated with platelet count (r = −0.426, P = 0.038), serum albumin (r = −0.670, P < 0.001), total bilirubin (r = 0.419, P = 0.041) and direct bilirubin levels (r = 0.518, P = 0.010) measured at 6 months after liver biopsy. Our results indicate that SSWE is a more promising tool to assess liver fibrosis than APRI and FIB-4 in children with BA. PMID:27511435

  11. The severity of liver fibrosis is associated with high leptin levels in chronic hepatitis C.

    Science.gov (United States)

    Piche, T; Vandenbos, F; Abakar-Mahamat, A; Vanbiervliet, G; Barjoan, E M; Calle, G; Giudicelli, J; Ferrua, B; Laffont, C; Benzaken, S; Tran, A

    2004-01-01

    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. PMID:14738564

  12. Expression of exogenous rat collagenase in vitro and in a rat model of liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Ji-Yao Wang; Jin-Sheng Guo; Chang-Qing Yang

    2002-01-01

    AIM: The present study was conducted to test thehypothesis that the introduction of the collagenase geneinto tissue culture cells and into a rat model of liver fibrosiswould result in the expression of enzymatically active product.METHODS: FLAG-tagged full-length rat collagenase cDNAwas PCR amplified and cloned into a mammalian expressionvector. NIH3T3 cells were then transiently transfected withthis construct. Expression of exogenous collagenase mRNAwas assessed by RT-PCR, and the exogenous collagenasedetected by Western blotting using anti-FLAG monoclonalantibodyEnzymatic activity was detected by gelatinzymography. To determine the effects of exogenouscollagenase production in vivo, the construct was boundto glycosyl-poly-L-lysine and then transduced into rats thathad developed liver fibrosis as a result of CCI4 plus ethanoltreatment. The hepatic expression of the construct and itseffect on the formation of liver fibrosis were demonstratedusing RT-PCR and immunohistochemistry.RESULTS: It was found that exogenously expressed ratcollagenase mRNA could be detected in NTH3T3 cellsfollowing transfection. Enzymatic ally active collagenase couldalso be detected in the culture medium. The recombinantplasmid was also expressed in rat liver after in vivo genetransfer. Expression of exogenous rat collagenase correlatedwith decreased deposition of collagen types I and Ⅲ in thelivers of rats with experimentally induced liver fibrosis.CONCLUSION: The expression of active exogenous ratcollagenase could be achieved in vitro and in vivo. It wassuggested that in vivo expression of active exogenouscollagenase may have therapeutic effects on the formationof liver fibrosis.

  13. ASSOCIATION OF CAFFEINE INTAKE AND LIVER FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS C

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    Kalinca da Silva OLIVEIRA

    2015-03-01

    Full Text Available Background Caffeine consumption has been associated to decreased levels of liver enzymes and lower risk of fibrosis in patients with hepatitis C virus. Objectives This study aimed to evaluate the association between caffeine consumption and inflammatory activity or degree of liver fibrosis in patients with hepatitis C virus infection. Methods A cross-sectional study of patients with chronic hepatitis C virus infection treated in an outpatient Gastroenterology Unit of Santa Casa Hospital (Porto Alegre - Brasil. Patients were interviewed regarding the consumption of caffeine and anthropometric assessment was performed. Liver biopsy was performed in a maximum period of 36 months before inclusion in the study Results There were 113 patients, 67 (59.3% females, 48 (42.5% were aged between 52 and 62 years, and 101 (89.4% were white. The average caffeine consumption was 251.41 ± 232.32 mg/day, and 70 (62% patients consumed up to 250 mg/day of caffeine. There was no association between caffeine consumption and inflammatory activity on liver biopsy. On the other hand, when evaluating the caffeine consumption liver fibrosis an inverse association was observed. Conclusions The greater consumption of caffeine was associated with lower liver fibrosis. There was no association between caffeine consumption and inflammatory activity.

  14. Metabolic Profile Changes of CCl₄-Liver Fibrosis and Inhibitory Effects of Jiaqi Ganxian Granule.

    Science.gov (United States)

    Wang, Ge; Li, Zehao; Li, Hao; Li, Lidan; Li, Jian; Yu, Changyuan

    2016-01-01

    Jiaqi Ganxian Granule (JGG) is a famous traditional Chinese medicine, which has been long used in clinical practice for treating liver fibrosis. However, the mechanism underlying its anti-hepatic fibrosis is still not clear. In this study, an Ultra-Performance Liquid Chromatography-Time-Of-Flight Mass Spectrometry (UPLC-TOF-MS)-based metabolomics strategy was used to profile the metabolic characteristic of serum obtained from a carbon tetrachloride (CCl₄)-induced hepatic fibrosis model in Sprague-Dawley (SD) rats with JGG treatment. Through Principal Component Analysis (PCA) and Partial Least Square Discriminant Analysis (PLS-DA), it was shown that metabolic perturbations induced by CCl₄ were inhibited after treatment of JGG, for 17 different metabolites related to CCl₄. Among these compounds, the change tendency of eight potential drug targets was restored after the intervention with JGG. The current study indicates that JGG has a significant anti-fibrosis effect on CCl₄-induced liver fibrosis in rats, which might be by regulating the dysfunction of sphingolipid metabolism, glycerophospholipid metabolism, N-acylethanolamine biosynthesis, fat digestion and absorption, while glycerophospholipid metabolism played vital roles in the inhibitory effects of JGG on hepatic fibrosis according to Metabolic Pathway Analysis (MetPA). Our findings indicated that the metabolomics approach may provide a useful tool for exploring potential biomarkers involved in hepatic fibrosis and elucidate the mechanisms underlying the action of therapies used in traditional Chinese medicine. PMID:27248993

  15. Present Situation in Preventing and Treating Liver Fibrosis with TCM Drugs

    Institute of Scientific and Technical Information of China (English)

    杜斌; 尤松鑫

    2001-01-01

    @@Liver fibrosis is a gradual process of increased secretion and decreased degradation of extracellular materials (ECM). Most author hold that the process is initiated by the damage of hepatic cells (HCs), which leads to activation and secretion of multiple cellular factors of Kupffer cells. These factors, along with the cellular factors secreted by damaged HCs, thrombocytes and endothelial cells of the hepatic sinusoid, and some chemical mediators are activators of hepatic stellate cells (HSCs). Being activated, HSCs differentiate into myofibroblasts, and, via self-secretion and parasecretion, proliferate and synthesize a massive amount of extracellular materials which gradually accumulate and lead to formation of liver fibrosis.1 Since fibrosis is a common course in a variety of chronic liver diseases, prevention against its formation is of great importance. The following are the recent achievements of traditional Chinese medicine (TCM) in this field.

  16. Detection of collagen by second harmonic microscopy as a diagnostic tool for liver fibrosis

    Science.gov (United States)

    Banavar, Maruth; Kable, Eleanor P. W.; Braet, Filip; Wang, X. M.; Gorrell, M. D.; Cox, Guy

    2006-02-01

    Liver fibrosis has many causes, including hepatitis C, alcohol abuse, and non-alcoholic steatohepatitis. It is characterized by abnormal deposition of extracellular matrix proteins, mainly collagen. The deposition of these proteins results in impaired liver function caused by distortion of the hepatic architecture by fibrous scar tissue. The unique triple helix structure of collagen and high level of crystallinity make it very efficient for generating second harmonic signals. In this study we have set out to see if second harmonic imaging of collagen can be used as a non-biased quantitative tool for classification of fibrosis levels in liver biopsies and if it can detect early fibrosis formation not detected by current methods.

  17. Long non-coding RNA APTR promotes the activation of hepatic stellate cells and the progression of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Fujun [Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai, 201508 (China); Zheng, Jianjian [Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 (China); Mao, Yuqing [Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai, 201508 (China); Dong, Peihong [Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 (China); Li, Guojun [Department of Hepatology, Ningbo Yinzhou Second Hospital, Ningbo, 315000 (China); Lu, Zhongqiu [Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 (China); Guo, Chuanyong; Liu, Zhanju [Department of Gastroenterology, Shanghai Tenth People' s Hospital, Tongji University School of Medicine, Shanghai, 200072 (China); Fan, Xiaoming, E-mail: ktsqdph@163.com [Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai, 201508 (China)

    2015-08-07

    In this study, we aimed at assessing a role of Alu-mediated p21 transcriptional regulator (APTR) in hepatofibrogenesis. APTR was upregulated in fibrotic liver samples and activated hepatic stellate cells (HSCs). Knockdown of APTR inhibited the activation of HSCs in vitro and mitigated the accumulation of collagen in vivo. Importantly, APTR silencing could abrogate TGF-β{sub 1}-induced upregulation of α-SMA in HSCs. In addition, inhibition of cell cycle and cell proliferation by APTR knockdown was attenuated by p21 siRNA1 in primary HSCs. Finally, serum APTR levels were increased in patients with liver cirrhosis, indicating a potential biomarker for liver cirrhosis. Collectively, evidence is proposed for a new biological role of APTR in hepatofibrogenesis. - Highlights: • APTR is upregulated in fibrotic liver tissues and activated HSCs. • APTR silencing inhibits HSC activation and the progression of liver fibrosis. • Antifibrotic effect of APTR silencing is achieved by increasing p21.

  18. A comparison of MR elastography and {sup 31}P MR spectroscopy with histological staging of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Godfrey, Edmund M. [St James' Hospital, Leeds (United Kingdom); St James' Hospital, Department of Radiology, Leeds (United Kingdom); Patterson, Andrew J.; Priest, Andrew N.; Davies, Susan E.; Joubert, Ilse; Krishnan, Anant S.; Shaw, Ashley S.; Alexander, Graeme J.; Allison, Michael E.; Griffiths, William J.H.; Gimson, Alexander E.S. [Addenbrooke' s Hospital, Cambridge (United Kingdom); Griffin, Nyree [St Thomas' s Hospital, London (United Kingdom); Lomas, David J. [University of Cambridge, Department of Radiology, Cambridge (United Kingdom)

    2012-12-15

    Conventional imaging techniques are insensitive to liver fibrosis. This study assesses the diagnostic accuracy of MR elastography (MRE) stiffness values and the ratio of phosphomonoesters (PME)/phosphodiesters (PDE) measured using {sup 31}P spectroscopy against histological fibrosis staging. The local research ethics committee approved this prospective, blinded study. A total of 77 consecutive patients (55 male, aged 49 {+-} 11.5 years) with a clinical suspicion of liver fibrosis underwent an MR examination with a liver biopsy later the same day. Patients underwent MRE and {sup 31}P spectroscopy on a 1.5 T whole body system. The liver biopsies were staged using an Ishak score for chronic hepatitis or a modified NAS fibrosis score for fatty liver disease. MRE increased with and was positively associated with fibrosis stage (Spearman's rank = 0.622, P < 0.001). PME/PDE was not associated with fibrosis stage (Spearman's rank = -0.041, p = 0.741). Area under receiver operating curves for MRE stiffness values were high (range 0.75-0.97). The diagnostic utility of PME/PDE was no better than chance (range 0.44-0.58). MRE-estimated liver stiffness increases with fibrosis stage and is able to dichotomise fibrosis stage groupings. We did not find a relationship between {sup 31}P MR spectroscopy and fibrosis stage. circle Magnetic resonance elastography (MRE) and MR spectroscopy can both assess the liver. (orig.)

  19. Selective Activation of At2 Receptor Attenuates Progression of Pulmonary Hypertension and Inhibits Cardiopulmonary Fibrosis

    DEFF Research Database (Denmark)

    Bruce, E; Shenoy, V; Rathinasabapathy, A;

    2015-01-01

    -ventricular hemodynamic parameters were measured and tissues collected for gene expression and histological analyses. KEY RESULTS: Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular...... fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines, and favorable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas......BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right heart failure and death. A dysregulated renin angiotensin system (RAS) has been implicated in the development and progression of PH...

  20. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease

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    Paloma Almeda-Valdes

    2015-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance.

  1. Analysis of the efficiency of FibroScan combined with serologic markers for diagnosing liver fibrosis

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    Dong JI

    2011-11-01

    Full Text Available Objective To determine the usefulness of transient elastography(FibroScan combined with other serologic markers in diagnosing liver fibrosis.Methods The study enrolled 313 patients with hepatitis B virus(HBV infection for routine biochemical examination,FibroScan,and liver biopsy.A Receive Operating Characteristic(ROC curve was drawn and the area under the curve was analyzed to determine the cutoff value,sensitivity,specificity,positive predictive value,and negative predictive value of FibroScan,APRI,and FIB-4 for diagnosing different stages of liver fibrosis.Results FibroScan,APRI,and FIB-4 were used to diagnose moderate liver fibrosis.The areas under the curve(AUROC were 0.791,0.792,and 0.796;the cutoff values were 9.3,0.65,and 1.15 kPa;the sensitivities were 55.1%,62.3%,and 69.1%;and specificities were 94.8%,88.3%,and 89.7%,respectively.For diagnosing liver cirrhosis,the AUROC were 0.947,0.911,and 0.953;the cutoff values were 15.4,1.14,and 2.96 kPa;the sensitivities were 90.0%,96.0%,and 88.0%;and the specificities were 87.8%,79.8%,and 92.8%,respectively.FibroScan combined with APRI or FIB-4 was used to diagnose moderate liver fibrosis,and the AUROC was 0.836,which is obviously higher than the AUROC(0.791,P < 0.05 obtained using FibroScan alone.Conclusion The combination of FibroScan with APRI or FIB-4 significantly improves the sensitivity of diagnosing moderate liver fibrosis without significantly reducing the specificity.It can be used as an alternative of liver biopsy,and in determining whether patients with transaminase levels less than twice the normal value need antiviral treatment or not.

  2. Cystamine ameliorates liver fibrosis induced by carbon tetrachloride via inhibition of tissue transglutaminase

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the anti-fibrosis effect of the tissue transglutaminase (tTG) specific inhibitor cystamine on liver fibrosis.METHODS: Sixty-eight male Sprague Dawley rats were divided into three groups: normal control, liver fibrosis control and cystamine-treated group. Liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl4), and Cystamine was administrated by intraperitoneal injection starting 2 d before the first administration of CCl4. Animals in each group were further divided into 2 subgroups according to two time points of 4 wk and 8 wk after treatment. Hepatic function, pathological evaluation (semi-quantitative scoring system, SSS) and liver hydroxyproline (Hyp)content were examined. Real-time PCR was used to detect the expression of tTG, smooth muscle alpha actin (α-SMA), tissue inhibitor of metalloproteinase 1 (TIMP-1)and collagen-1 mRNA. The expressions of tTG and α-SMA protein were detected by Western Blotting.RESULTS: Eight weeks after treatment, the SSS score of liver was significantly less in the cystamine group than that in the fibrosis control group (P < 0.01). The levels of alanine aminotransferase (ALT) and total bile acid (TBA)at the 4 wk and 8 wk time points were decreased in the cystamine group compared with those in fibrosis controls (P < 0.01). Liver hydroxyproline content at the 4 wk and 8 wk time points showed a substantial reduction in the cystamine group compared to fibrosis controls (P < 0.01).The expression of tTG, α-SMA, collagen-1, TIMP-1 mRNA and tTG, as well as α-SMA protein was downregulated in the cystamine group compared to fibrosis controls.CONCLUSION: Cystamine can ameliorate CCl4 induced liver fibrosis and protect hepatic function. The possible mechanism is related to the reduced synthesis of the extracellular matrix (ECM) caused by the inhibition of hepatic stellate cell activation and decreased expression of TIMP-1.

  3. Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children

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    Yasser E Nassef

    2013-11-01

    Full Text Available The aim of the present study was to identify specific markers that mirror liver fibrosis progression as an alternative to biopsy when biopsy is contraindicated, especially in children. After liver biopsies were performed, serum samples from 30 hepatitis C virus (HCV paediatric patients (8-14 years were analysed and compared with samples from 30 healthy subjects. All subjects were tested for the presence of serum anti-HCV antibodies. Direct biomarkers for liver fibrosis, including transforming growth factor-β1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1, hyaluronic acid (HA, procollagen type III amino-terminal peptide (PIIINP and osteopontin (OPN, were measured. The indirect biomarkers aspartate and alanine aminotransferases, albumin and bilirubin were also tested. The results revealed a significant increase in the serum marker levels in HCV-infected children compared with the healthy group, whereas albumin levels exhibited a significant decrease. Significantly higher levels of PIIINP, TIMP-1, OPN and HA were detected in HCV-infected children with moderate to severe fibrosis compared with children with mild fibrosis (p < 0.05. The diagnostic accuracy of these direct biomarkers, represented by sensitivity, specificity and positive predictive value, emphasises the utility of PIIINP, TIMP-1, OPN and HA as indicators of liver fibrosis among HCV-infected children.

  4. Staging of liver fibrosis in chronic hepatitis B patients with a composite predictive model:A comparative study

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To evaluate the efficacy of 6 noninvasive liver fibrosis models and to identify the most valuable model for the prediction of liver fibrosis stage in chronic hepatitis B(CHB) patients.METHODS:Seventy-eight CHB patients were consecutively enrolled in this study.Liver biopsy was performed and blood serum was obtained at admission.Histological diagnosis was made according to the METAVIR system.Significant fibrosis was defined as stage score ≥ 2,severe fibrosis as stage score ≥ 3.The diagnostic accuracy of ...

  5. Effects of a plasmid expressing antisense tissue inhibitor of metalloproteinase-1 on liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    JIANG Wei; WANG Ji-yao; YANG Chang-qing; LIU Wen-bin; WANG Yi-qing; HE Bo-ming

    2005-01-01

    Background No efficient therapy for liver fibrosis has been available. This study was aimed to provide evidence that the introduction of a plasmid expressing antisense tissue inhibitor of metalloproteinase-1 (TIMP-1) into a rat model of immunologically induced liver fibrosis can result in the increased activity of interstitial collagenase, thus enhancing the degradation of collagen.Methods Real-time nested polymerase chain reaction (RT-Nested-PCR) and gene recombination techniques were used to construct a rat antisense TIMP-1 recombinant plasmid that can be expressed in eukaryotic cells. Both the recombinant plasmid and an empty vector (pcDNA3) were encapsulated with glycosyl-poly-L-lysine and injected into rats suffering from pig serum-induced liver fibrosis. The expression of exogenous transfected plasmid was assessed by Northern blot, RT-PCR, and Western blot. Hepatic interstitial collagenase activity was detected using fluorescinisothiocyanate (FITC)-labeled type Ⅰ collagen. In addition to hepatic hydroxyproline content, hepatic collagen types Ⅰ and Ⅲ were detected by immunohistochemical staining, and the stages of liver fibrosis by Van Gieson staining.Results Exogenous antisense TIMP-1 was successfully expressed in vivo and could block the gene and protein expression of TIMP-1. Active and latent hepatic interstitial collagenase activities were elevated (P<0.01), hepatic hydroxyproline content and the accumulation of collagen types Ⅰ and Ⅲ were lowered, and liver fibrosis was alleviated in the antisense TIMP-1 group (P<0.01) as compared with the model group. Conclusion The results demonstrate that antisense TIMP-1 recombinant plasmids have some inhibitory effect on liver fibrosis.

  6. Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing.

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    Katsunari Makino

    Full Text Available Endothelin (ET-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF-α and connective tissue growth factor (CTGF were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach.

  7. Diffusion-weighted MRI versus transient elastography in quantification of liver fibrosis in patients with chronic cholestatic liver diseases

    Energy Technology Data Exchange (ETDEWEB)

    Kovač, Jelena Djokić, E-mail: jelenadjokic2003@yahoo.co.uk [Center for Radiology and Magnetic Resonance Imaging, Clinical Center of Serbia, Pasterova 2, 11000 Belgrade (Serbia); Daković, Marko [Center for Radiology and Magnetic Resonance Imaging, Clinical Center of Serbia, Faculty of Physical Chemistry, University of Belgrade, Pasterova 2, 11000 Belgrade (Serbia); Stanisavljević, Dejana [Institute for Statistics, Faculty of Medicine, University of Belgrade, Dr. Subotica 8, 11000 Belgrade (Serbia); Alempijević, Tamara; Ješić, Rada [Clinic for Gastroenterohepatology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Pasterova 2, 11000 Belgrade (Serbia); Seferović, Petar [Institute for Cardiovascular Diseases, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Pasterova 2, 11000 Belgrade (Serbia); Maksimović, Ružica [Center for Radiology and Magnetic Resonance Imaging, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade (Serbia)

    2012-10-15

    Purpose: To evaluate the diagnostic value of diffusion-weighted magnetic resonance imaging (DWMRI) and transient elastography (TE) in quantification of liver fibrosis in patients with chronic cholestatic liver diseases. Materials and methods: Forty-five patients underwent DWMRI, TE, and liver biopsy for staging of liver fibrosis. Apparent diffusion coefficient (ADC) was calculated for six locations in the liver for combination of five diffusion sensitivity values b = 0, 50, 200, 400 and 800 s/mm{sup 2}. A receiver operating characteristic (ROC) analysis was performed to determine the diagnostic performance of DWMRI and TE. Segmental ADC variations were evaluated by means of coefficient of variation. Results: The mean ADCs (×10{sup −3} mm{sup 2}/s; b = 0–800 s/mm{sup 2}) were significantly different at stage F1 versus F ≥ 2 (p < 0.05) and F2 versus F4. However, no significant difference was found between F2 and F3. For prediction of F ≥ 2 and F ≥ 3 areas under the ROC curves were 0.868 and 0.906 for DWMRI, and 0.966 and 0.960 for TE, respectively. The sensitivity and specificity were 90.9% and 89.3% for F ≥ 2 (ADC ≤ 1.65), and 92.3% and 92.1% for F ≥ 3 (ADC ≤ 1.63). Segmental ADC variation was lowest for F4 (CV = 9.54 ± 6.3%). Conclusion: DWMRI and TE could be used for assessment of liver fibrosis with TE having higher diagnostic accuracy and DWMRI providing insight into liver fibrosis distribution.

  8. Texture analysis of liver fibrosis microscopic images: a study on the effect of biomarkers

    Institute of Scientific and Technical Information of China (English)

    Amr Amin; Doaa Mahmoud-Ghoneim

    2011-01-01

    Chronic hepatic injury results in liver fibrosis with eventual progression to irreversible cirrhosis. Liver fibrogenesis involves the activation of the quiescent hepatic stellate cell into an activated myofibroblast that is characterized by α-smooth muscle actin (α-SMA) expression and the production of collagens (types Ⅰ and Ⅲ). In the present study,rats were randomly divided into three groups: (i) control group, where rats were only treated with a vehicle; (ii) fibrosis group, where rats were treated with carbon tetrachloride (CCl4) to induce liver fibrosis; and (iii) silymarin group,where rats were protected with silymarin during CCl4 treatment. Rats were sacrificed and sections of liver tissue were counterstained with hematoxylin and eosin and Masson's trichrome. Other sections were immunostained using collagens and α-SMA primary antibodies. Fibrosis was confirmed using serum marker measurements. Microscopic images of the stained sections were acquired and digitized.The Biomarker Index of Fibrosis (BIF) was calculated from the images by quantifying the percentage of stained fibers.Statistical methods of texture analysis (TA), namely cooccurrence and run-length matrices, were applied on the digital images followed by classification using agglomerative hierarchical clustering and linear discriminant analysis with cross validation. TA applied on different biomarkers was successful in discriminating between the groups,showing 100% sensitivity and specificity for classification between the control and fibrosis groups using any biomarker. Some classification attempts showed dependence on the biomarker used, especially for classification between the silymarin and fibrosis groups, which showed optimal results using Masson's trichrome. TA results were consistent with both BIF and serum marker measurements.

  9. Automated biphasic morphological assessment of hepatitis B-related liver fibrosis using second harmonic generation microscopy

    Science.gov (United States)

    Wang, Tong-Hong; Chen, Tse-Ching; Teng, Xiao; Liang, Kung-Hao; Yeh, Chau-Ting

    2015-08-01

    Liver fibrosis assessment by biopsy and conventional staining scores is based on histopathological criteria. Variations in sample preparation and the use of semi-quantitative histopathological methods commonly result in discrepancies between medical centers. Thus, minor changes in liver fibrosis might be overlooked in multi-center clinical trials, leading to statistically non-significant data. Here, we developed a computer-assisted, fully automated, staining-free method for hepatitis B-related liver fibrosis assessment. In total, 175 liver biopsies were divided into training (n = 105) and verification (n = 70) cohorts. Collagen was observed using second harmonic generation (SHG) microscopy without prior staining, and hepatocyte morphology was recorded using two-photon excitation fluorescence (TPEF) microscopy. The training cohort was utilized to establish a quantification algorithm. Eleven of 19 computer-recognizable SHG/TPEF microscopic morphological features were significantly correlated with the ISHAK fibrosis stages (P 0.82 for liver cirrhosis detection. Since no subjective gradings are needed, interobserver discrepancies could be avoided using this fully automated method.

  10. Liver fibrosis and Gd-EOB-DTPA-enhanced MRI: A histopathologic correlation.

    Science.gov (United States)

    Verloh, Niklas; Utpatel, Kirsten; Haimerl, Michael; Zeman, Florian; Fellner, Claudia; Fichtner-Feigl, Stefan; Teufel, Andreas; Stroszczynski, Christian; Evert, Matthias; Wiggermann, Philipp

    2015-01-01

    Gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) is a hepatocyte-specific MRI contrast agent. Because the hepatic uptake of Gd-EOB-DTPA depends on the integrity of the hepatocyte mass, this uptake can be quantified to assess liver function. We report the relationship between the extent of Gd-EOB-DTPA uptake and the degree of liver fibrosis. T1-weighted volume-interpolated breath-hold examination (VIBE) sequences with fat suppression were acquired before and 20 minutes after contrast injection. Strong correlations of the uptake characteristics of Gd-EOB-DTPA with the relative enhancement (RE) of the liver parenchyma and the grade of fibrosis/cirrhosis, classified using the Ishak scoring system, were observed. The subdivisions between the grades of liver fibrosis based on RE were highly significant for all combinations, and a ROC revealed sensitivities ≥82% and specificities ≥87% for all combinations. MR imaging is a satisfactorily sensitive method for the assessment of liver fibrosis/cirrhosis. PMID:26478097

  11. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

    Energy Technology Data Exchange (ETDEWEB)

    Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Coelho, A.M.M. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Xerfan, M.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Cogliati, B. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Barbeiro, D.F. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Mazo, D.F.C. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Kubrusly, M.S.; D' Albuquerque, L.A.C. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Souza, H.P. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Carrilho, F.J.; Oliveira, C.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-02-24

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg{sup -1}·day{sup -1} by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

  12. Liver Fibrosis progression using Fibroscan in HIV/HCV coinfected patients with undetectable HIV viral load

    Directory of Open Access Journals (Sweden)

    Laura Perez-Martinez

    2014-11-01

    Full Text Available Introduction: Several factors such as duration of infection, age, male gender, consumption of alcohol, HIV infection and low CD4 count have been associated with fibrosis progression rate. However, it is relatively scarce, the knowledge about the liver fibrosis progression rate in HIV-infected patients with undetectable HIV viral load (VL. For this reason, we performed the present study. Materials and Methods: Observational and multicenter study (2008–2012 conducted in four hospitals of the northern Spain. HIV/HCV (hepatitis c virus coinfected patients ≥18 years on stable combination antiretroviral therapy (cART (≥6 months and with a HIV VL <50 copies/mL were selected to analyze their liver fibrosis progression. Fibrosis progression was assessed using a Fibroscan® (502 STEP 3 model and measuring a basal test and a second one at least 12 months apart from baseline. This evolution was compared with different variables such as duration of HIV/HCV coinfection, gender, age, previous treatment for HCV, HCV genotype, CD4 lymphocyte counts and the cART employed at the basal test. Results: A total of 608 patients were included (median age 29.4 years, 71.7% men. Of these, 463 patients met the inclusion criteria. In these patients, the liver fibrosis progression was nearly flat and the only variables related to a higher liver fibrosis progression were the increasing age of the patients (p=0.02 and the duration of the coinfection (p=0.001. CD4 lymphocyte counts showed a tendency to improved liver fibrosis (p=0.056. Conclusions: In HIV/HCV coinfected patients on stable cART and HIV undetectable VL, the increase in liver fibrosis rate progression was nearly flat, although it was significantly associated with the duration of the coinfection and the age of the patient. The beneficial effects of the cART were independent of the antiretroviral drug employed. A tendency to a lower fibrosis progression was observed in those patients with a higher CD4 count.

  13. DNA methylation of angiotensin II receptor gene in nonalcoholic steatohepatitis-related liver fibrosis

    Science.gov (United States)

    Asada, Kiyoshi; Aihara, Yosuke; Takaya, Hiroaki; Noguchi, Ryuichi; Namisaki, Tadashi; Moriya, Kei; Uejima, Masakazu; Kitade, Mitsuteru; Mashitani, Tsuyoshi; Takeda, Kosuke; Kawaratani, Hideto; Okura, Yasushi; Kaji, Kosuke; Douhara, Akitoshi; Sawada, Yasuhiko; Nishimura, Norihisa; Seki, Kenichiro; Mitoro, Akira; Yamao, Junichi; Yoshiji, Hitoshi

    2016-01-01

    AIM To clarify whether Agtr1a methylation is involved in the development of nonalcoholic steatohepatitis (NASH)-related liver fibrosis in adult rats. METHODS A choline-deficient amino acid (CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis. Agtr1a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid (CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR. Hepatic stellate cells (HSCs) were isolated by collagenase digestion of the liver, followed by centrifugation of the crude cell suspension through a density gradient. Agtr1a methylation and its gene expression were also analyzed during the activation of HSCs. RESULTS The mean levels of Agtr1a methylation in the livers of CDAA-fed rats (11.5% and 18.6% at 8 and 12 wk, respectively) tended to be higher (P = 0.06 and 0.09, respectively) than those in the livers of CSAA-fed rats (2.1% and 5.3% at 8 and 12 wk, respectively). Agtr1a was not methylated at all in quiescent HSCs, but was clearly methylated in activated HSCs (13.8%, P renin-angiotensin system-related gene expression during liver fibrosis. PMID:27729955

  14. Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells.

    Science.gov (United States)

    Pan, Qin; Wang, Yu-Qin; Li, Guang-Ming; Duan, Xiao-Yan; Fan, Jian-Gao

    2015-01-01

    Activation of hepatic stellate cells (HSCs) depending on epithelial-to-mesenchymal transition (EMT) reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET) of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY) recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EMT and MET in HSCs. In contrast to the increased TGF-β 1/BMP-7 ratio in activated HSCs, FZHY administration induced significant upregulation of BMP-7 and downregulation of TGF-β 1 at both transcription and translation levels. Restoration of TGF-β 1/BMP-7 ratio inhibited the expression of p38 MAPK and phosphorylated p38 MAPK, resulting in the reversal of epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) as characterized by the abolishment of EMT markers (α-SMA and desmin) and reoccurrence of MET marker (E-cadherin). In vivo treatment of FZHY recipe also demonstrated the statistical reduction of activated HSCs with EMT phenotype, which attenuated the carbon tetrachloride- (CCl4-) induced liver fibrosis in a dose-dependent manner. These findings may highlight a novel antifibrotic role of FZHY recipe on the basis of rebalancing EMT and MET in HSCs. PMID:26881209

  15. Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells

    Directory of Open Access Journals (Sweden)

    Qin Pan

    2015-01-01

    Full Text Available Activation of hepatic stellate cells (HSCs depending on epithelial-to-mesenchymal transition (EMT reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EMT and MET in HSCs. In contrast to the increased TGF-β1/BMP-7 ratio in activated HSCs, FZHY administration induced significant upregulation of BMP-7 and downregulation of TGF-β1 at both transcription and translation levels. Restoration of TGF-β1/BMP-7 ratio inhibited the expression of p38 MAPK and phosphorylated p38 MAPK, resulting in the reversal of epithelial-to-mesenchymal transition (EMT to mesenchymal-to-epithelial transition (MET as characterized by the abolishment of EMT markers (α-SMA and desmin and reoccurrence of MET marker (E-cadherin. In vivo treatment of FZHY recipe also demonstrated the statistical reduction of activated HSCs with EMT phenotype, which attenuated the carbon tetrachloride- (CCl4- induced liver fibrosis in a dose-dependent manner. These findings may highlight a novel antifibrotic role of FZHY recipe on the basis of rebalancing EMT and MET in HSCs.

  16. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Westra, Inge M. [Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen (Netherlands); Oosterhuis, Dorenda [Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen (Netherlands); Groothuis, Geny M.M. [Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen (Netherlands); Olinga, Peter, E-mail: p.olinga@rug.nl [Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen (Netherlands)

    2014-01-15

    Induction of fibrosis during prolonged culture of precision-cut liver slices (PCLS) was reported. In this study, the use of rat PCLS was investigated to further characterize the mechanism of early onset of fibrosis in this model and the effects of antifibrotic compounds. Rat PCLS were incubated for 48 h, viability was assessed by ATP and gene expression of PDGF-B and TGF-β1 and the fibrosis markers Hsp47, αSma and Pcol1A1 and collagen1 protein expressions were determined. The effects of the antifibrotic drugs imatinib, sorafenib and sunitinib, PDGF-pathway inhibitors, and perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone, TGFβ-pathway inhibitors, were determined. After 48 h of incubation, viability of the PCLS was maintained and gene expression of PDGF-B was increased while TGF-β1 was not changed. Hsp47, αSma and Pcol1A1 gene expressions were significantly elevated in PCLS after 48 h, which was further increased by PDGF-BB and TGF-β1. The increased gene expression of fibrosis markers was inhibited by all three PDGF-inhibitors, while TGFβ-inhibitors showed marginal effects. The protein expression of collagen 1 was inhibited by imatinib, perindopril, tetrandrine and pirfenidone. In conclusion, the increased gene expression of PDGF-B and the down-regulation of fibrosis markers by PDGF-pathway inhibitors, together with the absence of elevated TGF-β1 gene expression and the limited effect of the TGFβ-pathway inhibitors, indicated the predominance of the PDGF pathway in the early onset of fibrosis in PCLS. PCLS appear a useful model for research of the early onset of fibrosis and for testing of antifibrotic drugs acting on the PDGF pathway. - Highlights: • During culture, fibrosis markers increased in precision-cut liver slices (PCLS). • Gene expression of PDGF-β was increased, while TGFβ was not changed in rat PCLS. • PDGF-pathway inhibitors down-regulated this increase of fibrosis markers. • TGFβ-pathway inhibitors had only

  17. Protective Effect of the Total Saponins from Rosa laevigata Michx Fruit against Carbon Tetrachloride-Induced Liver Fibrosis in Rats

    Directory of Open Access Journals (Sweden)

    Deshi Dong

    2015-06-01

    Full Text Available In this study, the protective effect of the total saponins from Rosa laevigata Michx (RLTS against liver fibrosis induced by carbon tetrachloride (CCl4 in rats was evaluated. The results showed that RLTS significantly rehabilitated the levels of alanine aminotransferase, aspartate aminotransferase, malondialdehyde, glutathione, glutathione peroxidase, catalase, superoxide dismutase, hydroxyproline, α-smooth muscle actin, collagen I, collagen III and fibronectin, which were confirmed using H&E, Sirius Red and Masson histopathological assays. Further research indicated that RLTS markedly reduced cytochrome P450 2E1 activity, attenuated oxidative stress, and suppressed inflammation. In addition, RLTS facilitated matrix degradation through down-regulation of matrix metalloproteinase2, matrix metalloproteinase 9 and metalloproteinases1, and exerted the anti-fibrotic effects through affecting transforming growth factor β/Smad, focal adhesion kinase/phosphatidylinositol-3-kinase/amino kinase terminal/70-kDa ribosomal S6 Kinase (FAK-PI3K-Akt-p70S6K and mitogen-activated protein kinase (MAPK signaling pathways. Taken together, our data indicate that RLTS can be applied as one effective candidate for the treatment of liver fibrosis in the future.

  18. Liver fibrosis and tissue architectural change measurement using fractal-rectified metrics and Hurst's exponent

    Institute of Scientific and Technical Information of China (English)

    Nicola Dioguardi; Fabio Grizzi; Barbara Franceschini; Paola Bossi; Carlo Russo

    2006-01-01

    AIM: To provide the accurate alternative metrical means of monitoring the effects of new antiviral drugs on the reversal of newly formed collagen.METHODS: Digitized histological biopsy sections taken from 209 patients with chronic C virus hepatitis with different grade of fibrosis or cirrhosis, were measured by means of a new, rapid, user-friendly, fully computeraided method based on the international system meter rectified using fractal principles.RESULTS: The following were described: geometric perimeter, area and wrinkledness of fibrosis; the collation of the Knodell, Sheuer, Ishak and METAVIR scores with fractal-rectified metric measurements; the meaning of the physical composition of fibrosis in relation to the magnitude of collagen islets; the intra- and inter-biopsy sample variability of these parameters; the "staging"of biopsy sections indicating the pathway covered by fibrosis formation towards its maximum known value;the quantitative liver tissue architectural changes with the Hurst exponent.CONCLUSION: Our model provides the first metrical evaluations of the geometric properties of fibrosis and the quantitative architectural changes of the liver tissue.The representativeness of histological sections of the whole liver is also discussed in the light of the results obtained with the Hurst coefficient.

  19. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects

    OpenAIRE

    Liedtke, Christian; Luedde, Tom; Sauerbruch, Tilman; Scholten, David; Streetz, Konrad; Tacke, Frank; Tolba, René; Trautwein, Christian; Trebicka, Jonel; Weiskirchen, Ralf

    2013-01-01

    Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 20...

  20. Fasudil, a Rho-Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Zuojun Xu

    2012-07-01

    Full Text Available The mechanisms underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF involve multiple pathways, such as inflammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes. The small GTPase, RhoA, and its target protein, Rho-kinase (ROCK, may interact with other signaling pathways known to contribute to pulmonary fibrosis. This study aimed to determine the beneficial effects and mechanisms of fasudil, a selective ROCK inhibitor, on bleomycin-induced pulmonary fibrosis in mice. Our results showed that the Aschcroft score and hydroxyproline content of the bleomycin-treated mouse lung decreased in response to fasudil treatment. The number of infiltrated inflammatory cells in the bronchoalveolar lavage fluid (BALF was attenuated by fasudil. In addition, fasudil reduced the production of transforming growth factor-β1 (TGF-β1, connective tissue growth factor (CTGF, alpha-smooth muscle actin (α-SMA, and plasminogen activator inhibitor-1 (PAI-1 mRNA and protein expression in bleomycin-induced pulmonary fibrosis. These findings suggest that fasudil may be a potential therapeutic candidate for the treatment of pulmonary fibrosis.

  1. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis

    Science.gov (United States)

    Fransén-Pettersson, Nina; Duarte, Nadia; Nilsson, Julia; Lundholm, Marie; Mayans, Sofia; Larefalk, Åsa; Hannibal, Tine D.; Hansen, Lisbeth; Schmidt-Christensen, Anja; Ivars, Fredrik; Cardell, Susanna; Palmqvist, Richard; Rozell, Björn

    2016-01-01

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders. PMID:27441847

  2. Routine blood tests to predict liver fibrosis in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Yung-Yu Hsieh; Shui-Yi Tung; Kamfai Lee; Cheng-Shyong Wu; Kuo-Liang Wei; Chien-Heng Shen; Te-Sheng Chang; Yi-Hsiung Lin

    2012-01-01

    AIM:To verify the usefulness of FibroQ for predicting fibrosis in patients with chronic hepatitis C,compared with other noninvasive tests.METHODS:This retrospective cohort study included 237 consecutive patients with chronic hepatitis C who had undergone percutaneous liver biopsy before treatment.FibroQ,aspartate aminotransferase (AST)/alanine aminotransferase ratio (AAR),AST to platelet ratio index,cirrhosis discriminant score,age-platelet index (API),Pohl score,FIB-4 index,and Lok's model were calculated and compared.RESULTS:FibroQ,FIB-4,AAR,API and Lok's model results increased significantly as fibrosis advanced (analysis of variance test:P < 0.001).FibroQ trended to be superior in predicting significant fibrosis score in chronic hepatitis C compared with other noninvasive tests.CONCLUSION:FibroQ is a simple and useful test for predicting significant fibrosis in patients with chronic hepatitis C.

  3. Iron deposition and fat accumulation in dimethylnitrosamine-induced liver fibrosis in rat

    Institute of Scientific and Technical Information of China (English)

    Jin-Yang He; Wen-Hua Ge; Yuan Chen

    2007-01-01

    AIM: To investigate if iron deposition and fat accumulation in the liver play a pathogenetic role in dimethylnitrosamine (DMN)-induced liver fibrosis in rat.METHODS: Thirty rats were treated with DMN at does consecutive days of 10 μL/kg daily, i.p., for 3 consecutive day each week for 4 wk. Rats (n = 30) were sacrificed on the first day (model group A) and 21st d (model group B) after cessation of DMN injection. The control group (n = 10) received an equivalent amount of saline. Liver tissues were stained with hematoxylin & eosin (HE) and Masson and Prussian blue assay and oberserved under electron microscopy. Serum alanine aminotransferase (ALT)and liver tissue hydroxyproline (Hyp) content were tested.RESULTS: The liver fibrosis did not automaticallyreverse, which was similar to previous reports, the perilobular deposition of iron accompanied with collagen showed marked characteristics at both the first and 21st d after cessation of DMN injection. However, fat accumulation in hepatocytes occurred only at the 21st d after cessation of DMN injection.CONCLUSION: Iron deposition and fat accumulation may play important roles in pathological changes in DMN-induced rat liver fibrosis. The detailed mechanisms of these characteristics need further research.

  4. Comparison on Efficacy between Astragalus-Polygonum Anti-Fibrosis Decoction and Jinshuibao (金水宝) Capsule in Treating Liver Fibrosis of Chronic Hepatitis B

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To observe the efficacy of Astragalus-Polygonum Anti-Fibrosis decoction (APAFD)and Jinshuibao capsule (JSBC) in treating liver fibrosis of chronic hepatitis B. Methods: Ninety-two cases of liver fibrosis of chronic hepatitis B were randomly divided into group A and group B. Patients in group A received APAFD for 48 weeks, and in group B, they received JSBC for 48 weeks. The effects on the level change of hyaluronic acid (HA), laminin (LN), pro-collagen Ⅲ (PCⅢ) and collagen Ⅳ (CⅣ) as well as liver functional tests and liver biochemical parameters before and after treatment were observed.Results: Level of serum HA, LN, PCⅢ and CⅣ in group A declined more obviously than that of group B, the difference was significant (P<0.01). The liver functional tests such as total bilirubin (TB), alanine aminotransferase (ALT), albumin/globulin (A/G) ratio, hepatitis related serum biochemical parameters such as cholylglycine (CG), serum ferritin (SF), prealbumin (PC) of group A were all improved more significantly than that of group B (P<0.01).Conclusion: APAFD is more effective than JSBC in treating liver fibrosis of chronic hepatitis B and in the inhibition of hepatic inflammation, hence it is a good composite Chinese herbal preparation against liver fibrosis.

  5. Berberine Inhibition of Fibrogenesis in a Rat Model of Liver Fibrosis and in Hepatic Stellate Cells

    Directory of Open Access Journals (Sweden)

    Ning Wang

    2016-01-01

    Full Text Available Aim. To examine the effect of berberine (BBR on liver fibrosis and its possible mechanisms through direct effects on hepatic stellate cells (HSC. Methods. The antifibrotic effect of BBR was determined in a rat model of bile duct ligation- (BDL- induced liver fibrosis. Multiple cellular and molecular approaches were introduced to examine the effects of BBR on HSC. Results. BBR potently inhibited hepatic fibrosis induced by BDL in rats. It exhibited cytotoxicity to activated HSC at doses nontoxic to hepatocytes. High doses of BBR induced apoptosis of activated HSC, which was mediated by loss of mitochondrial membrane potential and Bcl-2/Bax imbalance. Low doses of BBR suppressed activation of HSC as evidenced by the inhibition of α-smooth muscle actin (α-SMA expression and cell motility. BBR did not affect Smad2/3 phosphorylation but significantly activated 5′ AMP-activated protein kinase (AMPK signalling, which was responsible for the transcriptional inhibition by BBR of profibrogenic factors α-SMA and collagen in HSC. Conclusion. BBR is a promising agent for treating liver fibrosis through multiple mechanisms, at least partially by directly targeting HSC and by inhibiting the AMPK pathway. Its value as an antifibrotic drug in patients with liver disease deserves further investigation.

  6. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects.

    Science.gov (United States)

    Liedtke, Christian; Luedde, Tom; Sauerbruch, Tilman; Scholten, David; Streetz, Konrad; Tacke, Frank; Tolba, René; Trautwein, Christian; Trebicka, Jonel; Weiskirchen, Ralf

    2013-01-01

    Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 2013. These rules will create an urgent need for optimized standard operating procedures regarding animal experimentation and improved international communication in the liver fibrosis community. This review gives an update on current animal models, techniques and underlying pathomechanisms with the aim of fostering a critical discussion of the limitations and potential of up-to-date animal experimentation. We discuss potential complications in experimental liver fibrosis and provide examples of how the findings of studies in which these models are used can be translated to human disease and therapy. In this review, we want to motivate the international community to design more standardized animal models which might help to address the legally requested replacement, refinement and reduction of animals in fibrosis research. PMID:24274743

  7. Acoustic structure quantification by using ultrasound Nakagami imaging for assessing liver fibrosis.

    Science.gov (United States)

    Tsui, Po-Hsiang; Ho, Ming-Chih; Tai, Dar-In; Lin, Ying-Hsiu; Wang, Chiao-Yin; Ma, Hsiang-Yang

    2016-01-01

    Acoustic structure quantification (ASQ) is a recently developed technique widely used for detecting liver fibrosis. Ultrasound Nakagami parametric imaging based on the Nakagami distribution has been widely used to model echo amplitude distribution for tissue characterization. We explored the feasibility of using ultrasound Nakagami imaging as a model-based ASQ technique for assessing liver fibrosis. Standard ultrasound examinations were performed on 19 healthy volunteers and 91 patients with chronic hepatitis B and C (n = 110). Liver biopsy and ultrasound Nakagami imaging analysis were conducted to compare the METAVIR score and Nakagami parameter. The diagnostic value of ultrasound Nakagami imaging was evaluated using receiver operating characteristic (ROC) curves. The Nakagami parameter obtained through ultrasound Nakagami imaging decreased with an increase in the METAVIR score (p < 0.0001), representing an increase in the extent of pre-Rayleigh statistics for echo amplitude distribution. The area under the ROC curve (AUROC) was 0.88 for the diagnosis of any degree of fibrosis (≥F1), whereas it was 0.84, 0.69, and 0.67 for ≥F2, ≥F3, and ≥F4, respectively. Ultrasound Nakagami imaging is a model-based ASQ technique that can be beneficial for the clinical diagnosis of early liver fibrosis. PMID:27605260

  8. Berberine Inhibition of Fibrogenesis in a Rat Model of Liver Fibrosis and in Hepatic Stellate Cells.

    Science.gov (United States)

    Wang, Ning; Xu, Qihe; Tan, Hor Yue; Hong, Ming; Li, Sha; Yuen, Man-Fung; Feng, Yibin

    2016-01-01

    Aim. To examine the effect of berberine (BBR) on liver fibrosis and its possible mechanisms through direct effects on hepatic stellate cells (HSC). Methods. The antifibrotic effect of BBR was determined in a rat model of bile duct ligation- (BDL-) induced liver fibrosis. Multiple cellular and molecular approaches were introduced to examine the effects of BBR on HSC. Results. BBR potently inhibited hepatic fibrosis induced by BDL in rats. It exhibited cytotoxicity to activated HSC at doses nontoxic to hepatocytes. High doses of BBR induced apoptosis of activated HSC, which was mediated by loss of mitochondrial membrane potential and Bcl-2/Bax imbalance. Low doses of BBR suppressed activation of HSC as evidenced by the inhibition of α-smooth muscle actin (α-SMA) expression and cell motility. BBR did not affect Smad2/3 phosphorylation but significantly activated 5' AMP-activated protein kinase (AMPK) signalling, which was responsible for the transcriptional inhibition by BBR of profibrogenic factors α-SMA and collagen in HSC. Conclusion. BBR is a promising agent for treating liver fibrosis through multiple mechanisms, at least partially by directly targeting HSC and by inhibiting the AMPK pathway. Its value as an antifibrotic drug in patients with liver disease deserves further investigation. PMID:27239214

  9. Elastographic assessment of liver fibrosis in children: A prospective single center experience

    Energy Technology Data Exchange (ETDEWEB)

    Marginean, Cristina Oana, E-mail: marginean.oana@gmail.com [Department of Paediatrics, University of Medicine and Pharmacy of Tg. Mures (Romania); Marginean, Claudiu, E-mail: marginean.claudiu@gmail.com [Department of Obstetrics and Gynecology, University of Medicine and Pharmacy of Tg. Mures (Romania)

    2012-08-15

    Background: The assessment of liver damage in various disease states relies on a combination of clinical findings, biochemical parameters and invasive tests such as liver biopsy. The ultrasound elastography has emerged as a potential alternative test, providing quantifiable information on the elasticity/stiffness of the examined-tissues. We assessed the performance of ultrasound elastography using real-time Acoustic Radiation Force Imaging (ARFI) technology in evaluating the degree of liver fibrosis in children with and without liver disease. Methods: Children aged 0-18 years, hospitalized in the Emergency Clinical County Hospital Tg. Mures, Romania, between September 15, 2010 and January 15, 2011, were eligible for the study. Four groups were recruited as follow: patients with liver disease in the setting of various malignant disorders, children with non-malignant liver disease, overweight and obese children and healthy controls. The liver tissue elasticity was assessed in each individual using Shear Wave Velocity (SWV). Biochemical tests included transaminase levels. 19 children with chronic liver disease underwent biopsies. SWV was measured globally and separately for the liver-segments 1 and 8. Correlations between the SWV and laboratory test were established using non-parametric Spearman correlation test. Results: A total of 103 children underwent liver ultrasound elastographic assessments. Of these, 39 had malignancies, 19 had various chronic liver diseases, 13 had nonalcoholic fatty liver disease (NAFLD), and 32 were healthy controls. The transaminase values differed significantly between children with liver diseases and controls. In normal controls SWV values in the 1st segment were significantly lower compared to those in the in 8th segment of the liver (p = 0.0216). In the group with hepatic steatosis, the SWV values were statistically higher compared to those in healthy controls. Positive statistical correlations have been established between AST and SWV

  10. Elastographic assessment of liver fibrosis in children: A prospective single center experience

    International Nuclear Information System (INIS)

    Background: The assessment of liver damage in various disease states relies on a combination of clinical findings, biochemical parameters and invasive tests such as liver biopsy. The ultrasound elastography has emerged as a potential alternative test, providing quantifiable information on the elasticity/stiffness of the examined-tissues. We assessed the performance of ultrasound elastography using real-time Acoustic Radiation Force Imaging (ARFI) technology in evaluating the degree of liver fibrosis in children with and without liver disease. Methods: Children aged 0–18 years, hospitalized in the Emergency Clinical County Hospital Tg. Mures, Romania, between September 15, 2010 and January 15, 2011, were eligible for the study. Four groups were recruited as follow: patients with liver disease in the setting of various malignant disorders, children with non-malignant liver disease, overweight and obese children and healthy controls. The liver tissue elasticity was assessed in each individual using Shear Wave Velocity (SWV). Biochemical tests included transaminase levels. 19 children with chronic liver disease underwent biopsies. SWV was measured globally and separately for the liver-segments 1 and 8. Correlations between the SWV and laboratory test were established using non-parametric Spearman correlation test. Results: A total of 103 children underwent liver ultrasound elastographic assessments. Of these, 39 had malignancies, 19 had various chronic liver diseases, 13 had nonalcoholic fatty liver disease (NAFLD), and 32 were healthy controls. The transaminase values differed significantly between children with liver diseases and controls. In normal controls SWV values in the 1st segment were significantly lower compared to those in the in 8th segment of the liver (p = 0.0216). In the group with hepatic steatosis, the SWV values were statistically higher compared to those in healthy controls. Positive statistical correlations have been established between AST and

  11. Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-deficient mice.

    Science.gov (United States)

    van der Veen, Jelske N; Lingrell, Susanne; Gao, Xia; Quiroga, Ariel D; Takawale, Abhijit; Armstrong, Edward A; Yager, Jerome Y; Kassiri, Zamaneh; Lehner, Richard; Vance, Dennis E; Jacobs, René L

    2016-04-01

    Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt(-/-) mice are protected against high-fat diet (HFD)-induced obesity and insulin resistance; however, these mice develop nonalcoholic fatty liver disease (NAFLD). We hypothesized that peroxisomal proliferator-activated receptor-γ (PPARγ) activation by pioglitazone might stimulate adipocyte proliferation, thereby directing lipids from the liver toward white adipose tissue. Pioglitazone might also act directly on PPARγ in the liver to improve NAFLD. Pemt(+/+) and Pemt(-/-) mice were fed a HFD with or without pioglitazone (20 mg·kg(-1)·day(-1)) for 10 wk. Pemt(-/-) mice were protected from HFD-induced obesity but developed NAFLD. Treatment with pioglitazone caused an increase in body weight gain in Pemt(-/-) mice that was mainly due to increased adiposity. Moreover, pioglitazone improved NAFLD in Pemt(-/-) mice, as indicated by a 35% reduction in liver weight and a 57% decrease in plasma alanine transaminase levels. Livers from HFD-fed Pemt(-/-) mice were steatotic, inflamed, and fibrotic. Hepatic steatosis was still evident in pioglitazone-treated Pemt(-/-) mice; however, treatment with pioglitazone reduced hepatic fibrosis, as evidenced by reduced Sirius red staining and lowered mRNA levels of collagen type Iα1 (Col1a1), tissue inhibitor of metalloproteinases 1 (Timp1), α-smooth muscle actin (Acta2), and transforming growth factor-β (Tgf-β). Similarly, oxidative stress and inflammation were reduced in livers from Pemt(-/-) mice upon treatment with pioglitazone. Together, these data show that activation of PPARγ in HFD-fed Pemt(-/-) mice improved liver function, while these mice were still protected against diet-induced obesity and insulin resistance. PMID:26797396

  12. Intravenous injection of mesenchymal stem cells is effective in treating liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Wei Zhao; Jun-Jie Li; Da-Yong Cao; Xiao Li; Lin-Ying Zhang; Yong He; Shu-Qiang Yue

    2012-01-01

    AIM:To compare the influence of different transplant sites in bone marrow mesenchymal stem cell (MSC)-based therapy for liver fibrosis.METHODS:MSCs isolated from Sprague Dawley (SD) rats were induced into hepatocyte-like cells.Liver fibrosis in SD rats was induced with carbon tetrachloride.Following hepatocyte induction in vitro,4',6-diamidino2-phenylindole (DAPI)-labeled MSCs were transplanted by intravenous,intrahepatic,and intraperitoneal injection.Histopathological staining,immunohistochemistry,and biochemical analysis were used to compare the morphological and functional liver regeneration among different MSC injection modalities.The expression di-ferences of interleukins,growth factor,extracellular matrix,matrix metalloproteinases,and tissue inhibitor of metalloproteinase were examined by real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA).RESULTS:Four days after exposure to hepatocyte differentiation medium,MSCs that did not express hepatocyte markers could express α-fetoprotein,albumin,and cytokeratin 18.The results of histopathological staining,immunohistochemistry,and biochemical analysis indicated that intravenous injection is more effective at rescuing liver failure than other injection modalities.DAPI-labeled cells were found around liver lobules in all three injection site groups,but the intravenous group had the highest number of cells.PCR and ELISA analysis indicated that interleukin-10 (IL-10)was highest in the intravenous group,whereas il1β,il6,tnfα and tgfβ,which can be regulated by IL10 and are promoters of liver fibrosis,were significantly lower than in the other groups.CONCLUSION:MSC administration is able to protect against liver fibrosis.Intravenous injection is the most favorable treatment modality through promotion of IL10 expression.

  13. Liver Fibrosis Can Be Induced by High Salt Intake through Excess Reactive Oxygen Species (ROS) Production.

    Science.gov (United States)

    Wang, Guang; Yeung, Cheung-kwan; Wong, Wing-Yan; Zhang, Nuan; Wei, Yi-fan; Zhang, Jing-li; Yan, Yu; Wong, Ching-yee; Tang, Jun-jie; Chuai, Manli; Lee, Kenneth Ka Ho; Wang, Li-jing; Yang, Xuesong

    2016-02-24

    High salt intake has been known to cause hypertension and other side effects. However, it is still unclear whether it also affects fibrosis in the mature or developing liver. This study demonstrates that high salt exposure in mice (4% NaCl in drinking water) and chick embryo (calculated final osmolality of the egg was 300 mosm/L) could lead to derangement of the hepatic cords and liver fibrosis using H&E, PAS, Masson, and Sirius red staining. Meanwhile, Desmin immunofluorescent staining of mouse and chick embryo livers indicated that hepatic stellate cells were activated after the high salt exposure. pHIS3 and BrdU immunohistological staining of mouse and chick embryo livers indicated that cell proliferation decreased; as well, TUNEL analyses indicated that cell apoptosis increased in the presence of high salt exposure. Next, dihydroethidium staining on the cultured chick hepatocytes indicated the excess ROS was generated following high salt exposure. Furthermore, AAPH (a known inducer of ROS production) treatment also induced the liver fibrosis in chick embryo. Positive Nrf2 and Keap1 immunohistological staining on mouse liver suggested that Nrf2/Keap1 signaling was involved in high salt induced ROS production. Finally, the CCK8 assay was used to determine whether or not the growth inhibitory effect induced by high salt exposure can be rescued by antioxidant vitamin C. Meanwhile, the RT-PCR result indicated that the Nrf2/Keap1 downsteam genes including HO-1, NQO-1, and SOD2 were involved in this process. In sum, these experiments suggest that high salt intake would lead to high risk of liver damage and fibrosis in both adults and developing embryos. The pathological mechanism may be the result from an imbalance between oxidative stress and the antioxidant system. PMID:26843032

  14. Endocannabinoids Anandamide and Its Cannabinoid Receptors in Liver Fibrosis after Murine Schistosomiasis

    Institute of Scientific and Technical Information of China (English)

    Hongyan LIU; Xiao GAO; Ruixian DUAN; Qiao YANG; Yaowen ZHANG; Yongwei CHENG; Yan GUO; Wangxian TANG

    2009-01-01

    This study examined endogenous cannabinoid (ECB)-anandamide (AEA) and its can-nabinoid receptors (CBR) in mice liver with the development of schistosomajaponicum.Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens.Liver fibrosis was pathologically confirmed nine weeks after the infection.High performance liquid chromatography (HPLC) was employed to determine the concentration of AEA in the plasma of mice.Immunofluorescence was used to detect the expression of CBR 1 and CBR2 in liver tissue.Morphological examination showed typical pathological changes,with worm tubercles of schistosoma deposited in the liver tissue,fibrosis around the worm tubercles and infiltration or soakage ofinfiammatory cells.Also,CBRI and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups,but they were obviously enhanced in the schistosoma-infected mice.However,the average optical density of CBR1 in the negative control and fibrosis group was 13.28±7.32 and 30.55±7.78,and CBR2 were 28.13±6.42 and 52.29±4.24 (P<0.05).The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group.The concentrations of AEA were (0.37±0.07) and (5.67±1.34) ng/mL (P<0.05).It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice.Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.

  15. IkB kinase-beta inhibitor attenuates hepatic fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    Jue Wei; Min Shi; Wei Qi Wu; Ting Wang; Na Wang; Jia-Li Ma; Yu-Gang Wang

    2011-01-01

    AIM: To investigate the anti-fibrosis effect of IκkB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin- 6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κkB (NF-κkB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeⅠand type Ⅲ collagen proteins and mRNA. RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear translocation translocation of NF-κkB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeⅠcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type Ⅲ collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05).CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver

  16. Changes in fibrosis and oxygen metabolism index during perioperative period of patients with laparoscopic liver resection

    Institute of Scientific and Technical Information of China (English)

    Ya-Qi Jiang

    2016-01-01

    Objective:To observe the changes in fibrosis and oxygen metabolism index during perioperative period of patients with laparoscopic liver resection, and to explore the advantages of laparoscopic liver resection in the treatment of liver cancer.Methods:According to the inclusion criteria, 53 patients who processed with liver resection from February 2013 to March 2015 in our hospital were randomly divided into control group (open operation group, n=25) and study group (laparoscopic liver resection group,n=28). Then the operation and postoperative recovery of two groups were compared, and the fibrosis and oxygen metabolism indexes of two groups were compared too.Results:There was no significant difference in operation time, bleeding volume, tumor resection margin and liver resection volume between the two groups. The postoperative activity time, the first time for dieting post operation and time of postoperative hospital stay in study group were significantly shorter than the control group. After operation in 3, 7, 14 d, the serum levels of AST, ALT and CRP in study group were significantly lower than the control group. During perioperative period, there was no obvious change in the oxygen metabolism index in the study group, while which showed significantly change in the control group. After operation in the 3rd, 7th, 14th days, the levels of fibrosis related indexes HA, PCⅢ and Ⅳ C in study group were significantly lower than the control group.Conclusion:The efficacy of laparoscopic liver resection for the treatment of liver cancer is consistent with the open surgery, while the laparoscopic surgery has the advantages of less trauma, less liver damage and rapid recovery.

  17. Noninvasive estimation of liver fibrosis and response to interferon therapy by a serum fibrogenesis marker, YKL-40, in patients with HCV-associated liver disease

    Institute of Scientific and Technical Information of China (English)

    Yukiko Saitou; Katsuya Shiraki; Yutaka Yamanaka; Yumi Yamaguchi; Tomoyuki Kawakita; Norihiko Yamamoto; Kazushi Sugimoto; Kazumoto Murata; Takeshi Nakano

    2005-01-01

    AIM: To evaluate the clinical utility of serum fibrosis markers,including YKL-40, in patients with HCV-associated liver disease.METHODS: A total of 109 patients with HCV-associated liver disease were enrolled. We measured serum type Ⅳ collagen, amino-terminal peptide of type Ⅲ procollagen (PⅢP),hyaluronic acid (HA), YKL-40 levels and biochemical.Parameters by RIA or ELISA. Eighty-eight patients underwent liver biopsy, and 67 of 109 patients received interferon (IFN)therapy. We also investigated the relationship between the concentrations of serum fibrosis markers and histological fibrosis scores (METAVIR), and evaluated the changes of the levels of fibrosis markers before and after the IFN therapy.RESULTS: The increase in serum levels of all markers,particularly HA, was correlated with the progression of liver fibrosis (for type Ⅳ collagen, F= 9.076, P<0.0001; for PⅢP,F= 9.636, P<0.0001; for HA, F= 13.128, P<0.0001; and for YKL-40, F= 8.016, P<0.0001). YKL-40 had strong correlation with HA (r= 0.536, P<0.0001). Based on the receiver operating curve (ROC), the ability of serum HA exceeded the abilities of other serum markers to determine fibrosis score 4 from fibrosis score 0-3 (AUC = 0.854). While YKL-40 was superior to other fibrosis markers for predicting severe fibrosis (F2-F4) from mild fibrosis (F0-F1) (YKL-40, AUC = 0.809;HA, AUC = 0.805). After IFN therapy, only YKL-40 values significantly decreased not only in the responder group,but also in the nonresponder group (P = 0.03).CONCLUSION: YKL-40 may be a useful non-invasive serum marker to estimate the degree of liver fibrosis and to evaluate the efficacy of IFN therapies in patients with HCV-associated liver disease.

  18. Advances in mesenchymal stem cells combined with traditional Chinese medicine therapy for liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Shu Dong; Shi-bing Su

    2014-01-01

    Liver fibrosis is a primary cause of liver cirrhosis, and even hepatocarcinoma. Recently, the usage of mesenchymal stem cells (MSCs) has been investigated to improve liver ifbrosis. It has been reported that the differentiation, proliferation and migration of MSCs can be regulated by traditional Chinese medicine treatment;however, the mechanisms are still unclear. In this article, the authors review the characteristics of MSCs such as multidirectional differentiation and homing, and its application in animal experiments and clinical trials. The authors also list areas that need further investigation, and look at the future prospects of clinical application of MSCs.

  19. Pegylated interferon-alpha plus taurine in treatment of rat liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Ilker Tasci; Cihan Yurdaydin; Hakan Bozkaya; Ozden Uzunalimoglu; Ahmet Turan Isik; Harun M Said; Mehmet Refik Mas; Sevil Atalay Vural; Salih Deveci; Bilgin Comert; Gunay Alcigir; Nuket Mas; Cemal Akay; Mithat Bozdayi

    2007-01-01

    AIM: To investigate the antifibrotic effects of peginterferonalpha 2b and taurine on oxidative stress markers and hepatocellular apoptosis.METHODS: Sixty rats with CCl4-induced liver fibrosis were divided into 4 groups (n=15). Group 1 was left for spontaneous recovery (SR). Groups 2-4 received peginterferon-alpha 2b, taurine, and their combination,respectively, for four weeks. Histological fibrosis scores,histomorphometric analysis, tissue hydroxyproline, tissue MDA, GPx and SOD activities were determined. Activated stellate cells and hepatocellular apoptosis were also evaluated.RESULTS: The degree of fibrosis decreased in all treatment groups compared to spontaneous recovery group. Taurine alone and in combination with peginterferon-alpha 2b reduced oxidative stress markers,but peginterferon-alpha 2b alone did not. Apoptotic hepatocytes and activated stellate cells were higher in groups 2-4 than in group 1. Combined taurine and peginterferon-alpha 2b further reduced fibrosis and increased activated stellate cell apoptosis, but could not improve oxidative stress more than taurine alone.CONCLUSION: Peginterferon-alpha 2b exerts antifibrotic effects on rat liver fibrosis. It seems ineffective against oxidative stress in vivo. Peginterferon-alpha 2b in combination with taurine seems to be an antifibrotic strategy.

  20. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C

    Science.gov (United States)

    Thabet, Khaled; Asimakopoulos, Anastasia; Shojaei, Maryam; Romero-Gomez, Manuel; Mangia, Alessandra; Irving, William L.; Berg, Thomas; Dore, Gregory J.; Grønbæk, Henning; Sheridan, David; Abate, Maria Lorena; Bugianesi, Elisabetta; Weltman, Martin; Mollison, Lindsay; Cheng, Wendy; Riordan, Stephen; Fischer, Janett; Spengler, Ulrich; Nattermann, Jacob; Wahid, Ahmed; Rojas, Angela; White, Rose; Douglas, Mark W.; McLeod, Duncan; Powell, Elizabeth; Liddle, Christopher; van der Poorten, David; George, Jacob; Eslam, Mohammed; Gallego-Duran, Rocio; Applegate, Tanya; Bassendine, Margaret; Rosso, Chiara; Mezzabotta, Lavinia; Leung, Reynold; Malik, Barbara; Matthews, Gail; Grebely, Jason; Fragomeli, Vincenzo; Jonsson, Julie R.; Santaro, Rosanna

    2016-01-01

    Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis. PMID:27630043

  1. Oxidized low-density-lipoprotein accumulation is associated with liver fibrosis in experimental cholestasis

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    Güldeniz Karadeniz

    2008-01-01

    Full Text Available OBJECTIVE: The aim of the present study was to examine the probable relationship between the accumulation of oxLDL and hepatic fibrogenesis in cholestatic rats. INTRODUCTION: There is growing evidence to support the current theories on how oxidative stress that results in lipid peroxidation is involved in the pathogenesis of cholestatic liver injury and fibrogenesis. One of the major and early lipid peroxidation products, OxLDL, is thought to play complex roles in various immuno-inflammatory mechanisms. METHODS: A prolonged (21-day experimental bile duct ligation was performed on Wistar-albino rats. Biochemical analysis of blood, histopathologic evaluation of liver, measurement of the concentration of malondialdehyde (MDA and superoxide-dismutase (SOD in liver tissue homogenates, and immunofluorescent staining for oxLDL in liver tissue was conducted in bile-duct ligated (n = 8 and sham-operated rats (n = 8. RESULTS: Significantly higher levels of MDA and lower concentrations of SOD were detected in jaundiced rats than in the sham-operated rats. Positive oxLDL staining was also observed in liver tissue sections of jaundiced rats. Histopathological examination demonstrated that neither fibrosis nor other indications of hepatocellular injury were found in the sham-operated group, while features of severe hepatocellular injury, particularly fibrosis, were found in jaundiced rats. CONCLUSION: Our results support the finding that either oxLDLs are produced as an intermediate agent during exacerbated oxidative stress or they otherwise contribute to the various pathomechanisms underlying the process of liver fibrosis. Whatever the mechanism, it is clear that an association exists between elevated oxLDL levels and hepatocellular injury, particularly with fibrosis. Further studies are needed to evaluate the potential effects of oxLDLs on the progression of secondary biliary cirrhosis.

  2. Preventive effect of Qianggan-Rongxian Decoction on rat liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Chun-Hui Li; Li-Hui Pan; Zong-Wei Yang; Chun-Yu Li; Wen-Xie Xu

    2008-01-01

    AIM: To study the preventive effects of Qianggan-Rongxian Decoction on liver fibrosis induced by dimethylnitrosamine (DMN) in rats.METHODS: Male Wistar rats were randomly divided into hepatic fibrosis model group, control group and 3 treatment groups (12 rats in each group). Except for the normal control group, all the rats received 1% DMN (10μL/kg body weight, I. P), 3 times a week for 4wk. The rats in the 3 treatment groups including a high-dose DMN group (10mL/kg), a medium-dose DMN group (7 mL/kg), and a low-dose DMN group (4mL/kg) were daily gavaged with Qianggan-Rongxian Decoction, and the rats in the model and normal control groups were given saline vehicle. Enzyme-linked immunosorbent assay (ELISA) was used to determine the changes in serum hyaluronic acid (HA), laminin (LN), and type Ⅳ collagen levels. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured using routine laboratory methods. Pathologic changes, particularly fibrosis, were examined by hematoxylin and eosin (HE) and Sirius red staining. Hepatic stellate cells (HSC) were examined by transmission electron microscopy.RESULTS: Compared with the model control group, the serum levels of HA, LN, type Ⅳ collagen, ALT and AST were decreased markedly in the other groups after treatment with Qianggan-Rongxian Decoction, especially in the medium-dose DMN group (P<0.05). Moreover, the area-density percentage of collagen fibrosis was lower in the Qianggan-Rongxian Decoction treatment groups than in the model group, and a more significant drop was observed in the medium-dose DMN group (P<0.05).CONCLUSION: Qianggan-Rongxian Decoction can inhibit hepatic fibrosis due to chronic liver injury, delay the development of cirrhosis, and notably ameliorate liver function. It may be used as a safe and effective thera-peutic drug for patients with fibrosis.

  3. Molecular Mechanism and Treatment of Viral Hepatitis-Related Liver Fibrosis

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    Tung-Hung Su

    2014-06-01

    Full Text Available Hepatic fibrosis is a wound-healing response to various chronic stimuli, including viral hepatitis B or C infection. Activated myofibroblasts, predominantly derived from the hepatic stellate cells (HSCs, regulate the balance between matrix metalloproteinases and their tissue inhibitors to maintain extracellular matrix homeostasis. Transforming growth factor-β and platelet-derived growth factor are classic profibrogenic signals that activate HSC proliferation. In addition, proinflammatory cytokines and chemokines coordinate macrophages, T cells, NK/NKT cells, and liver sinusoidal endothelial cells in complex fibrogenic and regression processes. In addition, fibrogenesis involves angiogenesis, metabolic reprogramming, autophagy, microRNA, and epigenetic regulations. Hepatic inflammation is the driving force behind liver fibrosis; however, host single nucleotide polymorphisms and viral factors, including the genotype, viral load, viral mutation, and viral proteins, have been associated with fibrosis progression. Eliminating the underlying etiology is the most crucial antifibrotic therapy. Growing evidence has indicated that persistent viral suppression with antiviral therapy can result in fibrosis regression, reduced liver disease progression, decreased hepatocellular carcinoma, and improved chances of survival. Preclinical studies and clinical trials are currently examining several investigational agents that target key fibrogenic pathways; the results are promising and shed light on this debilitating illness.

  4. Liver-protecting and fibrosis-resisting effect of Ganxianning on rats withspleen deficiency and stagnation of Liver-qi

    Institute of Scientific and Technical Information of China (English)

    Zhen Qiu Guo; Xiao Wei Zhao; Xin Yu Chen

    2000-01-01

    AIM To study the liver-protecting and fibrosis-resisting effect of Ganxianning (GXN) and its mechanism.METHODS Model of carbon tetrachloride hepatic injury fibrosis rats was reproduced. In the experimentthere were six groups, the treatment groups with GXN's large, moderate and small dose (GXNb, GXNm andGXNs), the treatment group with colchicine, the blank model group and normal control group. The course of treatment was 30 days, then the rats were killed with their blood and liver tested.RESULTS In treatment groups, alanine aminotransferase (ALT) was lower than that in the model group(P<0.01), and albumin (Alb) higher than that in the model (P<0.01). Hydroxylproline (Hyp) and redcell membrane C3B receptor garland in GXNb's and GXNm's groups were lower and circulation complex(CIC) was slightly higher. Fibrinogen (Fb) in both colchicine and model groups was higher than that innormal group and the difference was significant (P<0.05, P<0.01). Compared with model group, acid-α-naphthyl acetate esterase (ANAE) increased in GXNb's and GXNm's groups (P<0.05, P<0.01). Underlight and electron microscopes, level of hepatic fibrosis of GXN groups was much lower than that of themodel group, P<0.01, and their difference was very significant. In GXNms group, liver cell was normal onthe whole and its chromatin was more than the model group and its nucleolus was evident.CONCLUSION GXN has rather good functions of protecting liver and resisting fibrosis, and thesefunctions are related to the increase of ANAE and C3b, decrease of CIC and Fb. and improvement of bodyimmunity function.

  5. Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats

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    Dong-Chang Zhao; Jun-Xia Lei; Rui Chen; Wei-Hua Yu; Xiu-Ming Zhang; Shu-Nong Li; Peng Xiang

    2005-01-01

    AIM: Recent reports have shown the capacity of mesenchymal stem cells (MSCs) to differentiate into hepatocytes in vitro and in vivo. MSCs administration could repair injured liver, lung, or heart through reducing inflammation, collagen deposition, and remodeling. These results provide a clue to treatment of liver fibrosis. The aim of this study was to investigate the effect of infusion of bone marrow (BM)-derived MSCs on the experimental liver fibrosis in rats.METHODS: MSCs isolated from BM in male Fischer 344 rats were infused to female Wistar rats induced with carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN).There were two random groups on the 42nd d of CCl4:CCl4/MSCs, to infuse a dose of MSCs alone; CCl4/saline,to infuse the same volume of saline as control. There were another three random groups after exposure to DMN: DMN10/MSCs, to infuse the same dose of MSCs on d 10; DMN10/saline, to infuse the same volume of saline on d 10; DMN20/MSCs, to infuse the same dose of MSCson d 20. The morphological and behavioral changes ofrats were monitored everyday. After 4-6 wk of MSCs administration, all rats were killed and fibrosis index were assessed by histopathology and radioimmunoassay. Smooth muscle alpha-actin (alpha-SMA) of liver were tested by immunohistochemistry and quantified by IBAS 2.5 software. Male rats sex determination region on the Y chromosome (sry) gene were explored by PCR.RESULTS: Compared to controls, infusion of MSCsreduced the mortality rates of incidence in CCl4-induced model (10% vs 20%) and in DMN-induced model (2040% vs 90%).The amount of collagen deposition and alpha-SMA staining was about 40-50% lower in liver of rats with MSCs than that of rats without MSCs. The similar results were observed in fibrosis index. And the effect of the inhibition of fibrogenesis was greater in DMN10/MSCs than in DMN20/MSCs. The sry gene was positive in the liver of rats with MSCs treatment by PCR.CONCLUSION: MSCs treatment can protect against

  6. Incidence and predictors of severe liver fibrosis in HIV-infected patients with chronic hepatitis C in Brazil.

    Science.gov (United States)

    Mendes-Correa, Maria Cássia; Widman, Azzo; Brussi, Maria Luiza Paes; Guastini, Cristina Fátima; Gianini, Reinaldo José

    2008-09-01

    The aim of this study was to examine the incidence and factors associated with the severity of liver fibrosis in 234 coinfected patients in Brazil. Patients were cared for in our clinic, from 1996 to 2004. Eligible patients were defined as patients with documented HIV and hepatitis C virus (HCV) infections and had previously undergone a liver biopsy. Patients with persistently normal alanine aminotransferase (ALT) were also included. The variables selected for study were age, gender, risk category, history of high alcohol consumption, CD4(+) T cell count, antiretroviral therapy usage, HCV genotype and duration of HCV infection. Stage of fibrosis was scored as follows: F0, no fibrosis; F1, portal fibrosis with no septa; F2, portal fibrosis with few septa; F3, bridging fibrosis with many septa; and F4, cirrhosis. The liver fibrosis stage was F3 in 39 (16.6%) and F4 in 20(8.5%) patients. Among patients with normal ALT, the liver fibrosis stage was F3-F4 in three patients (5.6%). Predictors of severe liver fibrosis (F3-F4) by multivariate analysis were age (older patients) and genotype 3 (genotype 1 = odds ratio [OR], 0.28; 95% confidence interval [CI], 0.12 0.65). In summary, in the present study severe liver fibrosis was found in 25% of our patients and was associated with an age of more than 38 years at the time of liver biopsy as well as, HCV genotype 3. No differences were found with respect to CD4(+) T cell counts although patients with a CD4(+) T cell count greater than 50 were excluded. PMID:18752463

  7. Non-coding keratin variants associate with liver fibrosis progression in patients with hemochromatosis.

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    Pavel Strnad

    Full Text Available BACKGROUND: Keratins 8 and 18 (K8/K18 are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with end-stage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. METHODS: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previously-generated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. RESULTS: We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2% and non-coding heterozygous variants in 6 additional patients (3.7%. Two novel K8 variants (Q169E/R275W were found. K8 R341H was the most common amino-acid altering variant (4 patients, and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. In mice, or ex vivo, the K8 G62C variant did not affect iron-accumulation in response to iron-rich diet or the extent of iron-induced hepatocellular injury. CONCLUSION: In patients with hemochromatosis, intronic but not exonic K8/K18 variants associate with liver fibrosis development.

  8. Multicenter clinical study on Fuzhenghuayu capsule against liver fibrosis due to chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Ping Liu; Mo-Bin Wan; Xiong Cai; Zhi-Qing Zhang; Jun Ye; Ren-Xing Zhou; Jia He; Bao-Zhang Tang; Yi-Yang Hu; Cheng Liu; Lie-Ming Xu; Cheng-Hai Liu; Ke-Wei Sun; De-Chang Hu; You-Kuan Yin; Xia-Qiu Zhou

    2005-01-01

    AIM: To study the efficacy and safety of Fuzhenghuayu capsule (FZHY capsule, a capsule for strengthening body resistance to remove blood stasis) against liver fibrosis due to chronic hepatitis B. METHODS: Multicenter, randomized, double blinded and parallel control experiment was conducted in patients (aged from 18 to 65 years) with liver fibrosis due to chronic hepatitis B. Hepatic histologic changes and HBV markers were examined at wk 0 and 24 during treatment. Serologic parameters (HA, LM, P-Ⅲ-P, Ⅳ-C) were determined and B ultrasound examination of the spleen and liver was performed at wk 0, 12 and 24. Liver function (liver function and serologic parameters for liver fibrosis) was observedat wk 0, 6, 12, 18 and 24. Blood and urine routine test, renal function and ECG were examined before and after treatment. RESULTS: There was no significant difference between experimental group (110 cases) and control group (106 cases) in demographic features, vital signs, course of illness, history for drug anaphylaxis and previous therapy, liver function, serologic parameters for liver fibrosis, liver histologic examination (99 cases in experimental group, 96 cases in control group), HBV markers, and renal function. According to the criteria for liver fibrosis staging, meanscore of fibrotic stage(s) in experimental group after treatment (1.80) decreased significantly compared to the previous treatment (2.33, P<0.05), but there was no significant difference in mean score of fibrotic stage(s) (2.11 and 2.14 respectively). There was a significant difference in reverse rate between experimental group (52%) and control group (23.3%) in liver biopsy. With marked effect on decreasing the mean value of inflammatory activity and score of inflammation (P<0.05), Fuzhenghuayu capsule had rather good effects on inhibiting inflammatory activity and was superior to that of Heluoshugan capsule. Compared to that of pretreatment, there was a significant decrease in HA, LM, P-Ⅲ-P and

  9. Serum metabolomic signatures discriminate early liver inflammation and fibrosis stages in patients with chronic hepatitis B.

    Science.gov (United States)

    Huang, Haijun; Sun, Zeyu; Pan, Hongying; Chen, Meijuan; Tong, Yongxi; Zhang, Jiajie; Chen, Deying; Su, Xiaoling; Li, Lanjuan

    2016-01-01

    Chronic HBV (CHB) infected patients with intermediate necroinflammation and fibrosis are recommended to receive antiviral treatment. However, other than liver biopsy, there is a lack of sensitive and specific objective method to determine the necroinflammation and fibrosis stages in CHB patients. This study aims to identify unique serum metabolomic profile associated with histological progression in CHB patients and to develop novel metabolite biomarker panels for early CHB detection and stratification. A comprehensive metabolomic profiling method was established to compare serum samples collected from health donor (n = 67), patients with mild (G indicator for antiviral treatment for CHB management. PMID:27498553

  10. Cystic Fibrosis Related Liver Disease—Another Black Box in Hepatology

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    Katharina Staufer

    2014-08-01

    Full Text Available Due to improved medical care, life expectancy in patients with cystic fibrosis (CF has veritably improved over the last decades. Importantly, cystic fibrosis related liver disease (CFLD has become one of the leading causes of morbidity and mortality in CF patients. However, CFLD might be largely underdiagnosed and diagnostic criteria need to be refined. The underlying pathomechanisms are largely unknown, and treatment strategies with proven efficacy are lacking. This review focuses on current invasive and non-invasive diagnostic standards, the current knowledge on the pathophysiology of CFLD, treatment strategies, and possible future developments.

  11. Effects of liver inflammation on FibroScan diagnosis of hepatic fibrosis in patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    刘志权

    2013-01-01

    Objective To investigate the influence of liver inflammation on the ability of the FibroScan non-invasive elastrography scanner to diagnose hepatic fibrosis in patients with chronic hepatitis B (CHB) .Methods A total of 124 CHB patients who received liver biopsy and concomitant liver stiffness measurement (LSM) by FibroScan

  12. The Impact of PNPLA3 rs738409 SNP on Liver Fibrosis Progression, Portal Hypertension and Hepatic Steatosis in HIV/HCV Coinfection.

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    Bernhard Scheiner

    Full Text Available Faster fibrosis progression and hepatic steatosis are hallmarks of HIV/HCV coinfection. A single nucleotide polymorphism (SNP of the PNPLA3-gene is associated with development of non-alcoholic steatohepatitis and a worse outcome in alcoholic liver disease. However, the role of PNPLA3 rs738409 SNP on liver fibrosis and steatosis, portal hypertension, and virological response in HIV/HCV coinfection remains unclear.In this cross-sectional study PNPLA3 (rs738409 and IL28B (rs12979860 SNPs were determined in 177 HIV/HCV coinfected patients. Liver fibrosis and steatosis-staged by liver biopsy and transient elastography using the Controlled Attenuation Parameter (CAP-and portal hypertension (hepatic venous pressure gradient, HVPG were compared across PNPLA3 genotypes.75 (42.4% patients tested positive for a PNPLA3 minor/major risk allele (G/C:66; G/G:9 showed comparable fibrosis stages (median F2 vs. F2; p = 0.292 and similar amounts of hepatic steatosis (CAP: 203.5 ± 41.9 vs. 215.5 ± 59.7 dB/m; p = 0.563 as compared to patients without a PNPLA3 risk allele. Advanced liver fibrosis was neither associated with PNPLA3 (p = 0.253 nor IL28B-genotype (p = 0.628, but with HCV-GT3 (p = 0.003, higher BMI (p = 0.008 and higher age (p = 0.007. Fibrosis progression rate (0.27 ± 0.41 vs. 0.20 ± 0.26 units/year; p = 0.984 and HVPG (3.9 ± 2.6 vs. 4.4 ± 3.0 mmHg; p = 0.472 were similar in patients with and without PNPLA3 risk alleles. SVR rates to PEGIFN/RBV therapy were similar across PNPLA3 genotypes.The presence of a PNPLA3 risk allele had no independent impact on liver disease or virological response rates to PEGIFN/RBV therapy in our cohort of HIV/HCV coinfected patients.

  13. PASS-Predicted Hepatoprotective Activity of Caesalpinia sappan in Thioacetamide-Induced Liver Fibrosis in Rats

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    Farkaad A. Kadir

    2014-01-01

    Full Text Available The antifibrotic effects of traditional medicinal herb Caesalpinia sappan (CS extract on liver fibrosis induced by thioacetamide (TAA and the expression of transforming growth factor β1 (TGF-β1, α-smooth muscle actin (αSMA, and proliferating cell nuclear antigen (PCNA in rats were studied. A computer-aided prediction of antioxidant and hepatoprotective activities was primarily performed with the Prediction Activity Spectra of the Substance (PASS Program. Liver fibrosis was induced in male Sprague Dawley rats by TAA administration (0.03% w/v in drinking water for a period of 12 weeks. Rats were divided into seven groups: control, TAA, Silymarin (SY, and CS 300 mg/kg body weight and 100 mg/kg groups. The effect of CS on liver fibrogenesis was determined by Masson’s trichrome staining, immunohistochemical analysis, and western blotting. In vivo determination of hepatic antioxidant activities, cytochrome P450 2E1 (CYP2E1, and matrix metalloproteinases (MPPS was employed. CS treatment had significantly increased hepatic antioxidant enzymes activity in the TAA-treated rats. Liver fibrosis was greatly alleviated in rats when treated with CS extract. CS treatment was noted to normalize the expression of TGF-β1, αSMA, PCNA, MMPs, and TIMP1 proteins. PASS-predicted plant activity could efficiently guide in selecting a promising pharmaceutical lead with high accuracy and required antioxidant and hepatoprotective properties.

  14. Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis.

    Science.gov (United States)

    Ziogas, Dimitrios C; Gras-Miralles, Beatriz; Mustafa, Sarah; Geiger, Brenda M; Najarian, Robert M; Nagel, Jutta M; Flier, Sarah N; Popov, Yury; Tseng, Yu-Hua; Kokkotou, Efi

    2013-05-15

    Fibrosis represents a major complication of several chronic diseases, including inflammatory bowel disease (IBD). Treatment of IBD remains a clinical challenge despite several recent therapeutic advances. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide shown to regulate appetite and energy balance. However, accumulating evidence suggests that MCH has additional biological effects, including modulation of inflammation. In the present study, we examined the efficacy of an MCH-blocking antibody in treating established, dextran sodium sulfate-induced experimental colitis. Histological and molecular analysis of mouse tissues revealed that mice receiving anti-MCH had accelerated mucosal restitution and lower colonic expression of several proinflammatory cytokines, as well as fibrogenic genes, including COL1A1. In parallel, they spared collagen deposits seen in the untreated mice, suggesting attenuated fibrosis. These findings raised the possibility of perhaps direct effects of MCH on myofibroblasts. Indeed, in biopsies from patients with IBD, we demonstrate expression of the MCH receptor MCHR1 in α-smooth muscle actin(+) subepithelial cells. CCD-18Co cells, a primary human colonic myofibroblast cell line, were also positive for MCHR1. In these cells, MCH acted as a profibrotic modulator by potentiating the effects of IGF-1 and TGF-β on proliferation and collagen production. Thus, by virtue of combined anti-inflammatory and anti-fibrotic effects, blocking MCH might represent a compelling approach for treating IBD. PMID:23538494

  15. TLR4 Deficiency Protects against Hepatic Fibrosis and Diethylnitrosamine-Induced Pre-Carcinogenic Liver Injury in Fibrotic Liver.

    Directory of Open Access Journals (Sweden)

    Susanne Nicole Weber

    Full Text Available The development of hepatocellular carcinoma (HCC is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN, with HCC formation depending amongst others on interleukin (IL 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis.ABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6 as well as hepatic apoptosis (TUNEL and proliferation (Ki67 rates.Hepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN.This study demonstrates that liver injury upon DEN challenge

  16. Prevention of liver fibrosis by triple helix-forming oligodeoxyribonucleotides targeted to the promoter region of type I collagen gene.

    Science.gov (United States)

    Koilan, Subramaniyan; Hamilton, David; Baburyan, Narina; Padala, Mythili K; Weber, Karl T; Guntaka, Ramareddy V

    2010-10-01

    Hepatic fibrosis leading to cirrhosis remains a global health problem. The most common etiologies are alcoholism and viral infections. Liver fibrosis is associated with major changes in both quantity and composition of extracellular matix and leads to disorganization of the liver architecture and irreversible damage to the liver function. As of now there is no effective therapy to control fibrosis. The end product of fibrosis is abnormal synthesis and accumulation of type I collagen in the extracellular matrix, which is produced by activated stellate or Ito cells in the damaged liver. Therefore, inhibition of transcription of type I collagen should in principle inhibit its production and accumulation in liver. Normally, DNA exists in a duplex form. However, under some circumstances, DNA can assume triple helical (triplex) structures. Intermolecular triplexes, formed by the addition of a sequence-specific third strand to the major groove of the duplex DNA, have the potential to serve as selective gene regulators. Earlier, we demonstrated efficient triplex formation between the exogenously added triplex-forming oligodeoxyribonucleotides (TFOs) and a specific sequence in the promoter region of the COL1A1 gene. In this study we used a rat model of liver fibrosis, induced by dimethylnitrosamine, to test whether these TFOs prevent liver fibrosis. Our results indicate that both the 25-mer and 18-mer TFOs, specific for the upstream nucleotide sequence from -141 to -165 (relative to the transcription start site) in the 5' end of collagen gene promoter, effectively prevented accumulation of liver collagen and fibrosis. We also observed improvement in liver function tests. However, mutations in the TFO that eliminated formation of triplexes are ineffective in preventing fibrosis. We believe that these TFOs can be used as potential antifibrotic therapeutic molecules. PMID:20818932

  17. Assessment of Liver Fibrosis Using Fast Strain-Encoded (FSENC) MRI Driven by Inherent Cardiac Motion

    Science.gov (United States)

    Harouni, Ahmed A.; Gharib, Ahmed M.; Osman, Nael F.; Morse, Caryn; Heller, Theo; Abd-Elmoniem, Khaled Z.

    2014-01-01

    Purpose An external driver-free MRI method for assessment of liver fibrosis offers a promising non-invasive tool for diagnosis and monitoring of liver disease. Lately, the heart’s intrinsic motion and MR tagging have been utilized for the quantification of liver strain. However, MR tagging requires multiple breath-hold acquisitions and substantial post-processing. This work proposes a fast strain-encoded (FSENC) MRI methodology to measure the peak strain (Sp) in the liver’s left lobe, which is in close proximity and caudal to the heart. Additionally, a new method is introduced to measure heart-induced shear wave velocity (SWV) inside the liver. Methods Phantom and in-vivo experiments (11 healthy subjects, and 11 patients with liver fibrosis) were conducted. Reproducibility experiments were performed in seven healthy subjects. Results Peak liver strain Sp significantly decreased in fibrotic liver compared healthy liver (6.46%±2.27% vs. 12.49%±1.76%, P<0.05). Heart-induced SWV significantly increased in patients compared to healthy subjects (0.15±0.04 m/s vs. 0.63±0.32 m/s, P<0.05). Reproducibility analysis yielded no significant difference in Sp (P=0.47) or SWV (P=0.56). Conclusion Accelerated external driver-free noninvasive assessment of left liver lobe strain and shear wave velocity is feasible using strain-encoded MRI. The two measures significantly separate healthy subjects from patients with fibrotic liver. PMID:25081734

  18. Clinical Study on Treatment of Liver Fibrosis of Chronic Hepatitis B Patients with Ginkgo Leaf

    Institute of Scientific and Technical Information of China (English)

    何云; 袁凤仪; 王建宾; 邵淑莲; 袁红波; 黄晓欣

    2002-01-01

    Objective: To study the anti-liver fibrosis effect of Ginkgo leaf in patients with chronic hepatitis B.Methods: Eighty-six patients with chronic hepatitis B were randomly divided into two groups with similar general condition. The 42 patients in the treated group were treated with Ginkgo leaf tablet (GLT), and the 44 patients in the control group were treated with Yiganling tablet (益肝灵片). The treatment was conducted for 3 successive months in both groups. Changes in the histo-pathology of liver, serum levels of platelet activating factor (PAF), hyaluronic acid (HA), collagen type Ⅳ (C-Ⅳ), laminin (LN) and pro-collagen peptide type Ⅲ (PCⅢ)were observed before and after treatment. Results: The markedly effective rate and the total effective rate in the treated group were 45.1% and 76.2% respectively, while in the control group the corresponding rates were 18.2% and 43.2%. Comparison between the two groups showed significant difference (P<0.01). Serum levels of PAF, HA, C-Ⅳ, LN and PCⅢ were lowered significantly in the treated group after treatment. Compared with the corresponding parameters in the control group after treatment, the differences were all significant (P<0.01 or P<0.05). The pathological examination of liver showed improvement in both groups, the inflammation grade lowered in 10 patients (55.6%) of the treated group and in 5 patients (35.7%) of the control group, insignificant difference was shown between them. But in comparing the fibrosis staging lowering patients between the two groups, 12 patients (66.7%) vs 3 patients (21.4%), the difference was significant (P<0.05). Moreover, there were 4 patients in the control group with their fibrosis aggravated, while in the treated group, none was aggravated (P<0.05).Conclusion: Ginkgo leaf tablet has some liver protective and anti-liver fibrosis benefits.

  19. Losartan may inhibit the progression of liver fibrosis in chronic HCV patients

    Science.gov (United States)

    Salama, Zakaria A.; Sadek, Ahmed; Abdelhady, Ahmed M.; Morsy, Shereif Ahmed; Esmat, Gamal

    2016-01-01

    Background Abundant experimental evidence indicates overproduction of angiotensin II in the injured liver, and a role in stimulation of hepatic stellate cell (HSC) activation and fibrogenesis thereby, representing an attractive antifibrotic target. The aim of this study was to examine the antifibrotic effect of losartan on histopathologic level in chronic HCV patients. Methods A prospective study on fifty patients with chronic HCV and liver fibrosis proved by liver biopsy was conducted. They included patients who did not respond (n=36) or comply (n=2) or receive therapy due to established cirrhosis (n=10), or refused to receive (n=2) combined interferon and ribavirin therapy. They were divided randomly into 2 groups. The 1st group (n=25) was given losartan 50 mg OD for 1 year and the 2nd group (25 patients) was given silymarin, 140 mg t.i.d., (silymarin group). Liver biopsy was done at baseline and 1 year from the onset of treatment (end of study). Results In the second liver biopsy after 1 year, the decrease in fibrosis stage was significantly different between losartan group and silymarin group (a decrease of 1.88±0.96 (50.9%) vs. 0.45±0.93 (11.7%), respectively; P<0.01). In patients treated with losartan, regression in fibrosis stage was observed in 14/16 patients vs. 2/11 in silymarin group (P<0.01). No differences were observed in inflammation grades in both groups. A significant increase in albumin and prothrombin levels and a decrease in systolic blood pressure were found in losartan but not in silymarin group (P=0.009, 0.001 & 0.018 respectively and P=0.158, 0.603 & 0.288, respectively). Conclusions Histopathological scores showed that losartan had an inhibitory effect on progression and even led to regression of fibrosis stage but had no effect on the grade of inflammation. PMID:27275467

  20. Aerobic Exercise Attenuated Bleomycin-Induced Lung Fibrosis in Th2-Dominant Mice

    Science.gov (United States)

    Oliveira-Junior, Manoel Carneiro; Assumpção-Neto, Erasmo; Brandão-Rangel, Maysa Alves Rodrigues; Damaceno-Rodrigues, Nilsa Regina; Garcia Caldini, Elia; Velosa, Ana Paula Pereira; Teodoro, Walcy Rosolia; Ligeiro de Oliveira, Ana Paula; Dolhnikoff, Marisa; Eickelberg, Oliver; Vieira, Rodolfo Paula

    2016-01-01

    Introduction The aim of this study was to investigate the effect of aerobic exercise (AE) in reducing bleomycin-induced fibrosis in mice of a Th2-dominant immune background (BALB/c). Methods BALB/c mice were distributed into: sedentary, control (CON), Exercise-only (EX), sedentary, bleomycin-treated (BLEO) and bleomycin-treated+exercised (BLEO+EX); (n = 8/group). Following treadmill adaptation, 15 days following a single, oro-tracheal administration of bleomycin (1.5U/kg), AE was performed 5 days/week, 60min/day for 4 weeks at moderate intensity (60% of maximum velocity reached during a physical test) and assessed for pulmonary inflammation and remodeling, and cytokine levels in bronchoalveolar lavage (BAL). Results At 45 days post injury, compared to BLEO, BLEO+EX demonstrated reduced collagen deposition in the airways (p<0.001) and also in the lung parenchyma (p<0.001). In BAL, a decreased number of total leukocytes (p<0.01), eosinophils (p<0.001), lymphocytes (p<0.01), macrophages (p<0.01), and neutrophils (p<0.01), as well as reduced pro-inflammatory cytokines (CXCL-1; p<0.01), (IL-1β; p<0.001), (IL-5; p<0.01), (IL-6; p<0.001), (IL-13; p<0.01) and pro-fibrotic growth factor IGF-1 (p<0.001) were observed. Anti-inflammatory cytokine IL-10 was increased (p<0.001). Conclusion AE attenuated bleomycin-induced collagen deposition, inflammation and cytokines accumulation in the lungs of mice with a predominately Th2-background suggesting that therapeutic AE (15–44 days post injury) attenuates the pro-inflammatory, Th2 immune response and fibrosis in the bleomycin model. PMID:27677175

  1. Detection of Hepatic Fibrosis in Ex Vivo Liver Samples Using an Open-Photoacoustic-Cell Method: Feasibility Study

    Science.gov (United States)

    Stolik, S.; Fabila, D. A.; de la Rosa, J. M.; Escobedo, G.; Suárez-Álvarez, K.; Tomás, S. A.

    2015-09-01

    Design of non-invasive and accurate novel methods for liver fibrosis diagnosis has gained growing interest. Different stages of liver fibrosis were induced in Wistar rats by intraperitoneally administering different doses of carbon tetrachloride. The liver fibrosis degree was conventionally determined by means of histological examination. An open-photoacoustic-cell (OPC) technique for the assessment of liver fibrosis was developed and is reported here. The OPC technique is based on the fact that the thermal diffusivity can be accurately measured by photoacoustics taking into consideration the photoacoustic signal amplitude versus the modulation frequency. This technique measures directly the heat generated in a sample, due to non-radiative de-excitation processes, following the absorption of light. The thermal diffusivity was measured with a home-made open-photoacoustic-cell system that was specially designed to perform the measurement from ex vivo liver samples. The human liver tissue showed a significant increase in the thermal diffusivity depending on the fibrosis stage. Specifically, liver samples from rats exhibiting hepatic fibrosis showed a significantly higher value of the thermal diffusivity than for control animals.

  2. A Novel Fibrosis Index Comprising a Non-Cholesterol Sterol Accurately Predicts HCV-Related Liver Cirrhosis

    DEFF Research Database (Denmark)

    Ydreborg, Magdalena; Lisovskaja, Vera; Lagging, Martin;

    2014-01-01

    Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim...... of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive...... significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5-6, as the outcome variable. A new index, referred...

  3. Diffusion-weighted MRI and fibroscan vs. histopathology for assessment of liver fibrosis in chronic HCV patients: (Pilot study

    Directory of Open Access Journals (Sweden)

    Ahmed Hosni Kamel Abdelmaksoud

    2015-06-01

    Conclusions: Diffusion MRI can distinguish non-fibrotic liver (F0 from advanced fibrosis (F3 and F4 but cannot be used to distinguish between the intermediate stages of fibrosis-fibroscan can differentiate between (F0, F1, F2 and (F3, F4.

  4. A specific gene-expression signature quantifies the degree of hepatic fibrosis in patients with chronic liver disease

    Institute of Scientific and Technical Information of China (English)

    Tohru Utsunomiya; Hiroshi Inoue; Graham F Barnard; Masaki Mori; Masahiro Okamoto; Shigeki Wakiyama; Masaji Hashimoto; Kengo Fukuzawa; Takahiro Ezaki; Shinichi Aishima; Yasuji Yoshikawa; Taizo Hanai

    2007-01-01

    AIM: To study a more accurate quantification of hepatic fibrosis which would provide clinically useful information for monitoring the progression of chronic liver disease.METHODS: Using a cDNA microarray containing over 22000 clones, we analyzed the gene-expression profiles of non-cancerous liver in 74 patients who underwent hepatic resection. We calculated the ratio of azan stained: total area, and determined the morphologic fibrosis index (MFI), as a mean of 9 section-images. We used the MFI as a reference standard to evaluate our method for assessing liver fibrosis.RESULTS: We identified 39 genes that collectively showed a good correlation (r>0.50) between geneexpression and the severity of liver fibrosis. Many of the identified genes were involved in immune responses and cell signaling. To quantify the extent of liver fibrosis,we developed a new genetic fibrosis index (GFI) based on gene-expression profiling of 4 clones using a linear support vector regression analysis. This technique, based on a supervised learning analysis, correctly quantified the various degrees of fibrosis in both 74 training samples (r= 0.76, 2.2% VS 2.8%, P<0.0001) and 12 independent additional test samples (r = 0.75, 9.8% vs 8.6%, P<0.005). It was far better in assessing liver fibrosis than blood markers such as prothrombin time (r= -0.53),type Ⅳ collagen 7s (r = 0.48), hyaluronic acid (r = 0.41),and aspartate aminotransferase to platelets ratio index(APRI) (r= 0.38).CONCLUSION: Our cDNA microarray-based strategy may help clinicians to precisely and objectively monitor the severity of liver fibrosis.

  5. Traditional herbal medicine use associated with liver fibrosis in rural Rakai, Uganda.

    Directory of Open Access Journals (Sweden)

    Brandon J Auerbach

    Full Text Available BACKGROUND: Traditional herbal medicines are commonly used in sub-Saharan Africa and some herbs are known to be hepatotoxic. However little is known about the effect of herbal medicines on liver disease in sub-Saharan Africa. METHODS: 500 HIV-infected participants in a rural HIV care program in Rakai, Uganda, were frequency matched to 500 HIV-uninfected participants. Participants were asked about traditional herbal medicine use and assessed for other potential risk factors for liver disease. All participants underwent transient elastography (FibroScan® to quantify liver fibrosis. The association between herb use and significant liver fibrosis was measured with adjusted prevalence risk ratios (adjPRR and 95% confidence intervals (CI using modified Poisson multivariable logistic regression. RESULTS: 19 unique herbs from 13 plant families were used by 42/1000 of all participants, including 9/500 HIV-infected participants. The three most-used plant families were Asteraceae, Fabaceae, and Lamiaceae. Among all participants, use of any herb (adjPRR = 2.2, 95% CI 1.3-3.5, p = 0.002, herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 2.9-8.7, p<0.001, and herbs from the Lamiaceae family (adjPRR = 3.4, 95% CI 1.2-9.2, p = 0.017 were associated with significant liver fibrosis. Among HIV infected participants, use of any herb (adjPRR = 2.3, 95% CI 1.0-5.0, p = 0.044 and use of herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 1.7-14.7, p = 0.004 were associated with increased liver fibrosis. CONCLUSIONS: Traditional herbal medicine use was independently associated with a substantial increase in significant liver fibrosis in both HIV-infected and HIV-uninfected study participants. Pharmacokinetic and prospective clinical studies are needed to inform herb safety recommendations in sub-Saharan Africa. Counseling about herb use should be part of routine health counseling and counseling of HIV-infected persons in Uganda.

  6. Expression of Basic Fibroblast Growth Factor in Rat Liver Fibrosis and Hepatic Stellate Cells

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The expression of basic fibroblast growth factor (bFGF) in rat liver fibrosis and hepatic stellate cells (HSCs) and the relationship between the expression of bFGF and rat liver fibrogenesis were studied. Sixty male SD rats (230-260 g) were divided into 4 groups randomly (the 0 week group, 1 week group, 4 week group and 8 week group). Liver fibrosis was induced by subcutaneous injection of carbon tetrachloride. The sections of rats' liver in each group were tested by VanGieson (V-G) staining and immunohistochemistry. The expression of bFGF mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR). HSCs were isolated by the combined methods of collagenase Ⅳ perfusion and density gradient centrifugation. The expression of bFGF protein in cultured HSCs was detected by Western blot. Images of immunohistochemistry detec tion, agarose gel electrophoresis of RT-PCR and SDS-polyacrylamide gel electrophoresis of Western blot were analyzed semiquantitatively by image-analyzing system. The results were analyzed by statistics. The results showed that the fibers were gradually increased in the sections of rat liver with the prolongation of the model induction. At the end of the 8th weeks, liver fibrosis was formed.The expression of bFGF detected by immunohistochemistry showed a similar tendency of gradual increase. At the end of the 8th weeks, the bFGF expression could be observed in many regions in sections and the strongest expression was in interstitial cells including HSCs and some hepatocytes in regions around the portal area and central veins. Also there was moderate expression widely in extracellular matrix (ECM). In RT-PCR detection and Western blot detection of HSCs cultured in vitro, the similar tendency of gradual increase was evident either. It is suggested that bFGF is related with liver fibrosis of rats closely and may be a fibrogenesis factor of liver. bFGF possibly regulates liver fibrogenesis through regulating metabolism of extracellular

  7. In vivo quantification of liver stiffness in a rat model of hepatic fibrosis with acoustic radiation force.

    Science.gov (United States)

    Wang, Michael H; Palmeri, Mark L; Guy, Cynthia D; Yang, Liu; Hedlund, Laurence W; Diehl, Anna Mae; Nightingale, Kathryn R

    2009-10-01

    Liver fibrosis is currently staged using needle biopsy, a highly invasive procedure with a number of disadvantages. Measurement of liver stiffness changes that accompany progression of the disease may provide a quantitative and noninvasive method to assess the health of the liver. The purpose of this study is to investigate the correlation between liver stiffness measured by radiation force induced shear waves and disease related changes in the liver. An additional aim is to present initial findings on the effects of liver viscosity on radiation force induced shear wave morphology. Liver fibrosis was induced in 10 rats using carbon tetrachloride (CCl(4)), while five rats acted as controls. Liver stiffness was measured in vivo in all rats after a treatment period of 8 weeks using a modified Siemens SONOLINE Antares scanner (Siemens Medical Solutions USA, Ultrasound Division, Issaquah, WA, USA). The spatial coherence of radiation force induced shear waves propagating in the viscoelastic rat liver decreased significantly with propagation distance, compared with shear waves in an elastic phantom and a finite element model of a purely elastic medium. Animals were sacrificed after imaging and liver samples were taken for histopathologic analysis and collagen quantification using picrosirius red staining and hydroxyproline assay. At the end of the treatment period, five rats had healthy livers (stage F0), while six had severe fibrosis (F3) and the rest had light to moderate fibrosis (F1 and F2). The measured liver stiffness for the F0 group was 1.5+/-0.1 kPa (mean+/-95% confidence interval) and for F3 livers was 1.8+/-0.2 kPa. In this study, liver stiffness was found to be linearly correlated with the amount of collagen in the liver measured by picrosirius red staining (r(2)=0.43, p=0.008). In addition, stiffness spatial heterogeneity was also linearly correlated with liver collagen content (r(2)=0.58, p=0.001) by picrosirius red staining. These results are consistent

  8. Hepatic and Splenic Acoustic Radiation Force Impulse Shear Wave Velocity Elastography in Children with Liver Disease Associated with Cystic Fibrosis

    OpenAIRE

    Teresa Cañas; Araceli Maciá; Rosa Ana Muñoz-Codoceo; Teresa Fontanilla; Patricia González-Rios; María Miralles; Gloria Gómez-Mardones

    2015-01-01

    Background. Liver disease associated with cystic fibrosis (CFLD) is the second cause of mortality in these patients. The diagnosis is difficult because none of the available tests are specific enough. Noninvasive elastographic techniques have been proven to be useful to diagnose hepatic fibrosis. Acoustic radiation force impulse (ARFI) imaging is an elastography imaging system. The purpose of the work was to study the utility of liver and spleen ARFI Imaging in the detection of CFLD. Method. ...

  9. Distribution of hepatic stellate cells and their role in the development of parasitic fibrosis and liver cirrhosis in domestic animals

    Directory of Open Access Journals (Sweden)

    Kukolj Vladimir

    2015-01-01

    Full Text Available Increasing of the extracellular matrix in rats, as well as in humans, occurs as a consequence of hepatic stellate cells (HSCs activity. The objective of this work was to investigation the role of these cells in the development of fibrosis and liver cirrhosis which occurs as a consequence of infection of sheep and goats with large (Fasciola hepatica and small (Dicrocoelium dendriticum fluke. Liver samples taken from 12 cattle and 10 sheep infected under natural conditions with large and small fluke were fixed in formalin and embedded in paraffin. Paraffin clips were stained with hematoxylin- eosin and masson trichrome method, and immunohistochemical method for α-smooth muscle actin (α-SMA. All tested samples were divided into three groups according to histological criteria: livers of infected animals with the first degree of fibrosis, livers of infected animals with the second degree of fibrosis, and livers of infected animals with cirrhosis. Distribution of HSCs depended on the degree of liver fibrosis. Immunohistochemically reactive HSCs were predominantly placed in perisinusoidal space. In liver samples with cirrhosis, HSCs were placed on the periphery of pseudolobulus. Cells of a different shape and size were positive to α-SMA. HSCs play an important role in synthesis of components of extracellular matrix during the development of parasitic fibrosis and liver cirrhosis in domestic animals.

  10. Clinical Observation on Effect of Ruangan Granule (软肝颗粒剂 ) in Treating Chronic Hepatitic Liver Fibrosis

    Institute of Scientific and Technical Information of China (English)

    李秀惠; 赵春惠; 金荣华; 黄春

    2002-01-01

    Objective: To observe the clinical effect of Ruangan granule (RGG) in treating liver fibrosis.Methods: One hundred and twenty patients of chronic viral hepatitis B were randomly divided into two groups, 60 patients in the treated group and 60 patients in the control group. They were treated with RGG or composite Biejia Ruangan tablet (复方鳖甲软肝片) respectively for three months. The changes of liver function, liver fibrosis indices, including fibronectin (FN), laminin (LN) and hyaluronic acid (HA), as well as liver morphology by B-ultrasonic examination were observed after treatment. A three-month follow-up study was also conducted. Results: In the treated group, the markedly effective rate was 50.0% and effective rate was 41.7%, while in the control group, the corresponding rates were 26.7% and 55.0% respectively. Comparison of the markedly effective rate between the two groups showed significant difference (P<0.01). The serum levels of FN, LN, HA as well as splenomegaly and portal vein widening in the treated group after treatment were significantly improved (P<0.05), as compared with those in the control group after treatment; significant difference was shown in comparison of serum FN, LN and HA. Conclusion: RGG could improve effectively serum liver fibrosis indices and liver function in patients of chronic hepatitic fibrosis. It is helpful in alleviating and inhibiting the genesis and development of liver fibrosis so as to block the progression of liver cirrhosis.

  11. Dynamic Observation of Liver Fibrosis in Mice Infected with Schistosoma japonica

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The expression of TNF-α in the liver at different periods post Schistosoma japonica infection and the effect on liver fibrosis after supplementary injection of these eytokines were investigated. The mice infected with schistosome cercariae were divided into 3 groups: normal control group, TNF-α-untreated infection group and TNF-α-treated infection group. ABC immunohistochemistry and pathologic image multimedia quantification system were applied to dynamically detect the activity of TNF-α. The results showed that the levels of TNF-α in the liver in TNF-α-untreated infection group were slowly decreased with prolongation of infection time (from 8th, 11th, 14th to 18th week), while in the TNF-α-treated infection group, those were increased significantly after intraperitoneal injection of TNF-α at 6th week after infection. At first to 8th week after the final injection of TNF-α, the intrahepatic TNF-α levels in the TNF-α-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-α from Th1 activated macrophages. Six weeks after infection (post egg deposition), exogenous supplement with intraperitoneal injection of TNF-α could induce the enhanced expression of Th1 cytokines and alleviate the liver granulomatous inflammation and fibrosis.

  12. Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats

    Institute of Scientific and Technical Information of China (English)

    Ali Riza Soylu; Huseyin Baloglu; Mevlut Ture; Kemal Kutlu; Kadir Kaymak; Nurettin Aydogdu; Umit Nusret Basaran; Semsi Altaner; Orhan Tarcin; Nursal Gedik; Hasan Umit; Ahmet Tezel; Gulbin Dokmeci

    2006-01-01

    AIM:To investigate whether antioxidants vitamin E and C can retard development of hepatic fibrosis in the biliary-obstructed rats.METHODS: Fifty Wistar albino rats were randomly assigned to 5 groups (10 rats in each). Bile duct was ligated in 40 rats and they were treated as follows: group vitC, vitamin C 10 rog/kg sc daily; group vitE, vitamin E 15 mg/kg sc daily; group vitEC, both of the vitamins; bile duct-ligated (BDL, control) group, physiological saline sc. The fifth group was assigned to sham operation. At the end of fourth week, the rats were decapitated, and hepatic tissue biochemical collagen content and collagen surface area were measured. Hepatic tissue specimens were histopathologically evaluated according to Scheuer system. Serum hyaluronate levels were measured by ELTSA method.RESULTS: Despite being higher than sham group, hepatic collagen level was significantly decreased in each of the vitC, vitE and vitEC groups (32.7 ± 1.2, 33.8 ±2.9, 36.7 ± 0.5 μg collagen/mg protein, respectively)compared to BDL (48.3 ± 0.6 mg collagen/g protein) (P< 0.001 for each vitamin group). Each isolated vitamin C, isolated vitamin E and combined vitamin E/C supplementation prevented the increase in hepatic collagen surface density (7.0% ± 1.1%, 6.2% ± 1.7%, 12.3% ±2.0%, respectively) compared to BDL (17.4% ± 5.6%) (P< 0.05 for each). The same beneficial effect of vitamin C,vitamin E and combined vitamin E/C treatment was also observed on the decrease of serum hyaluronate levels compared to BDL group (P < 0.001). The relative liver and spleen weights, serum transaminases, cholestatic enzymes, bilirubins and histopathological inflammation scores were not different between the antioxidant treatment groups and the control. However, fibrosis staging scores were obviously reduced only in the vitamin E/C combination group (vit EC: 2.4 ± 0.8 vs BDL: 3.1 ± 0.7;P < 0.05).CONCLUSION: Each antioxidant vitamin E, vitamin C and their combination retard hepatic

  13. Feasibility of histogram analysis of susceptibility-weighted MRI for staging of liver fibrosis

    Science.gov (United States)

    Yang, Zhao-Xia; Liang, He-Yue; Hu, Xin-Xing; Huang, Ya-Qin; Ding, Ying; Yang, Shan; Zeng, Meng-Su; Rao, Sheng-Xiang

    2016-01-01

    PURPOSE We aimed to evaluate whether histogram analysis of susceptibility-weighted imaging (SWI) could quantify liver fibrosis grade in patients with chronic liver disease (CLD). METHODS Fifty-three patients with CLD who underwent multi-echo SWI (TEs of 2.5, 5, and 10 ms) were included. Histogram analysis of SWI images were performed and mean, variance, skewness, kurtosis, and the 1st, 10th, 50th, 90th, and 99th percentiles were derived. Quantitative histogram parameters were compared. For significant parameters, further receiver operating characteristic (ROC) analyses were performed to evaluate the potential diagnostic performance for differentiating liver fibrosis stages. RESULTS The number of patients in each pathologic fibrosis grade was 7, 3, 5, 5, and 33 for F0, F1, F2, F3, and F4, respectively. The results of variance (TE: 10 ms), 90th percentile (TE: 10 ms), and 99th percentile (TE: 10 and 5 ms) in F0–F3 group were significantly lower than in F4 group, with areas under the ROC curves (AUCs) of 0.84 for variance and 0.70–0.73 for the 90th and 99th percentiles, respectively. The results of variance (TE: 10 and 5 ms), 99th percentile (TE: 10 ms), and skewness (TE: 2.5 and 5 ms) in F0–F2 group were smaller than those of F3/F4 group, with AUCs of 0.88 and 0.69 for variance (TE: 10 and 5 ms, respectively), 0.68 for 99th percentile (TE: 10 ms), and 0.73 and 0.68 for skewness (TE: 2.5 and 5 ms, respectively). CONCLUSION Magnetic resonance histogram analysis of SWI, particularly the variance, is promising for predicting advanced liver fibrosis and cirrhosis. PMID:27113421

  14. PATHOPHYSIOLOGIC BASIS OF LIVER DISEASE IN CYSTIC FIBROSIS EMPLOYING A ΔF508 MOUSE MODEL

    OpenAIRE

    Freudenberg, Folke; BRODERICK, ANNEMARIE L.; Yu, Bian B.; Leonard, Monika R.; Glickman, Jonathan N.; CAREY, MARTIN C.

    2008-01-01

    The molecular pathogenesis of cystic fibrosis (CF) liver disease is unknown. This study investigates its earliest pathophysiologic manifestations employing a mouse model carrying ΔF508, the commonest human CF mutation. We hypothesized that, if increased bile salt spillage into the colon occurs as in the human disease, this should lead to a hydrophobic bile salt profile and to “hyperbilirubinbilia” because of induced enterohepatic cycling of unconjugated bilirubin. Hyperbilirubinbilia may then...

  15. Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

    OpenAIRE

    Rath, Timo; Hage, Lisa; Kügler, Marion; Menendez Menendez, Katrin; Zachoval, Reinhart; Naehrlich, Lutz; Schulz, Richard; Roderfeld, Martin; Roeb, Elke

    2013-01-01

    Background and Aims Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. Methods 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting...

  16. Impact of OAS1 Exon 7 rs10774671 Genetic Variation on Liver Fibrosis Progression in Egyptian HCV Genotype 4 Patients.

    Science.gov (United States)

    Bader El Din, Noha G; Anany, Mohamed A; Dawood, Reham M; Ibrahim, Marwa K; El-Shenawy, Reem; El Abd, Yasmin S; El Awady, Mostafa K

    2015-11-01

    The aim of this study was to assess the impact of genetic variants of oligoadenylate synthetase 1 (OAS1) single-nucleotide polymorphism (SNP) rs10774671 at the exon 7 splice acceptor site on liver fibrosis progression and hepatitis C virus (HCV) outcome in Egyptian HCV genotype 4 patients. In this study, 195 subjects were enrolled; 60 controls and 135 chronic HCV genotype 4 patients with different fibrosis grades. All subjects were genotyped for OAS1 SNP rs10774671 polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. There was an increasing trend of liver fibrosis progression as 52.9% GG, 73.6% GA, and 83.3% AA genotypes were detected in late fibrosis patients (p = 0.025). The AA genotype was higher in the late fibrosis group than in the early fibrosis group (83.3% vs. 16.7%) (p = 0.001). The A allele was significantly affecting the liver fibrosis progression rate, more than the G allele (p = 0.001). The multivariate analysis showed that the OAS1 GA and AA genotypes were independent factors associated with liver progression (p = 0.009, odds ratio [OR] 3.467, 95% confidence interval [CI] 1.273-7.584). In addition, the A allele was associated with liver fibrosis progression (p = 0.014, OR 2.525, 95% CI 1.157-4.545). The polymorphism at OAS1 exon 7 rs3741981 might be a potential genetic marker and can be useful in the assessment of liver fibrosis progression and disease outcome in HCV-infected patients. PMID:26505957

  17. Effect of Astragalus complanatus fiavonoid on anti-liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Chun-Yu Liu; Zhen-Lun Gu; Wen-Xuan Zhou; Ci-Yi Guo

    2005-01-01

    AIM: To observe the anti-liver fibrosis effect of Astragalus complanatus fiavonoids (ACF) in rats.METHODS: The liver fibrosis model in rats was established by injecting interperitoneally 0.2 mL/100 g 0.5% dimethylnitrosamine, thrice a week. Meanwhile, the rats were administered ACF (30, 60, 120 mg/kg) or colchicine (0.1 mg/kg) once a day for 1 mo. Serum N-propeptide of type I procollagen (PINP) and type Ⅲ procollagen (PⅢNP) was measured using ELISA. Malondialdehyde (MDA) and superoxide dismutase (SOD) in hepatic tissue were evaluated. Matrix metal protease-1 (MMP-1) mRNA expression was assayed by RT-PCR and the protein expression of tissue inhibitor of metal protease-1 (TIMP-1) was analyzed by immunohistochemistry.RESULTS: In the ACF groups, SOD activity increased and MDA content decreased in comparison to the liver fibrosis model group. The serum PINP and PⅢNP contents in ACF-2 and -3 group decreased compared to those in model group.In ACF-2 and -3 group, the expression of MMP-1 mRNA increased significantly and the protein expression of TIMP-1 decreased compared to that in model group.CONCLUSION: The antifibrotic mechanisms of ACF are associated with its influence on lipid peroxidation and collagen synthesis and degradation.

  18. The diagnostic efficacy of quantitative liver MR imaging with diffusion-weighted, SWI, and hepato-specific contrast-enhanced sequences in staging liver fibrosis - a multiparametric approach

    Energy Technology Data Exchange (ETDEWEB)

    Feier, Diana [Medical University of Vienna, General Hospital of Vienna (AKH), Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Emergency County Hospital, Department of Radiology, Cluj-Napoca (Romania); Balassy, Csilla; Bastati, Nina; Fragner, Romana; Ba-Ssalamah, Ahmed [Medical University of Vienna, General Hospital of Vienna (AKH), Department of Biomedical Imaging and Image-guided Therapy, Vienna (Austria); Wrba, Friedrich [Medical University of Vienna, General Hospital of Vienna (AKH), Department of Pathology, Vienna (Austria)

    2016-02-15

    To assess the diagnostic efficacy of multiparametric MRI using quantitative measurements of the apparent diffusion coefficient (ADC) of the liver parenchyma on diffusion-weighted imaging (DWI), signal intensity (SI) on susceptibility-weighted imaging (SWI), and gadoxetic acid-enhanced T1-weighted imaging during the hepatobiliary phase for the staging of liver fibrosis. Seventy-seven patients underwent a 3T MRI examination, including DWI/SWI sequences and gadoxetic acid-enhanced T1-weighted MRI. Liver fibrosis according to liver biopsy was staged using the Metavir fibrosis score: F0 (n = 21, 27.3 %); F1 (n = 7, 9.1 %); F2 (n = 8, 10.4 %); F3 (n = 12, 15.6 %); and F4 (n = 29, 37.7 %). SI of the liver was defined using region-of-interest measurements to calculate the ADC values, the relative enhancement (RE) in the hepatobiliary phase, and the liver-to-muscle ratio (LMR) measurements for SWI. The values of RE, LMR, and ADC measurements were statistically significantly different among the five fibrosis stages (p < 0.004). Combining the three parameters in a multiparametric approach, the AUC for detecting F1 stage or greater (≥ F1) was 94 %, for F2 or greater (≥F2) was 95 %, for F3 or greater (≥F3) was 90 %, and for stage F4 was 93 %. Multiparametric MRI is an efficient non-invasive diagnostic tool for the staging of liver fibrosis. (orig.)

  19. The diagnostic efficacy of quantitative liver MR imaging with diffusion-weighted, SWI, and hepato-specific contrast-enhanced sequences in staging liver fibrosis - a multiparametric approach

    International Nuclear Information System (INIS)

    To assess the diagnostic efficacy of multiparametric MRI using quantitative measurements of the apparent diffusion coefficient (ADC) of the liver parenchyma on diffusion-weighted imaging (DWI), signal intensity (SI) on susceptibility-weighted imaging (SWI), and gadoxetic acid-enhanced T1-weighted imaging during the hepatobiliary phase for the staging of liver fibrosis. Seventy-seven patients underwent a 3T MRI examination, including DWI/SWI sequences and gadoxetic acid-enhanced T1-weighted MRI. Liver fibrosis according to liver biopsy was staged using the Metavir fibrosis score: F0 (n = 21, 27.3 %); F1 (n = 7, 9.1 %); F2 (n = 8, 10.4 %); F3 (n = 12, 15.6 %); and F4 (n = 29, 37.7 %). SI of the liver was defined using region-of-interest measurements to calculate the ADC values, the relative enhancement (RE) in the hepatobiliary phase, and the liver-to-muscle ratio (LMR) measurements for SWI. The values of RE, LMR, and ADC measurements were statistically significantly different among the five fibrosis stages (p < 0.004). Combining the three parameters in a multiparametric approach, the AUC for detecting F1 stage or greater (≥ F1) was 94 %, for F2 or greater (≥F2) was 95 %, for F3 or greater (≥F3) was 90 %, and for stage F4 was 93 %. Multiparametric MRI is an efficient non-invasive diagnostic tool for the staging of liver fibrosis. (orig.)

  20. Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus

    Science.gov (United States)

    Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

    2016-01-01

    The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully. PMID:27649152

  1. Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus.

    Science.gov (United States)

    Shigefuku, Ryuta; Takahashi, Hideaki; Nakano, Hiroyasu; Watanabe, Tsunamasa; Matsunaga, Kotaro; Matsumoto, Nobuyuki; Kato, Masaki; Morita, Ryo; Michikawa, Yousuke; Tamura, Tomohiro; Hiraishi, Tetsuya; Hattori, Nobuhiro; Noguchi, Yohei; Nakahara, Kazunari; Ikeda, Hiroki; Ishii, Toshiya; Okuse, Chiaki; Sase, Shigeru; Itoh, Fumio; Suzuki, Michihiro

    2016-01-01

    The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.

  2. Celastrol-Induced Suppression of the MiR-21/ERK Signalling Pathway Attenuates Cardiac Fibrosis and Dysfunction

    Directory of Open Access Journals (Sweden)

    Mian Cheng

    2016-05-01

    Full Text Available Backgroud: Myocardial fibrosis results in myocardial remodelling and dysfunction. Celastrol, a traditional oriental medicine, has been suggested to have cardioprotective effects. However, its underlying mechanism is unknown. This study investigated the ability of celastrol to prevent cardiac fibrosis and dysfunction and explored the underlying mechanisms. Methods: Animal and cell models of cardiac fibrosis were used in this study. Myocardial fibrosis was induced by transverse aortic constriction (TAC in mice. Cardiac hypertrophy and fibrosis were evaluated based on histological and biochemical measurements. Cardiac function was evaluated by echocardiography. The levels of transforming growth factor beta 1 (TGF-β1, extracellular signal regulated kinases 1/2 (ERK1/2 signalling were measured using Western blotting, while the expression of miR-21was analyzed by real-time qRT-PCR in vitro and in vivo. In vitro studies, cultured cardiac fibroblasts (CFs were treated with TGF-β1 and transfected with microRNA-21(miR21. Results: Celastrol treatment reduced the increased collagen deposition and down-regulated α-smooth muscle actin (α-SMA, atrial natriuretic peptide (ANP, brain natriuretic peptides (BNP, beta-myosin heavy chain (β-MHC, miR-21 and p-ERK/ERK. Cardiac dysfunction was significantly attenuated by celastrol treatment in the TAC mice model. Celastrol treatment reduced myocardial fibroblast viability and collagen content and down-regulated α-SMA in cultured CFs in vitro. Celastrol also inhibited the miR-21/ERK signalling pathway. Celastrol attenuated miR-21 up-regulation by TGF-β1 and decreased elevated p-ERK/ERK levels in CFs transfected with miR-21. Conclusion: MiR-21/ERK signalling could be a potential therapeutic pathway for the prevention of myocardial fibrosis. Celastrol ameliorates myocardial fibrosis and cardiac dysfunction, these probably related to miR-21/ERK signaling pathways in vitro and in vivo.

  3. Increased Expression of TGF-β1 in Correlation with Liver Fibrosis during Echinococcus granulosus Infection in Mice

    Science.gov (United States)

    Liu, Yumei; Abudounnasier, Gulizhaer; Zhang, Taochun; Liu, Xuelei; Wang, Qian; Yan, Yi; Ding, Jianbing; Wen, Hao; Yimiti, Delixiati; Ma, Xiumin

    2016-01-01

    To investigate the potential role of transforming growth factor (TGF)-β1 in liver fibrosis during Echinococcus granulosus infection, 96 BALB/c mice were randomly divided into 2 groups, experimental group infected by intraperitoneal injection with a metacestode suspension and control group given sterile physiological saline. The liver and blood samples were collected at days 2, 8, 30, 90, 180, and 270 post infection (PI), and the expression of TGF-β1 mRNA and protein was determined by real-time quantitative RT-PCR and ELISA, respectively. We also evaluated the pathological changes in the liver during the infection using hematoxylin and eosin (H-E) and Masson staining of the liver sections. Pathological analysis of H-E stained infected liver sections revealed liver cell edema, bile duct proliferation, and structural damages of the liver as evidenced by not clearly visible lobular architecture of the infected liver, degeneration of liver cell vacuoles, and infiltration of lymphocytes at late stages of infection. The liver tissue sections from control mice remained normal. Masson staining showed worsening of liver fibrosis at the end stages of the infection. The levels of TGF-β1 did not show significant changes at the early stages of infection, but there were significant increases in the levels of TGF-β1 at the middle and late stages of infection (Pgranulosus infection may play a significant role in liver fibrosis associated with E. granulosus infection. PMID:27658605

  4. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues.

    Science.gov (United States)

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health.Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper,we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameter scan provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  5. Mueller matrix microscope: a quantitative tool to facilitate detections and fibrosis scorings of liver cirrhosis and cancer tissues

    Science.gov (United States)

    Wang, Ye; He, Honghui; Chang, Jintao; He, Chao; Liu, Shaoxiong; Li, Migao; Zeng, Nan; Wu, Jian; Ma, Hui

    2016-07-01

    Today the increasing cancer incidence rate is becoming one of the biggest threats to human health. Among all types of cancers, liver cancer ranks in the top five in both frequency and mortality rate all over the world. During the development of liver cancer, fibrosis often evolves as part of a healing process in response to liver damage, resulting in cirrhosis of liver tissues. In a previous study, we applied the Mueller matrix microscope to pathological liver tissue samples and found that both the Mueller matrix polar decomposition (MMPD) and Mueller matrix transformation (MMT) parameters are closely related to the fibrous microstructures. In this paper, we take this one step further to quantitatively facilitate the fibrosis detections and scorings of pathological liver tissue samples in different stages from cirrhosis to cancer using the Mueller matrix microscope. The experimental results of MMPD and MMT parameters for the fibrotic liver tissue samples in different stages are measured and analyzed. We also conduct Monte Carlo simulations based on the sphere birefringence model to examine in detail the influence of structural changes in different fibrosis stages on the imaging parameters. Both the experimental and simulated results indicate that the polarized light microscope and transformed Mueller matrix parameters can provide additional quantitative information helpful for fibrosis detections and scorings of liver cirrhosis and cancers. Therefore, the polarized light microscope and transformed Mueller matrix parameters have a good application prospect in liver cancer diagnosis.

  6. Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection

    International Nuclear Information System (INIS)

    The molecular mechanisms of acute hepatitis C virus (HCV) infection, end-stage hepatitis (cirrhosis), and hepatocellular carcinoma have been extensively studied, but little is known of the changes in liver gene expression during the early stages of liver fibrosis associated with chronic HCV infection, that is, the transition from normal liver (NL) of uninfected patients to the first stage of liver fibrosis (F1-CH-C). To obtain insight into the molecular pathogenesis of F1-CH-C, we used real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to study the mRNA expression of 240 selected genes in liver tissue with F1-CH-C, in comparison with NL. The expression of 54 (22.5%) of the 240 genes was significantly different between F1-CH-C and NL; 46 genes were upregulated and 8 were downregulated in F1-CH-C. The most noteworthy changes in gene expression mainly affected the transcriptional network regulated by interferons (IFNs), including both IFN-α/β-inducible genes (STAT1, STAT2, ISGF3G/IRF9, IFI27, G1P3, G1P2, OAS2, MX1) and IFN-γ-inducible genes (CXCL9, CXCL10, CXCL11). Interesting, upregulation of IFN-α/β-inducible genes (but not IFN-γ-inducible genes) was independent of histological scores (grade and stage of fibrosis) and HCV characteristics (hepatic HCV mRNA levels and the HCV genotype), and was specific to HCV (as compared to hepatitis B virus (HBV)). Other genes dysregulated in F1-CH-C, albeit less markedly than IFN-α/β- and IFN-γ-inducible genes, were mainly involved in the activation of lymphocytes infiltrating the liver (IFNG, TNF, CXCL6, IL6, CCL8, CXCR3, CXCR4, CCR2), cell proliferation (p16/CDKN2A, MKI67, p14/ARF), extracellular matrix remodeling (MMP9, ITGA2), lymphangiogenesis (XLKD1/LYVE), oxidative stress (CYP2E1), and cytoskeleton microtubule organization (STMN2/SCG10). Thus, a limited number of signaling pathways, and particularly the transcriptional network regulated by interferons, are dysregulated in the first

  7. Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

    Directory of Open Access Journals (Sweden)

    Timo Rath

    Full Text Available BACKGROUND AND AIMS: Cystic Fibrosis associated liver disease (CFLD develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. METHODS: 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. RESULTS: 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. CONCLUSIONS: Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD.

  8. Serum Proteome Profiling Identifies Novel and Powerful Markers of Cystic Fibrosis Liver Disease

    Science.gov (United States)

    Kügler, Marion; Menendez Menendez, Katrin; Zachoval, Reinhart; Naehrlich, Lutz; Schulz, Richard; Roderfeld, Martin; Roeb, Elke

    2013-01-01

    Background and Aims Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. Methods 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. Results 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. Conclusions Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD. PMID:23516586

  9. 晚期血吸虫病肝纤维化程度与生化指标的相关性%Correlation between levels of liver fibrosis and liver fibrosis biochemical pa-rameters of advanced schistosomiasis patients

    Institute of Scientific and Technical Information of China (English)

    吴一鸣; 徐晓菲; 乌文琳; 邬万新; 高树兴; 朱文军

    2014-01-01

    目的:探讨晚期血吸虫病肝纤维化程度与肝纤维化生化指标之间的相关性。方法以48例晚期血吸虫病肝病患者为研究对象,行肝活检及B超影像学检查,同时检测谷氨酰胺转肽酶(GGT)、碱性磷酸酶(AKP)、Ⅲ型前胶原(PC-Ⅲ)、Ⅳ型胶原(Ⅳ-C)、透明质酸(HA)及层粘连蛋白(LN)等肝纤维化生化指标。分别以肝活检病理结果和B超影像学检查确定肝纤维化程度,分析肝纤维化程度与上述肝纤维化生化指标间的相关性。结果肝活检病理检查确定的肝纤维化程度与各生化指标之间无相关性;B超影像学检查确定的肝纤维化程度与GGT、AKP、LN和PC-Ⅲ之间有一定相关性,与HA和Ⅳ-C呈显著相关。结论 B超检查是一种较好的无创性血吸虫病肝纤维化检查方法,结合肝纤维化生化指标能更好地反映肝脏整体状况。%Objective To explore the correlation between the levels of liver fibrosis and liver fibrosis biochemical parameters of advanced schistosomiasis patients. Methods A total of 48 advanced schistosomiasis patients were investigated and they were examined by the liver biopsy and B ultrasound imaging. At the same time,the liver fibrosis biochemical parameters,including glu-tamine transpeptidase(GGT),alkaline phosphatase(AKP),procollagenⅢ(PC-Ⅲ),collagen typeⅣ(Ⅳ-C),hyaluronic acid (HA)and laminin(LN),were detected. The liver fibrosis levels were classified by the liver biopsy and B ultrasound imaging,re-spectively,and the correlation between the levels of liver fibrosis and liver fibrosis biochemical parameters were analyzed statisti-cally. Results There was no correlation between the liver fibrosis levels classified by the liver biopsy and all the liver fibrosis bio-chemical parameters;there was a weak correlation between the liver fibrosis levels classified by the B ultrasound imaging and GGT,AKP,LN and PC-Ⅲ,respectively;there was a significant

  10. Potentials of the elevated circulating miR-185 level as a biomarker for early diagnosis of HBV-related liver fibrosis

    Science.gov (United States)

    Li, Bin-bin; Li, Dong-liang; Chen, Chao; Liu, Bao-hai; Xia, Chun-yan; Wu, Han-jun; Wu, Chao-qun; Ji, Guo-qin; Liu, Su; Ni, Wu; Yao, Ding-kang; Zeng, Zhi-yu; Chen, Da-gui; Qin, Bao-dong; Xin, Xuan; Yan, Gang-li; Dan Tang; Liu, Hui-min; He, Jin; Yan, Hongli; Zhu, Wei-Jian; Yu, Hong-yu; Zhu, Liang

    2016-01-01

    Early diagnosis of liver fibrosis is critical for early intervention and prognosis of various chronic liver diseases. Conventional repeated histological assessment is impractical due to the associated invasiveness. In the current study, we evaluated circulating miR-185 as a potential biomarker to predict initiation and progression of liver fibrosis. We found that miR-185 was significantly up-regulated in blood specimens from patients with HBV-liver fibrosis and rats with liver fibrosis, the miR-185 levels were correlated with liver fibrosis progression, but not with the different viral loads in HBV-infected patients. miR-185 was observed in collagen deposition regions during advanced liver fibrosis. We found that differences in miR-185 levels facilitated the discrimination between early-staged or advanced-staged liver fibrosis and the healthy controls with high specificity, sensitivity, and likelihood ratio using receiver-operator characteristic analysis. miR-185 targeted SREBF1, and increased expression of COL1A1 and a-SMA genes that are hallmarks of liver fibrosis. Our data supported that circulating miR-185 levels could be used as potential biomarkers for the early diagnosis of liver fibrosis. PMID:27677421

  11. Diagnostic accuracy of enhanced liver fibrosis test to assess liver fibrosis in patients with chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Roberto Catanzaro; Michele Milazzo; Silvia Arona; Chiara Sapienza; Dario Vasta

    2013-01-01

    BACKGROUND: The  prognosis  and  clinical  management  of patients  with  chronic  liver  diseases  are  closely  related  to  the severity  of  liver  fibrosis.  Liver  biopsy  is  considered  the  gold standard  for  the  staging  of  liver  fibrosis.  However,  it  is  an invasive  test  sometimes  related  to  complications.  This  study aimed to assess the diagnostic value of enhanced liver fibrosis (ELF)  test  to  predict  liver  fibrosis  in  patients  with  chronic hepatitis C. METHODS: This study included 162 patients with liver disease and  67  healthy  controls.  Hyaluronic  acid,  tissue  inhibitor of  matrix  metalloproteinase  type  1,  and  amino-terminal propeptide  type  III  procollagen  were  measured  by  enzyme-linked immunosorbent assay with the ELF test ADVIA Centaur ® (Siemens  Healthcare  Diagnostics  Inc.).  Fibrosis  stage  was determined using the Metavir scoring system. RESULTS: In our study, for the diagnosis of significant fibrosis (Metavir  F≥2)  a  cut-off  value  >7.72  provides  a  sensitivity  of 93.0% and a specificity of 83.0%. The areas under the receiver operator  characteristic  curve,  sensitivity,  specificity,  and positive and negative predictive values were 0.94, 93.3%, 81.0%, 93.3%,  and  81.0%,  respectively  (P9.3  provides  a sensitivity of 93.0% and a specificity of 86.0%. The areas under the receiver operator characteristic curve, sensitivity, specificity, and  positive  and  negative  predictive  values  were  0.94,  79.1%, 90.8%, 75.6%, and 92.3%, respectively (P CONCLUSIONS: The  ELF  test  is

  12. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes

    Energy Technology Data Exchange (ETDEWEB)

    Queisser, Nina; Happ, Kathrin; Link, Samuel [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany); Jahn, Daniel [Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg (Germany); Zimnol, Anna [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany); Geier, Andreas [Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg (Germany); Schupp, Nicole, E-mail: schupp@uni-duesseldorf.de [Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg (Germany)

    2014-11-01

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague–Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased. - Highlights: • Aldosterone has direct profibrotic effects on the liver independent of blood pressure. • Fibrosis is mediated by the mineralocorticoid receptor and

  13. Is it better to use two elastographic methods for liver fibro-sis assessment?

    Institute of Scientific and Technical Information of China (English)

    Ioan Sporea; Roxana (S)irli; Alina Popescu; Simona Bota; Radu Badea; Monica Lup(s)or; Mircea Foc(s)a; Mirela D(a)nil(a)

    2011-01-01

    AIM: To find out if by combining 2 ultrasound based elastographic methods: acoustic radiation force impulse (ARFI) elastography and transient elastography (TE), we can improve the prediction of fibrosis in patients with chronic hepatitis C.METHODS: Our study included 197 patients with chronic hepatitis C. In each patient, we performed, in the same session, liver stiffness (LS) measurements by means of TE and ARFI, respectively, and liver biopsy (LB), assessed according to the Metavir score. 10 LS measurements were performed both by TE and ARFI; median values were calculated and expressed in kilopascals (kPa) and meters/second (m/s), respectively. Only TE and ARFI measurements with IQR < 30% and SR ≥ 60% were considered reliable. RESULTS: On LB 13 (6.6%) patients had F0, 32 (16.2%) had F1, 52 (26.4%) had F2, 47 (23.9%) had F3, and 53 (26.9%) had F4. A direct, strong correlation was found between TE measurements and fibrosis (r = 0.741), between ARFI and fibrosis (r = 0.730) and also between TE and ARFI (r = 0.675). For predicting significant fibrosis (F ≥ 2), for a cut-off of 6.7 kPa, TE had 77.5% sensitivity (Se) and 86.5% specificity (Sp) [area under the receiver operating characteristic curve (AUROC) 0.87] and for a cut-off of 1.2 m/s, ARFI had 76.9% Se and 86.7% Sp (AUROC 0.84). For predicting cirrhosis (F = 4), for a cut-off of 12.2 kPa, TE had 96.2% Se and 89.6% Sp (AUROC 0.97) and for a cut-off of 1.8 m/s, ARFI had 90.4% Se and 85.6% Sp (AUROC 0.91). When both elastographic methods were taken into consideration, for predicting significant fibrosis (F ≥ 2), (TE ≥ 6.7 kPa and ARFI ≥ 1.2 m/s) we obtained 60.5% Se, 93.3% Sp, 96.8% positive predictive value (PPV), 41.4% negative predictive value (NPV) and 68% accuracy, while for predicting cirrhosis (TE ≥ 12.2 kPa and ARFI ≥ 1.8 m/s) we obtained 84.9% Se, 94.4% Sp, 84.9% PPV, 94.4% NPV and 91.8% accuracy.CONCLUSION: TE used in combination with ARFI is highly specific for predicting significant

  14. Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Gallego-Durán, Rocío; Cerro-Salido, Pablo; Gomez-Gonzalez, Emilio; Pareja, María Jesús; Ampuero, Javier; Rico, María Carmen; Aznar, Rafael; Vilar-Gomez, Eduardo; Bugianesi, Elisabetta; Crespo, Javier; González-Sánchez, Francisco José; Aparcero, Reyes; Moreno, Inmaculada; Soto, Susana; Arias-Loste, María Teresa; Abad, Javier; Ranchal, Isidora; Andrade, Raúl Jesús; Calleja, Jose Luis; Pastrana, Miguel; Iacono, Oreste Lo; Romero-Gómez, Manuel

    2016-01-01

    There is a need, in NAFLD management, to develop non-invasive methods to detect steatohepatitis (NASH) and to predict advanced fibrosis stages. We evaluated a tool based on optical analysis of liver magnetic resonance images (MRI) as biomarkers for NASH and fibrosis detection by investigating patients with biopsy-proven NAFLD who underwent magnetic resonance (MR) protocols using 1.5T General Electric (GE) or Philips devices. Two imaging biomarkers (NASHMRI and FibroMRI) were developed, standardised and validated using area under the receiver operating characteristic curve (AUROC) analysis. The results indicated NASHMRI diagnostic accuracy for steatohepatitis detection was 0.83 (95% CI: 0.73-0.93) and FibroMRI diagnostic accuracy for significant fibrosis determination was 0.85 (95% CI: 0.77-0.94). These findings were independent of the MR system used. We conclude that optical analysis of MRI has high potential to define non-invasive imaging biomarkers for the detection of steatohepatitis (NASHMRI) and the prediction of significant fibrosis (FibroMRI) in NAFLD patients. PMID:27514671

  15. A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis.

    Directory of Open Access Journals (Sweden)

    Nina Fransén-Pettersson

    Full Text Available Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

  16. Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease

    Science.gov (United States)

    Gallego-Durán, Rocío; Cerro-Salido, Pablo; Gomez-Gonzalez, Emilio; Pareja, María Jesús; Ampuero, Javier; Rico, María Carmen; Aznar, Rafael; Vilar-Gomez, Eduardo; Bugianesi, Elisabetta; Crespo, Javier; González-Sánchez, Francisco José; Aparcero, Reyes; Moreno, Inmaculada; Soto, Susana; Arias-Loste, María Teresa; Abad, Javier; Ranchal, Isidora; Andrade, Raúl Jesús; Calleja, Jose Luis; Pastrana, Miguel; Iacono, Oreste Lo; Romero-Gómez, Manuel

    2016-01-01

    There is a need, in NAFLD management, to develop non-invasive methods to detect steatohepatitis (NASH) and to predict advanced fibrosis stages. We evaluated a tool based on optical analysis of liver magnetic resonance images (MRI) as biomarkers for NASH and fibrosis detection by investigating patients with biopsy-proven NAFLD who underwent magnetic resonance (MR) protocols using 1.5T General Electric (GE) or Philips devices. Two imaging biomarkers (NASHMRI and FibroMRI) were developed, standardised and validated using area under the receiver operating characteristic curve (AUROC) analysis. The results indicated NASHMRI diagnostic accuracy for steatohepatitis detection was 0.83 (95% CI: 0.73–0.93) and FibroMRI diagnostic accuracy for significant fibrosis determination was 0.85 (95% CI: 0.77–0.94). These findings were independent of the MR system used. We conclude that optical analysis of MRI has high potential to define non-invasive imaging biomarkers for the detection of steatohepatitis (NASHMRI) and the prediction of significant fibrosis (FibroMRI) in NAFLD patients. PMID:27514671

  17. Bone marrow stem cells contribute to alcohol liver fibrosis in humans.

    Science.gov (United States)

    Dalakas, Evangelos; Newsome, Philip N; Boyle, Shelagh; Brown, Rachael; Pryde, Anne; McCall, Shonna; Hayes, Peter C; Bickmore, Wendy A; Harrison, David J; Plevris, John N

    2010-09-01

    Bone marrow-derived stem cell (BMSC) contribution to liver repair varies considerably and recent evidence suggests these cells may contribute to liver fibrosis. We investigated the mobilization and hepatic recruitment of bone marrow (BM) stem cells in patients with alcohol liver injury and their contribution to parenchymal/non-parenchymal liver cell lineages. Liver biopsies from alcoholic hepatitis (AH) patients and male patients, who received a female liver transplant and developed AH, were analyzed for BM stem cell content by fluorescence in situ hybridization and immunostaining. Y chromosome analysis was performed, along with co-staining for hepatocyte, biliary, myofibroblast, and Ki-67 markers. Blood CD34(+) levels were quantified in AH patients by flow cytometry. AH patients had increased CD34(+) cell counts in liver tissue (1.834% +/- 0.605%; P < 0.05) and in blood (0.195% +/- 0.063%; P < 0.05) as compared with matched controls (0.299% + 0.208% and 0.067% +/- 0.01%). A proportion of hepatic myofibroblasts were BM-derived (7.9%-26.8%) as deemed by the co-localization of Y chromosome/alpha-smooth muscle actin (alpha-SMA) staining. In the cross-sex liver grafts with AH, 5.025% of the myofibroblasts were co-staining for CD34, suggesting that a population of CD34(+) cells were contributing to the hepatic myofibroblast population. There was no evidence of BM contribution to hepatocyte or biliary cell differentiation, nor evidence of increased hepatocyte regeneration. Alcohol liver injury mobilizes CD34(+) stem cells into the circulation and recruits them into the liver. These BMSCs contribute to the hepatic myofibroblast population but not to parenchymal lineages and do not promote hepatocyte repair.

  18. Rapid Development of Advanced Liver Fibrosis after Acquisition of Hepatitis C Infection during Primary HIV Infection

    Science.gov (United States)

    Osinusi, Anu; Kleiner, David; Wood, Brad; Polis, Michael; Masur, Henry

    2009-01-01

    Abstract We report the first reported case of a 61-year-old MSM who was diagnosed with syphilis, primary HIV infection, and acute hepatitis C (HCV) within the same time period who rapidly developed significant liver fibrosis within 6 months of acquisition of both infections. It has been well described that individuals with primary HIV infection have an increase in activated CD8+ T cells, which causes a state of immune activation as was evident in this patient. Acquisition of HCV during this time could have further skewed this response resulting in massive hepatocyte destruction, inflammation, and subsequent liver fibrosis. Recent literature suggest that MSM with primary HIV infection have higher rates of acquisition of HCV than other HIV-positive cohorts and HCV acquisition can occur very soon after acquiring HIV. This case of rapid hepatic fibrosis progression coupled with the increasing incidence of HCV in individuals with primary HIV infection demonstrates a need for this phenomenon to be studied more extensively. PMID:19519227

  19. Epigallocatechin-3-gallate attenuates cadmium-induced chronic renal injury and fibrosis.

    Science.gov (United States)

    Chen, Jinglou; Du, Lifen; Li, Jingjing; Song, Hongping

    2016-10-01

    Cadmium (Cd) pollution is a serious environmental problem. Kidney is a main target organ of Cd toxicity. This study was undertaken to investigate the potential protective effects of epigallocatechin-3-gallate (EGCG) against chronic renal injury and fibrosis induced by CdCl2. Rat model was induced by exposing to 250 mg/L CdCl2 through drinking water. The renal function was evaluated by detecting the levels of blood urea nitrogen (BUN) and serum creatinine (SCR). The oxidative stress was measured by detecting the levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione/oxidized glutathione (GSH/GSSG) and renal enzymatic antioxidant status. Additionally, the renal levels of transforming growth factor-β1 (TGF-β1), Smad3, phosphorylation-Smad3 (pp-Smad3), α-smooth muscle actin (α-SMA), vimentin and E-cadherin were measured by western blot assay. Renal levels of microRNA-21 (miR-21), miR-29a/b/c and miR-192 were measured by quantitative RT-PCR. It was found that EGCG ameliorated the CdCl2-induced renal injury, inhibited the level of oxidative stress, normalized renal enzymatic antioxidant status and E-cadherin level, as well as attenuated the over generation of TGF-β1, pp-Smad3, vimentin and α-SMA. EGCG also decreased the production of miR-21 and miR-192, and enhanced the levels of miR-29a/b/c. These results showed that EGCG could attenuate Cd induced chronic renal injury. PMID:27474435

  20. Epigallocatechin-3-gallate attenuates cadmium-induced chronic renal injury and fibrosis.

    Science.gov (United States)

    Chen, Jinglou; Du, Lifen; Li, Jingjing; Song, Hongping

    2016-10-01

    Cadmium (Cd) pollution is a serious environmental problem. Kidney is a main target organ of Cd toxicity. This study was undertaken to investigate the potential protective effects of epigallocatechin-3-gallate (EGCG) against chronic renal injury and fibrosis induced by CdCl2. Rat model was induced by exposing to 250 mg/L CdCl2 through drinking water. The renal function was evaluated by detecting the levels of blood urea nitrogen (BUN) and serum creatinine (SCR). The oxidative stress was measured by detecting the levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione/oxidized glutathione (GSH/GSSG) and renal enzymatic antioxidant status. Additionally, the renal levels of transforming growth factor-β1 (TGF-β1), Smad3, phosphorylation-Smad3 (pp-Smad3), α-smooth muscle actin (α-SMA), vimentin and E-cadherin were measured by western blot assay. Renal levels of microRNA-21 (miR-21), miR-29a/b/c and miR-192 were measured by quantitative RT-PCR. It was found that EGCG ameliorated the CdCl2-induced renal injury, inhibited the level of oxidative stress, normalized renal enzymatic antioxidant status and E-cadherin level, as well as attenuated the over generation of TGF-β1, pp-Smad3, vimentin and α-SMA. EGCG also decreased the production of miR-21 and miR-192, and enhanced the levels of miR-29a/b/c. These results showed that EGCG could attenuate Cd induced chronic renal injury.

  1. Biomarkers of fibrosis and impaired liver function in chronic hepatitis C: how well do they predict clinical outcomes?

    DEFF Research Database (Denmark)

    Peters, L.; Rockstroh, J.K.

    2010-01-01

    patients at risk of liver-related complications. Findings from studies investigating the validity of the Model for End-Stage Liver Disease (MELD) score in HIV-infected liver transplant candidates are conflicting. Two large studies of HIV/hepatitis C virus (HCV) coinfected patients have shown that plasma...... levels of the fibrosis marker hyaluronic acid are a strong predictor of clinical complications. A smaller study found hyaluronic acid and two other fibrosis tests, aspartate aminotransferase-to-platelet ratio index (APRI) and Fib-4, to be independent predictors of mortality when included in models...

  2. Effects of heparin on liver fibrosis in patients with chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Jun Shi; Jing-Hua Hao; Wan-Hua Ren; Ju-Ren Zhu

    2003-01-01

    AIM: To evaluate the effects of heparin on liver fibrosis in patients with chronic hepatitis B.METHODS: Fifty-two cases under study were divided into two groups, group A and group B. The two groups were given regular treatment and heparin/low molecular weight heparin (LMWH) treatment respectively. Hepatic functions,serum hyaluronic acid (HA) and type IV collagen levels were measured before and after the treatment, and six caseswere taken liver biopsy twice.RESULTS: After treatment, hepatic functions became significantly better in both groups. Serum HA and type IV collagen levels in group B compared with group A, decreased significantly after treatment. Collagen proliferation also decreased in group B after treatment.CONCLUSION: Heparin/LMWH can inhibit collagen proliferation in liver tissues with hepatitis B.

  3. Liver fibrosis identification based on ultrasound images captured under varied imaging protocols

    Institute of Scientific and Technical Information of China (English)

    CAO Gui-tao; SHI Peng-fei; HU Bing

    2005-01-01

    Diagnostic ultrasound is a useful and noninvasive method in clinical medicine. Although due to its qualitative, subjective and experience-based nature, ultrasound image interpretation can be influenced by image conditions such as scanning frequency and machine settings. In this paper, a novel method is proposed to extract the liver features using the joint features of fractal dimension and the entropies of texture edge co-occurrence matrix based on ultrasound images, which is not sensitive to changes in emission frequency and gain. Then, Fisher linear classifier and support vector machine are employed to test a group of99 in-vivo liver fibrosis images from 18 patients, as well as other 273 liver images from 18 normal human volunteers.

  4. MicroRNA-17-5p-activated Wnt/β-catenin pathway contributes to the progression of liver fibrosis

    OpenAIRE

    Yu, Fujun; Lu, Zhongqiu; HUANG, KATE; Wang, Xiaodong; Xu, Ziqiang; Chen, Bicheng; Dong, Peihong; Zheng, Jianjian

    2015-01-01

    Aberrant Wnt/β-catenin pathway contributes to the development of liver fibrosis. MicroRNAs (MiRNAs) are found to act as regulators of the activation of hepatic stellate cell (HSC) in liver fibrosis. However, whether miRNAs activate Wnt/β-catenin pathway in activated HSCs during liver fibrosis is largely unknown. In this study, we found that Salvianolic acid B (Sal B) treatment significantly inhibited liver fibrosis in CCl4-treated rats, HSC-T6 cells and rat primary HSCs, resulting in the supp...

  5. Evaluation of liver stiffness measurement by fibroscan as compared to liver biopsy for assessment of hepatic fibrosis in children with chronic hepatitis C.

    Science.gov (United States)

    Awad, Mohiee El-Deen Abd El-Aziz; Shiha, Gamal Elsayed; Sallam, Fersan Abdallah; Mohamed, Amany; El Tawab, Abd

    2013-12-01

    The study evaluated liver stiffness measurement (LSM) using non-invasive transient elastography (TE) in comparison with liver biopsy for assessment of hepatic fibrosis in children with chronic hepatitis C (CHC). Thirty children (mean age 10.13 +/- 3.4 years) with CHC were subjected to histopathological assessment of liver biopsy specimens using METAVIER score and LSM using TE (FibroScan) as well as appropriate laboratory investigations. The results showed a highly significant stepwise increase of the mean liver stiffness values with increasing histological severity of hepatic fibrosis with the highest level detected in patients with stage F4 "cirrhosis" and significant differences for F3 and F4 vs. other fibrosis stages. There were significant positive correlations between LSM and several parameters of activity and progression of the chronic liver disease including METAVIER fibrosis stages (r=0.774, p=0.0001), necroinflammatory activity grades, AST, ALT, total serum bilirubin, prothrombin time and Child-Pugh grades as well as biochemical serum fibrosis markers (Fibrotest, Actitest, AST-to-platelet ratio index, Forns index and hyaluronic acid). The variables significantly negatively associated with the LSM were platelets count and serum albumin. The highest predictive performance of LSM was detected for stage F4 "cirrhosis", followed by F3 "advanced fibrosis" where accuracy of(96.7%, 85.3%) and AUROC of (1.00, 0.815) were obtained for these fibrosis stages at cutoff values of 9.5 and 12.5 kPa, respectively. The negative predictive values to exclude advanced fibrosis and cirrhosis at these cutoffs were high, whereas positive predictive values were modest.

  6. Impaired function of bone marrow-derived endothelial progenitor cells in murine liver fibrosis.

    Science.gov (United States)

    Shirakura, Katsuya; Masuda, Haruchika; Kwon, Sang-Mo; Obi, Syotaro; Ito, Rie; Shizuno, Tomoko; Kurihara, Yusuke; Mine, Tetsuya; Asahara, Takayuki

    2011-01-01

    Liver fibrosis (LF) caused by chronic liver damage has been considered as an irreversible disease. As alternative therapy for liver transplantation, there are high expectations for regenerative medicine of the liver. Bone marrow (BM)- or peripheral blood-derived stem cells, including endothelial progenitor cells (EPCs), have recently been used to treat liver cirrhosis. We investigated the biology of BM-derived EPC in a mouse model of LF. C57BL/6J mice were subcutaneously injected with carbon tetrachloride (CCl(4)) every 3 days for 90 days. Sacrificed 2 days after final injection, whole blood (WB) was collected for isolation of mononuclear cells (MNCs) and biochemical examination. Assessments of EPC in the peripheral blood and BM were performed by flow cytometry and EPC colony-forming assay, respectively, using purified MNCs and BM c-KIT(+), Sca-1(+), and Lin(-) (KSL) cells. Liver tissues underwent histological analysis with hematoxylin/eosin/Azan staining, and spleens were excised and weighed. CCl(4)-treated mice exhibited histologically bridging fibrosis, pseudolobular formation, and splenomegaly, indicating successful induction of LF. The frequency of definitive EPC-colony-forming-units (CFU) as well as total EPC-CFU at the equivalent cell number of 500 BM-KSL cells decreased significantly (p changes in primitive EPC-CFU occurred in LF mice. The frequency of WB-MNCs of definitive EPC-CFU decreased significantly (p < 0.01) in LF mice compared with control mice. Together, these findings indicated the existence of impaired EPC function and differentiation in BM-derived EPCs in LF mice and might be related to clinical LF.

  7. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

    Directory of Open Access Journals (Sweden)

    Abdulaleem Alnajar

    Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

  8. Effects of six months losartan administration on liver fibrosis in chronic hepatitis C patients: A pilot study

    Institute of Scientific and Technical Information of China (English)

    Silvia Sookoian; Maria Alejandra Fernández; Gustavo Casta(n)o

    2005-01-01

    AIM: To evaluate the safety and efficacy of chronic administration of losartan on hepatic fibrosis in chronic hepatitis C patients.METHODS: Fourteen patients with chronic hepatitis C non-responders (n = 10), with contraindications (n = 2)or lack of compliance (n = 2) to interferon plus ribavirin therapy and liver fibrosis were enrolled. Liver and renal function test, clinical evaluation, and liver biopsies were performed at baseline and after losartan administration at a dose of 50 mg/d during the 6 mo. The control group composed of nine patients with the same inclusion criteria and paired liver biopsies (interval 6-14 mo).Histological activity index (HAI) with fibrosis stage was assessed under blind conditions by means of Ishak's score. Subendothelial fibrosis was evaluated by digital image analyses.RESULTS: The changes in the fibrosis stage were significantly different between losartan group (decrease of 0.5±1.3) and controls (increase of 0.89±1.27;P<0.03). In the treated patients, a decrease in fibrosis stage was observed in 7/14 patients vs 1/9 control patients (P<0.04). A decrease in sub-endothelial fibrosis was observed in the losartan group. No differences were found in HAI after losartan administration. Acute and chronic decreases in systolic arterial pressures (P<0.05)were observed after the losartan administration, without changes in mean arterial pressure or renal function.CONCLUSION: Chronic AT-Ⅱ type 1 receptor (AT1R)blockade may reduce liver fibrosis in patients with chronic hepatitis C.

  9. Apelin-13 attenuates pressure overload-induced aortic adventitial remodeling and fibrosis in Sprague-Dawley rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Zhen-zhou; ZHANG Yan; XU Ran; CHEN Lai-jiang; GUO Shu-jie; XU Ying-le; CHANG Qing; GAO Ping-jin; ZHONG Jiu-chang

    2016-01-01

    AIM:To investigate regulatory roles of Apelin in adventitial remodeling and fibrosis in rats with transverse aortic constriction ( TAC) .METHODS:The male Sprague-Dawley rats with TAC were randomized to daily deliver either pyroglutamyl Apelin-13 ( 50μg/kg) or saline for 4 weeks.RESULTS:Histomorphometric analysis by HE and Masson Trichrome staining revealed increased medi -al and adventitial thicknesses , especially in the adventitia , in ascending aortas in rats with TAC when compared with the sham-operated rats.Downregulation of APJ receptor and elevations in phosphorylated mTOR and ERK 1/2 levels were observed in rats with TAC . There are marked increases in heart weight ( HW) , HW/body weight ratio , and aortic fibrosis in rats with TAC .The pressure over-load-mediated pathological adventitial remodeling was strikingly rescued by Apelin-13, associated with attenuation of aortic fibrosis and reduced mRNA expression of TGF-β1, fibronectin and collagen I .CONCLUSION:Our results demonstrate the importance of Apelin-13 in amelioration of aortic adventitial remodeling and fibrosis in rats with TAC via modulation of the mTOR /ERK signaling , thus indi-cating potential therapeutic strategies by enhancing Apelin /APJ action for preventing pressure overload-and fibrosis-associated cardio-vascular disorders .

  10. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.

    Directory of Open Access Journals (Sweden)

    Yiannis N Kallis

    Full Text Available Liver fibrosis results from the co-ordinated actions of myofibroblasts and macrophages, a proportion of which are of bone marrow origin. The functional effect of such bone marrow-derived cells on liver fibrosis is unclear. We examine whether changing bone marrow genotype can down-regulate the liver's fibrotic response to injury and investigate mechanisms involved. Proteinase activated receptor 1 (PAR1 is up-regulated in fibrotic liver disease in humans, and deficiency of PAR1 is associated with reduced liver fibrosis in rodent models. In this study, recipient mice received bone marrow transplantation from PAR1-deficient or wild-type donors prior to carbon tetrachloride-induced liver fibrosis. Bone marrow transplantation alone from PAR1-deficient mice was able to confer significant reductions in hepatic collagen content and activated myofibroblast expansion on wild-type recipients. This effect was associated with a decrease in hepatic scar-associated macrophages and a reduction in macrophage recruitment from the bone marrow. In vitro, PAR1 signalling on bone marrow-derived macrophages directly induced their chemotaxis but did not stimulate proliferation. These data suggest that the bone marrow can modulate the fibrotic response of the liver to recurrent injury. PAR1 signalling can contribute to this response by mechanisms that include the regulation of macrophage recruitment.

  11. Dynamic changes of capillarization and peri-sinusoid fibrosis in alcoholic liver diseases

    Institute of Scientific and Technical Information of China (English)

    Guang-Fu Xu; Xin-Yue Wang; Gui-Ling Ge; Peng-Tao Li; Xu Jia; De-Lu Tian; Liang-Duo Jiang; Jin-Xiang Yang

    2004-01-01

    AIM: To investigate the dynamic changes of capillarization and peri-sinusoid fibrosis in an alcoholic liver disease model induced by a new method.METHODS: Male SD rats were randomly divided into 6 groups, namely normal, 4 d, 2 w, 4 w, 9 w and 11 w groups.The animals were fed with a mixture of alcohol for designated days and then decollated, and their livers were harvested to examine the pathological changes of hepatocytes, hepatic stellate cells, sinusoidal endothelial cells, sinusoid, peri-sinusoid. The generation of three kinds of extra cellular matrix was also observed.RESULTS: The injury of hepatocytes became severer as modeling going on. Under electronic microscope, fatty vesicles and swollen mitochondria in hepatocytes, activated hepatic stellate cells with fibrils could been seen near or around it. Fenestrae of sinusoidal endothelial cells were decreased or disappeared, sinusoidal basement was formed.Under light microscopy typical peri-sinusoid fibrosis, gridding-like fibrosis, broaden portal areas, hepatocyte's fatty and balloon denaturation, iron sediment, dot necrosis,congregated lymphatic cells and leukocytes were observed.Type Ⅰ collagen showed an increasing trend as modeling going on, slightly recovered when modeling stopped for 2 weeks. Meanwhile, type Ⅳ collagen decreased rapidly when modeling began and recovered after modeling stopped for 2 weeks. Laminin increased as soon as modeling began and did not recover when modeling stopped for 2 weeks.CONCLUSION: The pathological changes of the model were similar to that of human ALD, but mild in degree. It had typical peri-sinusoid fibrosis; however, capillarization seemed to be instable. It may be related with the reduction of type Ⅳ collagen in the basement of sinusoid during modeling.

  12. Protective Effect of Astaxanthin on Liver Fibrosis through Modulation of TGF-β1 Expression and Autophagy

    Directory of Open Access Journals (Sweden)

    Miao Shen

    2014-01-01

    Full Text Available Liver fibrosis is a common pathway leading to cirrhosis and a worldwide clinical issue. Astaxanthin is a red carotenoid pigment with antioxidant, anticancer, and anti-inflammatory properties. The aim of this study was to investigate the effect of astaxanthin on liver fibrosis and its potential protective mechanisms. Liver fibrosis was induced in a mouse model using CCL4 (intraperitoneal injection, three times a week for 8 weeks, and astaxanthin was administered everyday at three doses (20, 40, and 80 mg/kg. Pathological results indicated that astaxanthin significantly improved the pathological lesions of liver fibrosis. The levels of alanine aminotransferase aspartate aminotransferase and hydroxyproline were also significantly decreased by astaxanthin. The same results were confirmed in bile duct liagtion, (BDL model. In addition, astaxanthin inhibited hepatic stellate cells (HSCs activation and formation of extracellular matrix (ECM by decreasing the expression of NF-κB and TGF-β1 and maintaining the balance between MMP2 and TIMP1. In addition, astaxanthin reduced energy production in HSCs by downregulating the level of autophagy. These results were simultaneously confirmed in vivo and in vitro. In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors.

  13. Assessment of liver fibrosis with 2-D shear wave elastography in comparison to transient elastography and acoustic radiation force impulse imaging in patients with chronic liver disease.

    Science.gov (United States)

    Gerber, Ludmila; Kasper, Daniela; Fitting, Daniel; Knop, Viola; Vermehren, Annika; Sprinzl, Kathrin; Hansmann, Martin L; Herrmann, Eva; Bojunga, Joerg; Albert, Joerg; Sarrazin, Christoph; Zeuzem, Stefan; Friedrich-Rust, Mireen

    2015-09-01

    Two-dimensional shear wave elastography (2-D SWE) is an ultrasound-based elastography method integrated into a conventional ultrasound machine. It can evaluate larger regions of interest and, therefore, might be better at determining the overall fibrosis distribution. The aim of this prospective study was to compare 2-D SWE with the two best evaluated liver elastography methods, transient elastography and acoustic radiation force impulse (point SWE using acoustic radiation force impulse) imaging, in the same population group. The study included 132 patients with chronic hepatopathies, in which liver stiffness was evaluated using transient elastography, acoustic radiation force impulse imaging and 2-D SWE. The reference methods were liver biopsy for the assessment of liver fibrosis (n = 101) and magnetic resonance imaging/computed tomography for the diagnosis of liver cirrhosis (n = 31). No significant difference in diagnostic accuracy, assessed as the area under the receiver operating characteristic curve (AUROC), was found between the three elastography methods (2-D SWE, transient elastography, acoustic radiation force impulse imaging) for the diagnosis of significant and advanced fibrosis and liver cirrhosis in the "per protocol" (AUROCs for fibrosis stages ≥2: 0.90, 0.95 and 0.91; for fibrosis stage [F] ≥3: 0.93, 0.95 and 0.94; for F = 4: 0.92, 0.96 and 0.92) and "intention to diagnose" cohort (AUROCs for F ≥2: 0.87, 0.92 and 0.91; for F ≥3: 0.91, 0.93 and 0.94; for F = 4: 0.88, 0.90 and 0.89). Therefore, 2-D SWE, ARFI imaging and transient elastography seem to be comparably good methods for non-invasive assessment of liver fibrosis. PMID:26116161

  14. Initial study of biexponential model of intravoxel incoherent motion magnetic resonance imaging in evaluation of the liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Chen Cuiyun; Wang Bin; Shi Dapeng; Fu Fangfang; Zhang Jiliang; Wen Zejun; Zhu Shaocheng

    2014-01-01

    Background The diagnosis of liver fibrosis is a difficult task at any time using conventional clinical imaging.Intravoxel incoherent motion (IVIM) can be used to investigate both diffusion and perfusion changes in tissues.This study was designed to determine the value of IVIM in the diagnosis and staging of liver fibrosis.Methods IVIM examinations were performed on a GE 3.0T MR scanner in 25 patients with liver fibrosis and 25 healthy volunteers as the control group.Patients with liver fibrosis diagnosis were confirmed by pathology and staged on a scale of F0-4.The standard ADC values and the values of a biexponential model (slow ADC (Dslow),fast ADC (Dfast) and fraction of fast ADC (FF)) were measured in three liver regions per person.The mean standard ADC values,Dslow values,Dfast values and FF values from the study group were compared among the right posterior hepatic lobe,right anterior hepatic lobe and medial segment of the left lobe.Receiver Operating Characteristic (ROC) curves and independent-samples t-tests were used to calculate the mean standard ADC values,Dslow values,Dfast values and FF values from the study group and the control group.Spearman rho correlation analysis was used for the stage of liver fibrosis.The liver fibrosis stages between the groups F0-1 and F2-4,the groups F0-2 and F3-4 were compared.Results Among the liver fibrosis,there was no significant difference in the mean standard ADC values,Dslow values,Dfast values,and FF values obtained from the right posterior hepatic lobe,right anterior hepatic lobe and medial segment of the left lobe.Using ROC analysis,the Area Under the Curve (AUC) values of standard ADC,Dslow,Dfast,FF were all between 0.7 to 0.9.The mean standard ADC values,Dslow values,Dfast values and FF values of the liver in the study group were significantly lower than the values in the control group (P <0.05).As the stage of the fibrosis increased,the values decreased by Spearman rho correlation analysis.The mean values

  15. Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis

    Science.gov (United States)

    Ibrahim, Marwa K.; Salum, Ghada Maher; Bader El Din, Noha G.; Dawood, Reham M.; Barakat, Ahmed; Khairy, Ahmed; El Awady, Mostafa K.

    2016-01-01

    IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention. PMID:27135246

  16. microRNA are central players in anti- and profibrotic gene regulation during liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Andrea eNoetel

    2012-03-01

    Full Text Available miRNA are small noncoding RNA molecules that posttranscriptionally effect mRNA stability and translation by targeting the 3´-untranslated region (3`-UTR of various transcripts. Thus, dysregulation of miRNA affects a wide range of cellular processes such as cell proliferation and differentiation involved in organ remodelling processes. Divergent miRNA patterns wereobserved during chronic liver diseases of various etiologies. Chronic liver diseases result in uncontrolled scar formation ending up in liver fibrosis or even cirrhosis. Since it has been shown that miR-29 dysregulation is involved in synthesis of extracellular matrix (ECM proteins, miR-29 is of special interest. The importance of miR-29 in hepatic collagen homeostasis is underlined by in vivo data showing that experimental severe fibrosis is associated with a prominent miR-29 decrease. The loss of miR-29 is due to the response of hepatic stellate cells to exposure to the profibrogenic mediators TGF-β and PDGF-BB. Several putative binding sites for the Smad proteins and the Ap-1 complex are located in the miR-29 promoter, which are suggested to mediate miR-29 decrease in fibrosis. Other miRNA are highly increased after profibrogenic stimulation, such as miR-21. miR-21 is transcriptionally upregulated in response to Smad-3 rather than Smad-2 activation after TGF-β stimulation. In addition, TGF-β promotes miR-21 expression by formation of a microprocessor complex containing Smad proteins. Elevated miR-21 may then act as a profibrogenic miRNA by its repression of the TGF-β inhibitory Smad-7 protein.

  17. Diagnostic performance of conventional diffusion weighted imaging and diffusion tensor imaging for the liver fibrosis and inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Tosun, Mesude, E-mail: mesude.tosun@kocaeli.edu.tr [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Inan, Nagihan, E-mail: inannagihan@ekolay.net [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Sarisoy, Hasan Tahsin, E-mail: htssarisoy@yahoo.com [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Akansel, Gur, E-mail: gakansel@gmail.com [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Gumustas, Sevtap, E-mail: svtgumustas@hotmail.com [Department of Radiology, School of Medicine, University of Kocaeli (Turkey); Gürbüz, Yeşim, E-mail: yesimgurbuz2002@yahoo.com [Department of Pathology, School of Medicine, University of Kocaeli (Turkey); Demirci, Ali, E-mail: alidemirci@kocaeli.edu.tr [Department of Radiology, School of Medicine, University of Kocaeli (Turkey)

    2013-02-15

    Objective: To evaluate the diagnostic accuracy of liver apparent diffusion coefficient (ADC) measured with conventional diffusion-weighted imaging (CDI) and diffusion tensor imaging (DTI) for the diagnosis of liver fibrosis and inflammation. Materials and methods: Thirty-seven patients with histologic diagnosis of chronic viral hepatitis and 34 healthy volunteers were included in this prospective study. All patients and healthy volunteers were examined by 3 T MRI. CDI and DTI were performed using a breath-hold single-shot echo-planar spin echo sequence with b factors of 0 and 1000 s/mm{sup 2}. ADCs were obtained with CDI and DTI. Histopathologically, fibrosis of the liver parenchyma was classified with the use of a 5-point scale (0–4) and inflammation was classified with use of a 4-point scale (0–3) in accordance with the METAVIR score. Quantitatively, signal intensity and the ADCs of the liver parenchyma were compared between patients stratified by fibrosis stage and inflammation grade. Results: With a b factor of 1000 s/mm{sup 2}, the signal intensity of the cirrhotic livers was significantly higher than those of the normal volunteers. In addition, ADCs reconstructed from CDI and DTI of the patients were significantly lower than those of the normal volunteers. Liver ADC values inversely correlated with fibrosis and inflammation but there was only statistically significant for inflammatory grading. CDI performed better than DTI for the diagnosis of fibrosis and inflammation. Conclusion: ADC values measured with CDI and DTI may help in the detection of liver fibrosis. They may also give contributory to the inflammatory grading, particularly in distinguishing high from low grade.

  18. Ameliorative effect of Ganoderma lucidum on carbon tetrachloride-induced liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Wen-Chuan Lin; Wei-Lii Lin

    2006-01-01

    AIM: To investigate the effects of Reishi mushroom,Ganoderma lucidum extract (GLE), on liver fibrosis induced by carbon tetrachloride (CCl4) in rats.METHODS: Rat hepatic fibrosis was induced by CCl4.Forty Wistar rats were divided randomly into 4 groups:control, CCl4, and two GLE groups. Except for rats in control group, all rats were administered orally with CCl4(20%, 0.2 mL/100 g body weight) twice a week for 8weeks. Rats in GLE groups were treated daily with GLE (1 600 or 600 mg/kg) via gastrogavage throughout the whole experimental period. Liver function parameters,such as ALT, AST, albumin, and albumin/globulin (A/G)ratio, spleen weight and hepatic amounts of protein,malondiladehyde (MDA) and hydroxyproline (HP) were determined. Histochemical staining of Sirius red was performed. Expression of transforming growth factor β1(TGF-β1), methionine adenosyltransferase (MAT1) 1A and MAT2A mRNA were detected by using RT-PCR.RESULTS: CCl4 caused liver fibrosis, featuring increase in plasma transaminases, hepatic MDA and HP contents,and spleen weight; and decrease in plasma albumin,A/G ratio and hepatic protein level. Compared with CCl4group, GLE (600, 1 600 mg/kg) treatment significantly increased plasma albumin level and A/G ratio (P< 0.05)and reduced the hepatic HP content (P<0.01). GLE (1600 mg/kg) treatment markedly decreased the activities of transaminases (P< 0.05), spleen weight (P< 0.05) and hepatic MDA content (P<0.05); but increased hepatic protein level (P<0.05). Liver histology in the GLE (1600 mg/kg)-treated rats was also improved (P<0.01).RT-PCR analysis showed that GLE treatment decreased the expression of TGF-β1 (P< 0.05-0.001) and changed the expression of MAT1A (P<0.05-0.01) and MAT2A (P< 0.05-0.001).CONCLUSION: Oral administration of GLE significantly reduces CCl4-induced hepatic fibrosis in rats, probably by exerting a protective effect against hepatocellular necrosis by its free-radical scavenging ability.

  19. Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest

    Directory of Open Access Journals (Sweden)

    Bismut Françoise

    2010-04-01

    Full Text Available Abstract Background FibroTest and elastography have been validated as biomarkers of liver fibrosis in the most frequent chronic liver diseases and in the fibrosis screening of patients with diabetes. One challenge was to use them for estimating the prevalence of fibrosis, identifying independent risk factors and to propose screening strategies in the general population. Methods We prospectively studied 7,463 consecutive subjects aged 40 years or older. Subjects with presumed advanced fibrosis (FibroTest greater than 0.48 were re-investigated in a tertiary center. Results The sample characteristics were similar to those of the French population. FibroTest was interpretable in 99.6%. The prevalence of presumed fibrosis was 2.8%, (209/7,463, including cirrhosis in 0.3% (25/7,463; 105/209 (50% subjects with presumed fibrosis accepted re-investigation. Fibrosis was confirmed in 50, still suspected in 27, indeterminate in 25 and not confirmed with false positive FibroTest or false negative elastography in 3 subjects. False negative rate of FibroTest estimated using elastography was 0.4% (3/766. The attributable causes for confirmed fibrosis were both alcoholic and nonalcoholic fatty liver disease (NAFLD in 66%, NAFLD in 13%, alcohol in 9%, HCV in 6%, and other in 6%. Factors independently associated (all P Conclusions Biomarkers have permitted to estimate prevalence of advanced fibrosis around 2.8% in a general population aged 40 years or older, and several risk factors which may be used for the validation of selective or non-selective screening strategies.

  20. Assessment of liver fibrosis by a noninvasive method of transient elastography and biochemical markers

    Institute of Scientific and Technical Information of China (English)

    Masaki Kawamoto; Toru Mizuguchi; Tadashi Katsuramaki; Minoru Nagayama; Hideki Oshima; Hiroyuki Kawasaki; Takayuki Nobuoka; Yasutoshi Kimura; Koichi Hirata

    2006-01-01

    AIM: To assess the correlation between the fibrotic area (FA) as calculated by a digital image analysis (DIA), and to compare the diagnostic accuracy of FibroScan to the other existing Liver fibrosis (LF) markers using the receiver operating curve analysis.METHODS: We recruited 30 patients who underwent a liver resection for three different etiologies including normal liver, hepatitis B, and hepatitis C. Liver stiffness was measured by using a FibroScan. The FA was then calculated by DIA to evaluate LF in order to avoid any sampling bias.RESULTS: The FA negatively correlated with Prothrombin time (PT), platelet count, lecithin-cholesterol acyltransferase (LCAT), and pre-albumin (ALB). On the other hand, the findings of FibroScan correlated with similar markers. The FA positively correlated with FibroScan, serum hyaluronate level, and type Ⅳ collagen level, and aspartate transaminase to platelet ratio index (APRI). The area under the receiver operating curve for FibroScan was higher than that for the other markers,even though the statistical significance was minimal.CONCLUSION: Our findings suggest that FibroScan can initially be used to assess LF as an alternative to a liver biopsy (LB) and serum diagnosis, because it is a safe method with comparable diagnostic accuracy regarding the existing LF markers.

  1. Identification of Novel Markers for Liver Fibrosis in HIV/HCV Co-infected individuals using Genomics-based Approach

    Science.gov (United States)

    Suzman, Daniel L.; McLaughlin, Mary; Hu, Zonghui; Kleiner, David E.; Wood, Brad; Vailati, Mary; Lempicki, Richard A.; Mican, JoAnn M.; Suffredini, Anthony; Masur, Henry; Polis, Michael A.; Kottilil, Shyam

    2009-01-01

    Objective The degree of liver fibrosis is a determinant for initiation of therapy for HCV. Liver biopsy is invasive, risky and costly, but is required to assess fibrosis. This study intended to identify novel non-invasive markers to accurately assess fibrosis in HIV/HCV co-infection. Methods Using 100 biopsies from 68 HIV/HCV co-infected patients, we developed a predictive model consisting of six serum markers along with age and ART experience. DNA microarray analysis of PBMCs associated with a subset of 51 biopsies obtained from 28 patients was performed and incorporated into a second model. Results: The 8-marker model yielded an AUROC of 0.904. Combined analysis of clinical and DNA microarray data in the 51 biopsy subset identified two genes (alanine amino peptidase-N and mitogen-activated protein kinase kinase-3) that predicted fibrosis with high significance. The 4-marker model that included the two genes and two serum markers had an AUROC of 0.852, which did not differ significantly from the 8-marker model on this subset (AUROC = 0.856, p=0.96). Conclusion Both models accurately predicted fibrosis with an accuracy of 87.9%, thereby sparing 83% of patients from obtaining a biopsy. DNA microarray analysis can be invaluable in identifying novel biomarkers of liver fibrosis. PMID:18614866

  2. High-attenuation mucus plugs on MDCT in a child with cystic fibrosis: potential cause and differential diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Morozov, Andrey; Brown, Shanaree [Indiana University Medical School, Indianapolis, IN (United States); Applegate, Kimberly E. [Riley Hospital for Children, Department of Radiology, Indiana University Medical Center, Indianapolis, IN (United States); Howenstine, Michelle [Riley Hospital for Children, Department of Pulmonology, Indiana University Medical Center, Indianapolis, IN (United States)

    2007-06-15

    High-attenuation mucus plugging is a rare finding in both adults and children. When it occurs, the field of differential diagnoses is typically quite small and includes acute hemorrhage, aspiration of radiodense material, and allergic bronchopulmonary aspergillosis (ABPA). The last of these three diagnoses is the most difficult to make, although ABPA is more commonly seen in children with cystic fibrosis (CF) or asthma. ABPA is radiographically characterized by recurrent mucus plugging, atelectasis, and central bronchiectasis. Thus far, high-attenuation mucus plugs have only been reported in adults. We report a rare case of a child with CF who had high-attenuation mucus plugs and atelectasis that raised the possibility of ABPA. We discuss the differential diagnoses of this finding and the role of multidetector CT in these children. (orig.)

  3. High-attenuation mucus plugs on MDCT in a child with cystic fibrosis: potential cause and differential diagnosis

    International Nuclear Information System (INIS)

    High-attenuation mucus plugging is a rare finding in both adults and children. When it occurs, the field of differential diagnoses is typically quite small and includes acute hemorrhage, aspiration of radiodense material, and allergic bronchopulmonary aspergillosis (ABPA). The last of these three diagnoses is the most difficult to make, although ABPA is more commonly seen in children with cystic fibrosis (CF) or asthma. ABPA is radiographically characterized by recurrent mucus plugging, atelectasis, and central bronchiectasis. Thus far, high-attenuation mucus plugs have only been reported in adults. We report a rare case of a child with CF who had high-attenuation mucus plugs and atelectasis that raised the possibility of ABPA. We discuss the differential diagnoses of this finding and the role of multidetector CT in these children. (orig.)

  4. Immunological detection of the type V collagen propeptide fragment, PVCP-1230, in connective tissue remodeling associated with liver fibrosis

    DEFF Research Database (Denmark)

    Vassiliadis, Efstathios; Veidal, Sanne Skovgård; Simonsen, Henrik;

    2011-01-01

    CO5-1230, indicate the amount of collagen deposited during liver fibrosis. METHODS: A specific competitive enzyme-linked immunosorbent assay (ELISA) was developed to measure CO5-1230 levels. The sequence TAALGDIMGH located at the start of the C-terminal propeptide between amino acid position 1230......AIM: Liver fibrosis involves excessive remodeling and deposition of fibrillar extracellular matrix (ECM) components, which leads to malfunction of the organ, causing significant morbidity and mortality. The aim of this study was to assess whether levels of a type V collagen fragment, the propeptide......' and 1239' (CO5-1230) of the a2 chain was selected as the immunogen. Monoclonal antibodies were raised against this fragment. An assay developed using the biotin-streptavidin system was evaluated in two rat models of liver fibrosis: bile duct ligation (BDL) and carbon tetrachloride (CCl(4))-treated rats...

  5. AST-to-platelet ratio index in non-invasive assessment of long-term graft fibrosis following pediatric liver transplantation.

    Science.gov (United States)

    D'Souza, Rashmi S; Neves Souza, Lara; Isted, Alexander; Fitzpatrick, Emer; Vimalesvaran, Sunitha; Cotoi, Corina; Amin, Saista; Heaton, Nigel; Quaglia, Alberto; Dhawan, Anil

    2016-03-01

    Long-term graft fibrosis occurs in the majority of pediatric liver transplant recipients. Serial biopsies to monitor graft health are impractical and invasive. The APRI has been evaluated in pediatric liver disease, but not in the context of post-transplantation fibrosis. We aimed to investigate the validity of APRI as a predictor of long-term graft fibrosis in pediatric liver transplant recipients. This was a retrospective, observational study of a cohort of children who underwent liver transplantation at King's College Hospital between 1989 and 2003, with a relevant dataset available. Protocol liver biopsies were performed at 10-yr follow-up and fibrosis was graded using the Ishak scoring system, with S3-6 denoting "significant fibrosis." APRI was calculated concurrently with biopsy. A total of 39 asymptomatic patients (20 males; median age at transplant, 1.43 yr) underwent protocol liver biopsies at a median of 10.39 yr post-transplantation. APRI was associated with significant fibrosis (p = 0.012). AUROC for APRI as a predictor of significant fibrosis was 0.74 (p = 0.013). The optimal cutoff APRI value for significant fibrosis was 0.45 (sensitivity = 0.67; specificity = 0.79; PPV = 0.67; NPV = 0.79). APRI appears to be a useful non-invasive adjunct in the assessment of significant graft fibrosis in the long-term follow-up of pediatric liver transplant survivors. PMID:26806646

  6. Gardenia jasminoides attenuates hepatocellular injury and fibrosis in bile duct-ligated rats and human hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    Ying-Hua Chen; Tian Lan; Jing Li; Chun-Hui Qiu; Teng Wu; Hong-Ju Gou; Min-Qiang Lu

    2012-01-01

    AIM:To investigate the anti-hepatofibrotic effects of Gardenia jasminoides in liver fibrosis.METHODS:Male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 d and were treated with Gardenia jasminoides by gavage.The effects of Gardenia jasminoides on liver fibrosis and the detailed molecular mechanisms were also assessed in human hepatic stellate cells (LX-2) in vitro.RESULTS:Treatment with Gardenia jasminoides decreased serum alanine aminotransferase (BDL vs BDL +100 mg/kg Gardenia jasminoides,146.6 ± 15 U/L vs 77± 6.5 U/L,P =0.0007) and aspartate aminotransferase (BDL vs BDL + 100 mg/kg Gardenia jasminoides,188 ± 35.2 U/L vs 128 ± 19 U/L,P =0.005) as well as hydroxyproline (BDL vs BDL + 100 mg/kg Gardenia jasminoides,438 ± 40.2 μg/g vs 228 ± 10.3 μg/g liver tissue,P =0.004) after BDL.Furthermore,Gardenia jasminoides significantly reduced liver mRNA and/or protein expression of transforming growth factor β1(TGF-β1),collagen type Ⅰ (Col Ⅰ) and α-smooth muscle actin (α-SMA).Gardenia jasminoides significantly suppressed the upregulation of TGF-β1,Col Ⅰ and α-SMA in LX-2 exposed to recombinant TGF-β1.Moreover,Gardenia jasminoides inhibited TGF-β1-induced Smad2 phosphorylation in LX-2 cells.CONCLUSION:Gardeniajasminoides exerts antifibrotic effects in the liver fibrosis and may represent a novel antifibrotic agent.

  7. Resveratrol attenuates renal injury and fibrosis by inhibiting transforming growth factor-β pathway on matrix metalloproteinase 7.

    Science.gov (United States)

    Xiao, Zhou; Chen, Chen; Meng, Ting; Zhang, Wenzheng; Zhou, Qiaoling

    2016-01-01

    Renal injury has a strong relationship to the subsequent development of renal fibrosis. In developing renal fibrosis, tubular epithelial cells in the kidney underwent epithelial-mesenchymal transition (EMT). Matrix metalloproteinase 7 (MMP7) was reported to reduce E-cadherin and induce EMT by up-regulation of β-catenin/lymphoid enhancer-binding factor 1 (LEF1) signaling. In this research, we tried to evaluate the role of resveratrol (RSV) on EMT process in renal injury and fibrosis. Human tubular epithelial cell HK-2 cells were treated with aristolochic acid (AAs) and transforming growth factor-β(TGF-β) to induce EMT with or without the administration of RSV. The inhibitory role of RSV on EMT in renal injury and fibrosis was determined by Western blotting, real-time PCR, and immunofluorescence staining. The EMT repressing role of RSV was also evaluated in vivo by renal ischemia-reperfusion (I/R) injury and unilateral ureteral obstruction (UUO) models. The underlying mechanism was investigated by shRNA interfering MMP7 and sirtuin 1 (SIRT1) expression. The results indicated that RSV reversed human kidney 2 (HK-2) cell EMT, renal I/R injury, and renal fibrosis. MMP7 inhibition was responsible for RSV-induced EMT repression. SIRT1 was up-regulated by RSV inhibited TGF-β pathway on MMP7 via deacetylating Smad4. In conclusion, RSV attenuated renal injury and fibrosis by inhibiting EMT process which was attributed to the fact that the up-regulated SIRT1 by RSV deacetylated Smad4 and inhibited MMP7 expression.

  8. Circulating levels of citrullinated and MMP-degraded vimentin (VICM) in liver fibrosis related pathology

    DEFF Research Database (Denmark)

    Vassiliadis, E.; Oliveira, C. P.; Alvares-da-Silva, M. R.;

    2012-01-01

    Aim: To investigate whether increased levels of vimentin citrullinated peptides identified by MS in articular cartilage can be measured in pathologies other than rheumatoid arthritis and be utilised for diagnostic purposes. Methods: A monoclonal antibody against the sequence RLRSSVPGV-citrulline ......Aim: To investigate whether increased levels of vimentin citrullinated peptides identified by MS in articular cartilage can be measured in pathologies other than rheumatoid arthritis and be utilised for diagnostic purposes. Methods: A monoclonal antibody against the sequence RLRSSVPGV......-citrulline (VICM) was developed and evaluated in a carbon tetrachloride (CCl4) (n=52 + 28 controls) rat model of liver fibrosis and two clinical cohorts of adult patients with hepatitis C (HCV) (n=92) and non-alcoholic fatty liver disease (NAFLD) (n=62), and compared to healthy controls. Results: In CCl4-treated...

  9. Circulating levels of citrullinated and MMP-degraded vimentin (VICM) in liver fibrosis related pathology

    DEFF Research Database (Denmark)

    Vassiliadis, Efstathios; Oliveira, Claudia P; Alvares-da-Silva, Mario R;

    2012-01-01

    AIM: To investigate whether increased levels of vimentin citrullinated peptides identified by MS in articular cartilage can be measured in pathologies other than rheumatoid arthritis and be utilised for diagnostic purposes. METHODS: A monoclonal antibody against the sequence RLRSSVPGV-citrulline ......AIM: To investigate whether increased levels of vimentin citrullinated peptides identified by MS in articular cartilage can be measured in pathologies other than rheumatoid arthritis and be utilised for diagnostic purposes. METHODS: A monoclonal antibody against the sequence RLRSSVPGV......-citrulline (VICM) was developed and evaluated in a carbon tetrachloride (CCl(4)) (n=52 + 28 controls) rat model of liver fibrosis and two clinical cohorts of adult patients with hepatitis C (HCV) (n=92) and non-alcoholic fatty liver disease (NAFLD) (n=62), and compared to healthy controls. RESULTS: In CCl(4...

  10. Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population.

    Directory of Open Access Journals (Sweden)

    Rabea A Hall

    Full Text Available The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury.

  11. Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population.

    Science.gov (United States)

    Hall, Rabea A; Liebe, Roman; Hochrath, Katrin; Kazakov, Andrey; Alberts, Rudi; Laufs, Ulrich; Böhm, Michael; Fischer, Hans-Peter; Williams, Robert W; Schughart, Klaus; Weber, Susanne N; Lammert, Frank

    2014-01-01

    The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL) analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs) with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury. PMID:24586654

  12. Angiotensin-converting enzyme inhibitor prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride-treated rat liver.

    Science.gov (United States)

    Reza, Hasan Mahmud; Tabassum, Nabila; Sagor, Md Abu Taher; Chowdhury, Mohammed Riaz Hasan; Rahman, Mahbubur; Jain, Preeti; Alam, Md Ashraful

    2016-01-01

    Hepatic fibrosis is a common feature of chronic liver injury, and the involvement of angiotensin II in such process has been studied earlier. We hypothesized that anti-angiotensin II agents may be effective in preventing hepatic fibrosis. In this study, Long Evans female rats were used and divided into four groups such as Group-I, Control; Group-II, Control + ramipril; Group-III, CCl4; and Group-IV, CCl4 + ramipril. Group II and IV are treated with ramipril for 14 d. At the end of treatment, the livers were removed, and the level of hepatic marker enzymes (aspartate aminotransferase, Alanine aminotransferase, and alkaline phosphatase), nitric oxide, advanced protein oxidation product , catalase activity, and lipid peroxidation were determined. The degree of fibrosis was evaluated through histopathological staining with Sirius red and trichrome milligan staining. Carbon-tetrachloride (CCl4) administration in rats developed hepatic dysfunction and raised the hepatic marker enzymes activities significantly. CCl4 administration in rats also produced oxidative stress, inflammation, and fibrosis in liver. Furthermore, angiotensinogen-inhibitor ramipril normalized the hepatic enzymes activities and improved the antioxidant enzyme catalase activity. Moreover, ramipril treatment ameliorated lipid peroxidation and hepatic inflammation in CCl4-treated rats. Ramipril treatment also significantly reduced hepatic fibrosis in CCl4-administered rats. In conclusion, our investigation suggests that the antifibrotic effect of ramipril may be attributed to inhibition of angiotensin-II mediated oxidative stress and inflammation in liver CCl4-administered rats. PMID:26862777

  13. Sequential algorithms combining non-invasive markers and biopsy for the assessment of liver fibrosis in chronic hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Giada Sebastiani; Alessandro Vario; Maria Guido; Alfredo Alberti

    2007-01-01

    AIM: To assess the performance of several noninvasive markers and of our recently proposed stepwise combination algorithms to diagnose significant fibrosis (F ≥ 2 by METAVIR) and cirrhosis (F4 by METAVIR) in chronic hepatitis B (CHB).METHODS: One hundred and ten consecutive patients (80 males, 30 females, mean age: 42.6 ± 11.3) with CHB undergoing diagnostic liver biopsy were included. ASTto-Platelet ratio (APRI), Forns' index, AST-to-ALT Ratio,Goteborg University Cirrhosis Index (GUCI), Hui's model and Fibrotest were measured on the day of liver biopsy.The performance of these methods and of sequential algorithms combining Fibrotest, APRI and biopsy was defined by positive (PPV) and negative (NPV) predictive values, accuracy and area under the curve (AUC).RESULTS: PPV for significant fibrosis was excellent (100%) with Forns and high (> 92%) with APRI, GUCI,Fibrotest and Hui. However, significant fibrosis could not be excluded by any marker (NPV < 65%). Fibrotest had the best PPV and NPV for cirrhosis (87% and 90%, respectively). Fibrotest showed the best AUC for both significant fibrosis and cirrhosis (0.85 and 0.76,respectively). Stepwise combination algorithms of APRI,Fibrotest and biopsy showed excellent performance (0.96 AUC, 100% NPV) for significant fibrosis and 0.95 AUC,98% NPV for cirrhosis, with 50%-80% reduced need for liver biopsy.CONCLUSION: In CHB sequential combination of APRI,Fibrotest and liver biopsy greatly improves the diagnostic performance of the single non-invasive markers. Need for liver biopsy is reduced by 50%-80% but cannot be completely avoided. Non-invasive markers and biopsy should be considered as agonists and not antagonists towards the common goal of estimating liver fibrosis.

  14. Spleen dynamic contrast-enhanced magnetic resonance imaging as a new method for staging liver fibrosis in a piglet model.

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    Li Zhou

    Full Text Available OBJECTIVE: To explore spleen hemodynamic alteration in liver fibrosis with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI, and to determine how to stage liver fibrosis with spleen DCE-MRI parameters. MATERIALS AND METHODS: Sixteen piglets were prospectively used to model liver fibrosis staged by liver biopsy, and underwent spleen DCE-MRI on 0, 5th, 9th, 16th and 21st weekend after modeling this disease. DCE-MRI parameters including time to peak (TTP, positive enhancement integral (PEI, maximum slope of increase (MSI and maximum slope of decrease (MSD of spleen were measured, and statistically analyzed to stage this disease. RESULTS: Spearman's rank correlation tests showed that TTP tended to increase with increasing stages of liver fibrosis (r = 0.647, P0.05, and decreased from stage 2 to 4 (P0.05. Mann-Whitney tests demonstrated that TTP and PEI could classify fibrosis between stage 0 and 1-4, between 0-1 and 2-4, between 0-2 and 3-4, or between 0-3 and 4 (all P<0.01. MSD could discriminate between 0-2 and 3-4 (P = 0.006, or between 0-3 and 4 (P = 0.012. MSI could not differentiate between any two stages. Receiver operating characteristic analysis illustrated that area under receiver operating characteristic curve (AUC of TTP was larger than of PEI for classifying stage ≥1 and ≥2 (AUC = 0.851 and 0.783, respectively. PEI could best classify stage ≥3 and 4 (AUC = 0.903 and 0.96, respectively. CONCLUSION: Spleen DCE-MRI has potential to monitor spleen hemodynamic alteration and classify liver fibrosis stages.

  15. Lactoferrin protects against chemical-induced rat liver fibrosis by inhibiting stellate cell activation.

    Science.gov (United States)

    Tung, Yu-Tang; Tang, Ting-Yu; Chen, Hsiao-Ling; Yang, Shang-Hsun; Chong, Kowit-Yu; Cheng, Winston T K; Chen, Chuan-Mu

    2014-01-01

    Liver diseases, which can be caused by alcohol abuse, chemical intoxication, viral hepatitis infection, and autoimmune disorders, are a significant health issue because they can develop into liver fibrosis and cirrhosis. Lactoferrin (LF), a siderophilic protein with 2 iron-binding sites, has been demonstrated to possess a multitude of biological functions, including antiinflammation, anticancer, and antimicrobial effects, as well as immunomodulatory-enhancing functions. In the current study, we induced hepatotoxicity in rats with dimethylnitrosamine (DMN) to establish a situation that would enable us to evaluate the hepatoprotective effects of LF against hepatic injury. Our results showed that DMN-induced hepatic pathological damage significantly decreased the body weight and liver index, increased the mRNA and protein levels of collagen α-1(I) (ColIα-1) and α-smooth muscle actin, and increased the hydroxyproline content. However, treatment with LF significantly increased body weight and liver index, decreased the mRNA and protein levels of ColIα-1 and α-smooth muscle actin, and suppressed the hydroxyproline content when compared with the DMN-treated group. Liver histopathology also showed that low-dose LF (100mg/kg of body weight) or high-dose LF (300 mg/kg of body weight) could significantly reduce the incidences of liver lesions induced by DMN. These results suggest that the LF exhibits potent hepatoprotection against DMN-induced liver damage in rats and that the hepatoprotective effects of LF may be due to the inhibition of collagen production and to stellate cell activation. PMID:24731632

  16. Is magnetic resonance imaging of hepatic hemangioma any different in liver fibrosis and cirrhosis compared to normal liver?

    Energy Technology Data Exchange (ETDEWEB)

    Duran, Rafael, E-mail: rafael.duran@chuv.ch [Centre Hospitalier Universitaire Vaudois, University of Lausanne, Diagnostic and Interventional Radiology, Lausanne (Switzerland); Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); Ronot, Maxime, E-mail: Maxime.ronot@bjn.aphp.fr [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); University Paris Diderot, Sorbonne Paris Cité, INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3 Paris (France); Di Renzo, Sara, E-mail: Direnzo.sara@gmail.com [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); Gregoli, Bettina, E-mail: Bettinagregoli@yahoo.it [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); Van Beers, Bernard E., E-mail: Bernard.van-beers@bjn.aphp.fr [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); Vilgrain, Valérie, E-mail: Valerie.vilgrain@bjn.aphp.fr [Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, Department of Radiology, Clichy (France); University Paris Diderot, Sorbonne Paris Cité, INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3 Paris (France)

    2015-05-15

    Highlights: • Hemangiomas were similar in patients with or without chronic liver disease on MRI. • Decrease in size & number of hemangiomas could start before the onset of cirrhosis. • T2 shine-through effect was less frequently observed in cirrhosis. - Abstract: Purpose: To compare qualitative and quantitative magnetic resonance (MR) imaging characteristics of hepatic hemangiomas in patients with normal, fibrotic and cirrhotic livers. Materials and methods: Retrospective, institutional review board approved study (waiver of informed consent). Eighty-nine consecutive patients with 231 hepatic hemangiomas who underwent liver MR imaging for lesion characterization were included. Lesions were classified into three groups according to the patients’ liver condition: no underlying liver disease (group 1), fibrosis (group 2) and cirrhosis (group 3). Qualitative and quantitative characteristics (number, size, signal intensities on T1-, T2-, and DW MR images, T2 shine-through effect, enhancement patterns (classical, rapidly filling, delayed filling), and ADC values) were compared. Results: There were 160 (69%), 45 (20%), and 26 (11%) hemangiomas in groups 1, 2 and 3, respectively. Lesions were larger in patients with normal liver (group 1 vs. groups 2 and 3; P = .009). No difference was found between the groups on T2-weighted images (fat-suppressed fast spin-echo (P = .82) and single-shot (P = .25)) and in enhancement patterns (P = .56). Mean ADC values of hemangiomas were similar between groups 1, 2 and 3 (2.11 ± .52 × 10{sup −3} mm{sup 2}/s, 2.1 ± .53 × 10{sup −3} mm{sup 2}/s and 2.14 ± .44 × 10{sup −3} mm{sup 2}/s, P = 87, respectively). T2 shine-through effect was less frequently observed in cirrhosis (P = .02). Conclusion: MR imaging characteristics of hepatic hemangioma were similar in patients with normal compared to fibrotic and cirrhotic livers. Smaller lesion size was observed with liver disease and less T2 shine-through effect was seen in

  17. Immunological tolerance to pig-serum partially inhibits the formation of septal fibrosis of the liver in Capillaria hepatica-infected rats

    OpenAIRE

    Rodrigo Guimarães Andrade; Bruna Magalhães Gotardo; Bárbara Cristina A Assis; José Mengel; Zilton A. Andrade

    2004-01-01

    Systhematized septal fibrosis of the liver can be induced in rats either by repeated intraperitoneal injections of pig-serum or by Capillaria hepatica infection. The relationship between these two etiological factors, as far as hepatic fibrosis is concerned, is not known, and present investigation attempts to investigate it. C. hepatica-induced septal fibrosis of the liver was considerably inhibited in rats previously rendered tolerant to pig-serum. Pig-serum-tolerant rats developed antibodie...

  18. Increased Expression of TGF-β1 in Correlation with Liver Fibrosis during Echinococcus granulosus Infection in Mice.

    Science.gov (United States)

    Liu, Yumei; Abudounnasier, Gulizhaer; Zhang, Taochun; Liu, Xuelei; Wang, Qian; Yan, Yi; Ding, Jianbing; Wen, Hao; Yimiti, Delixiati; Ma, Xiumin

    2016-08-01

    To investigate the potential role of transforming growth factor (TGF)-β1 in liver fibrosis during Echinococcus granulosus infection, 96 BALB/c mice were randomly divided into 2 groups, experimental group infected by intraperitoneal injection with a metacestode suspension and control group given sterile physiological saline. The liver and blood samples were collected at days 2, 8, 30, 90, 180, and 270 post infection (PI), and the expression of TGF-β1 mRNA and protein was determined by real-time quantitative RT-PCR and ELISA, respectively. We also evaluated the pathological changes in the liver during the infection using hematoxylin and eosin (H-E) and Masson staining of the liver sections. Pathological analysis of H-E stained infected liver sections revealed liver cell edema, bile duct proliferation, and structural damages of the liver as evidenced by not clearly visible lobular architecture of the infected liver, degeneration of liver cell vacuoles, and infiltration of lymphocytes at late stages of infection. The liver tissue sections from control mice remained normal. Masson staining showed worsening of liver fibrosis at the end stages of the infection. The levels of TGF-β1 did not show significant changes at the early stages of infection, but there were significant increases in the levels of TGF-β1 at the middle and late stages of infection (P<0.05). RT-PCR results showed that, when compared with the control group, TGF-β1 mRNA was low and comparable with that in control mice at the early stages of infection, and that it was significantly increased at day 30 PI and remained at high levels until day 270 PI (P<0.05). The results of this study suggested that increased expression of TGF-β1 during E. granulosus infection may play a significant role in liver fibrosis associated with E. granulosus infection. PMID:27658605

  19. Increased Expression of TGF-β1 in Correlation with Liver Fibrosis during Echinococcus granulosus Infection in Mice.

    Science.gov (United States)

    Liu, Yumei; Abudounnasier, Gulizhaer; Zhang, Taochun; Liu, Xuelei; Wang, Qian; Yan, Yi; Ding, Jianbing; Wen, Hao; Yimiti, Delixiati; Ma, Xiumin

    2016-08-01

    To investigate the potential role of transforming growth factor (TGF)-β1 in liver fibrosis during Echinococcus granulosus infection, 96 BALB/c mice were randomly divided into 2 groups, experimental group infected by intraperitoneal injection with a metacestode suspension and control group given sterile physiological saline. The liver and blood samples were collected at days 2, 8, 30, 90, 180, and 270 post infection (PI), and the expression of TGF-β1 mRNA and protein was determined by real-time quantitative RT-PCR and ELISA, respectively. We also evaluated the pathological changes in the liver during the infection using hematoxylin and eosin (H-E) and Masson staining of the liver sections. Pathological analysis of H-E stained infected liver sections revealed liver cell edema, bile duct proliferation, and structural damages of the liver as evidenced by not clearly visible lobular architecture of the infected liver, degeneration of liver cell vacuoles, and infiltration of lymphocytes at late stages of infection. The liver tissue sections from control mice remained normal. Masson staining showed worsening of liver fibrosis at the end stages of the infection. The levels of TGF-β1 did not show significant changes at the early stages of infection, but there were significant increases in the levels of TGF-β1 at the middle and late stages of infection (PTGF-β1 mRNA was low and comparable with that in control mice at the early stages of infection, and that it was significantly increased at day 30 PI and remained at high levels until day 270 PI (PTGF-β1 during E. granulosus infection may play a significant role in liver fibrosis associated with E. granulosus infection.

  20. Accurate Prediction of Advanced Liver Fibrosis Using the Decision Tree Learning Algorithm in Chronic Hepatitis C Egyptian Patients

    Directory of Open Access Journals (Sweden)

    Somaya Hashem

    2016-01-01

    Full Text Available Background/Aim. Respectively with the prevalence of chronic hepatitis C in the world, using noninvasive methods as an alternative method in staging chronic liver diseases for avoiding the drawbacks of biopsy is significantly increasing. The aim of this study is to combine the serum biomarkers and clinical information to develop a classification model that can predict advanced liver fibrosis. Methods. 39,567 patients with chronic hepatitis C were included and randomly divided into two separate sets. Liver fibrosis was assessed via METAVIR score; patients were categorized as mild to moderate (F0–F2 or advanced (F3-F4 fibrosis stages. Two models were developed using alternating decision tree algorithm. Model 1 uses six parameters, while model 2 uses four, which are similar to FIB-4 features except alpha-fetoprotein instead of alanine aminotransferase. Sensitivity and receiver operating characteristic curve were performed to evaluate the performance of the proposed models. Results. The best model achieved 86.2% negative predictive value and 0.78 ROC with 84.8% accuracy which is better than FIB-4. Conclusions. The risk of advanced liver fibrosis, due to chronic hepatitis C, could be predicted with high accuracy using decision tree learning algorithm that could be used to reduce the need to assess the liver biopsy.

  1. Serial changes in expression of functionally clustered genes in progression of liver fibrosis in hepatitis C patients

    Institute of Scientific and Technical Information of China (English)

    Yoshiyuki Takahara; Mitsuo Takahashi; Qing-Wei Zhang; Hirotaka Wagatsuma; Maiko Mori; Akihiro Tamori; Susumu Shiomi; Shuhei Nishiguchi

    2008-01-01

    AIM: To investigate the relationship of changes in expression of marker genes in functional categories or molecular networks comprising one functional category or multiple categories in progression of hepatic fibrosis in hepatitis C (HCV) patients.METHODS: Marker genes were initially identified using DNA microarray data from a rat liver fibrosis model. The expression level of each fibrosis associated marker gene was analyzed using reverse transcription-polymerase chain reaction (RT-PCR) in clinical biopsy specimens from HCV-positive patients (n = 61). Analysis of changes in expression patterns and interactions of marker genes in functional categories was used to assess the biological mechanism of fibrosis.RESULTS: The profile data showed several biological changes associated with progression of hepatic fibrosis. Clustered genes in functional categories showed sequential changes in expression. Several sets of clustered genes, including those related to the extracellular matrix (ECM), inflammation, lipid metabolism, steroid metabolism, and some transcription factors important for hepatic biology showed expression changes in the immediate early phase (F1/F2) of fibrosis. Genes associated with aromatic amino acid (AA) metabolism, sulfur-containing AA metabolism and insulin/ Wnt signaling showed expression changes in the middle phase (F2/F3), and some genes related to glucose metabolism showed altered expression in the late phase of fibrosis (F3/F4). Therefore, molecular networks showing serial changes in gene expression are present in liver fibrosis progression in hepatitis C patients.CONCLUSION: Analysis of gene expression profiles from a perspective of functional categories or molecular networks provides an understanding of disease and suggests new diagnostic methods. Selected marker genes have potential utility for biological identification of advanced fibrosis.

  2. Tumor necrosis factor-α promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells.

    Directory of Open Access Journals (Sweden)

    Yosuke Osawa

    Full Text Available Tumor necrosis factor (TNF-α, which is a mediator of hepatotoxicity, has been implicated in liver fibrosis. However, the roles of TNF-α on hepatic stellate cell (HSC activation and liver fibrosis are complicated and remain controversial. To explore this issue, the role of TNF-α in cholestasis-induced liver fibrosis was examined by comparing between TNF-α(-/- mice and TNF-α(+/+ mice after bile duct ligation (BDL. Serum TNF-α levels in mice were increased by common BDL combined with cystic duct ligation (CBDL+CDL. TNF-α deficiency reduced liver fibrosis without affecting liver injury, inflammatory cell infiltration, and liver regeneration after CBDL+CDL. Increased expression levels of collagen α1(I mRNA, transforming growth factor (TGF-β mRNA, and α-smooth muscle actin (αSMA protein by CBDL+CDL in the livers of TNF-α(-/- mice were comparable to those in TNF-α(+/+ mice. Exogenous administration of TNF-α decreased collagen α1(I mRNA expression in isolated rat HSCs. These results suggest that the reduced fibrosis in TNF-α(-/- mice is regulated in post-transcriptional level. Tissue inhibitor of metalloproteinase (TIMP-1 plays a crucial role in the pathogenesis of liver fibrosis. TIMP-1 expression in HSCs in the liver was increased by CBDL+CDL, and the induction was lower in TNF-α(-/- mice than in TNF-α(+/+ mice. Fibrosis in the lobe of TIMP-1(-/- mice with partial BDL was also reduced. These findings indicate that TNF-α produced by cholestasis can promote liver fibrosis via TIMP-1 production from HSCs. Thus, targeting TNF-α and TIMP-1 may become a new therapeutic strategy for treating liver fibrosis in cholestatic liver injury.

  3. Aqueous garlic extract alleviates liver fibrosis and renal dysfunction in bile-duct-ligated rats.

    Science.gov (United States)

    Mahmoud, Mona F; Zakaria, Sara; Fahmy, Ahmed

    2014-01-01

    There is accumulating evidence that the renin-angiotensin system (RAS) is involved in hepatic inflammation and fibrogenesis. Garlic was found to lower the activity of the angiotensin converting enzyme (ACE) in the serum of rats in a diabetic model. We examined the effect of an aqueous garlic extract (AGE) on the ACE activity, cholestasis-induced liver fibrosis, and associated renal dysfunction in comparison with the effect of the standard drug enalapril. Both AGE and enalapril were administered orally for six weeks starting from the third day after bile duct ligation (BDL). BDL significantly increased the serum activities of liver enzymes, serum lactate dehydrogenase (LDH) activity, an indicator of liver cell death, serum total bilirubin (TB) level, liver myeloperoxidase (MPO) activity, and liver malondialdehyde (MDA) content. BDL was associated with elevation of serum urea and creatinine levels indicating renal dysfunction. BDL also caused an increase in the transcript levels of the genes coding for tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta-1 (TGF-beta1), and matrix metalloproteinase-13 (MMP-13), a collagenase, in liver tissues. A significant decrease in hepatic reduced glutathione (GSH) was observed in BDL rats, while serum ACE activity was increased. Both AGE and enalapril counteracted all these deleterious changes, with the exception that only AGE reduced the MPO activity. These findings suggest that AGE possesses hepato- and renoprotective properties, similar to enalapril, probably by modulating the levels of proteins such as TNF-alpha, TGF-beta1 and MMP-13, and involving a reduction of ACE and of oxidative stress. PMID:24873034

  4. Excess body weight, liver steatosis, and early fibrosis progression due to hepatitis C recurrence after liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Pierluigi Toniutto; Carlo Fabris; Claudio Avellini; Rosalba Minisini; Davide Bitetto; Elisabetta Rossi; Carlo Smirne; Mario Pirisi

    2005-01-01

    AIM: To investigate how weight gain after OLT affects the speed of fibrosis progression (SFP) during recurrent hepatitis C virus (HCV) infection of the graft.METHODS: Ninety consecutive patients (63 males,median age 53 years; 55 with HCV-related liver disease),transplanted at a single institution, were studied. All were followed for at least 2 years after OLT and had at least one follow-up graft biopsy, performed not earlier than 1 year after the transplant operation. For each biopsy, a single,experienced pathologist gave an estimate of both the staging according to Ishak and the degree of hepatic steatosis.The SFP was quantified in fibrosis units/month (FU/mo).The lipid metabolism status of patients was summarized by the plasma triglycerides/cholesterol (T/C) ratio. Body mass index (BMI) was measured before OLT, and 1 and 2 years after it.RESULTS: In the HCV positive group, the highest SFP was observed in the first post-OLT year. At that time point,a SFP ≤0.100 FU/mo was observed more frequently among recipients who had received their graft from a young donor and had a pre-transplant BMI value >26.0 kg/m2. At completion of the first post-transplant year, a BMI value >26.5 kg/m2 was associated with a T/C ratio ≤1. The proportion of patients with SFP >0.100 FU/mo descended in the following order: female recipients with a high T/C ratio, male recipients with high T/C ratio, and recipients of either gender with low T/C ratio. Hepatic steatosis was observed more frequently in recipients who, in the first post-transplant year, had increased their BMI ≥1.5 kg/m2 in comparison to the pre-transplant value. Hepatic steatosis was inversely associated with the staging score.CONCLUSION: Among HCV positive recipients, excessweight gain post-OLT does not represent a factor favoring early liver fibrosis development and might even be protective against it.

  5. Characteristics of liver tissue for attenuate the gamma radiation

    International Nuclear Information System (INIS)

    It was determined the lineal attenuation coefficient of hepatic tissue before gamma radiation of a source of 137 Cs. When exposing organic material before X or gamma radiation fields, part of the energy of the photons is absorbed by the material, while another part crosses it without producing any effect. The quantity of energy that is absorbed is a measure of the dose that receives the material. The three main mechanisms by means of which the gamma rays interacting with the matter are: The Photoelectric Effect, the Compton dispersion and the Even production; the sum of these three processes is translated in the attenuation coefficient of the radiation. In this work we have used hepatic tissue of bovine, as substitute of the human hepatic tissue, and we have measured the lineal attenuation coefficient for photons of 0.662 MeV. Through a series of calculations we have determined the lineal attenuation coefficient for photons from 10-3 to 10-5 MeV and the measured coefficient was compared with the one calculated. (Author)

  6. Effect of host-related factors on the intensity of liver fibrosis in patients with chronic hepatitis C virus infection

    Directory of Open Access Journals (Sweden)

    Costa Luciano Bello

    2002-01-01

    Full Text Available There is increasing interest in the identification of factors associated with liver disease progression in patients infected with hepatitis C virus (HCV. We assessed host-related factors associated with a histologically advanced stage of this disease and determined the rate of liver fibrosis progression in HCV-infected patients. We included patients submitted to liver biopsy, who were anti-HCV and HCV RNA positive, who showed a parenteral risk factor (blood transfusion or intravenous drug use, and who gave information about alcohol consumption.Patients were divided into two groups for analysis: group 1 - grades 0 to 2; group 2 - grades 3 to 4. The groups were compared in terms of sex, age at the time of infection, estimated duration of infection and alcoholism. The rate of fibrosis progression (index of fibrosis was determined based on the relationship between disease stage and duration of infection (years. Logistic regression analysis revealed that age at the time of infection (P or = 40 years (median = 0.47. The main factors associated with a more rapid fibrosis progression were age at the time of infection and the estimated duration of infection. Patients who acquired HCV after 40 years of age showed a higher rate of fibrosis progression.

  7. Hepatectomy After Yttrium-90 (Y90) Radioembolization-Induced Liver Fibrosis.

    Science.gov (United States)

    Maker, Ajay V; August, Carey; Maker, Vijay K; Weisenberg, Elliot

    2016-04-01

    survival in patients with neuroendocrine liver metastases; however, hepatectomy after radioembolization is unique and carries increased morbidity/mortality, likely due to Y90-induced liver fibrosis. We demonstrate images of fibrotic yttrium-90 radiation-affected liver and histological sections of radioembolic microbeads in blood vessels and distributed around resected tumors. PMID:26847353

  8. Distribution of hepatic stellate cells and their role in the development of parasitic fibrosis and liver cirrhosis in domestic animals

    OpenAIRE

    Kukolj Vladimir; Nešić Slađan; Vučićević Ivana

    2015-01-01

    Increasing of the extracellular matrix in rats, as well as in humans, occurs as a consequence of hepatic stellate cells (HSCs) activity. The objective of this work was to investigation the role of these cells in the development of fibrosis and liver cirrhosis which occurs as a consequence of infection of sheep and goats with large (Fasciola hepatica) and small (Dicrocoelium dendriticum) fluke. Liver samples taken from 12 cattle and 10 sheep infected under n...

  9. Prospective validation of FibroTest in comparison with liver stiffness for predicting liver fibrosis in Asian subjects with chronic hepatitis B.

    Directory of Open Access Journals (Sweden)

    Beom Kyung Kim

    Full Text Available Diagnostic values of FibroTest (FT for hepatic fibrosis have rarely been assessed in Asian chronic hepatitis B (CHB patients. We aimed to validate its diagnostic performances in comparison with liver stiffness (LS.From 2008 to 2010, 194 CHB patients who underwent liver biopsies along with FT and transient elastography were prospectively enrolled. Fibrosis stage was assessed according to the Batts and Ludwig system.To predict significant fibrosis (F≥2, advanced fibrosis (F≥3, and cirrhosis (F = 4, areas under receiver operating characteristic curves (AUROCs of FT were 0.903, 0.907, and 0.866, comparable to those of LS (0.873, 0.897, and 0.910, respectively. Optimized cutoffs of FT to maximize sum of sensitivity and specificity were 0.32, 0.52, and 0.68 for F≥2, F≥3, and F = 4, while those of LS were 8.8, 10.2, and 14.1 kPa, respectively. According to FT and LS cutoffs, 123 (63.4% and 124 (63.9% patients were correctly classified consistent with histological fibrosis (F1, F2, F3, and F4, respectively. Overall concordance between each fibrosis stage estimated by FT and LS was observed in 111 patients, where 88 were correctly classified with histological results. A combination formula adding LS to FT (LS+FT showed similar AUROC levels (0.885, 0.905, and 0.915, while another multiplying LS by FT (LS×FT showed the best AUROCs (0.941, 0.931, and 0.929 for F≥2, F≥3, and F4, respectively.FT provides good fibrosis prediction, with comparable outcomes to LS in Asian CHB patients. FT substantially reduces need for liver biopsy, especially when used in combination with LS.

  10. Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model.

    Science.gov (United States)

    Karthikeyan, Swathi; Potter, James J; Geschwind, Jean-Francois; Sur, Surojit; Hamilton, James P; Vogelstein, Bert; Kinzler, Kenneth W; Mezey, Esteban; Ganapathy-Kanniappan, Shanmugasundaram

    2016-01-15

    Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis. PMID:26525850

  11. Treatment with L-valine ameliorates liver fibrosis and restores thrombopoiesis in rats exposed to carbon tetrachloride.

    Science.gov (United States)

    Nakanishi, Chikashi; Doi, Hideyuki; Katsura, Kazunori; Satomi, Susumu

    2010-06-01

    It has been reported that treatment with branched chain amino acids (BCAAs) increases the survival rates in cirrhotic patients. In this study, we investigated the effect of L-valine, one of BCAAs, on liver fibrosis in rat. To induce liver fibrosis, male Wistar rats were injected carbon tetrachloride (CCl(4)) intraperitoneally (2.0 mL/kg) twice a week for 12 weeks. The rats (seven to fifteen rats for each group) were then administered 1.688 g/kg/day of L-valine intravenously for 7 days or 10% amino acid preparation that provided the same amount of nitrogen. Seven days after the last administration, blood platelet counts and bone marrow megakaryocyte counts were significantly higher in the valine group than in the control group (131.2 +/- 38.3 vs. 106.3 +/- 14.5 x 10(4)/microL, p = 0.04; 18.0 +/- 2.1 vs. 13.5 +/- 2.2 per field, p valine group than the control group. Furthermore, hepatic fibrosis was significantly reduced in the valine group, and the mRNA levels of factors associated with liver fibrosis such as procollagen alpha1(III), transforming growth factor-beta1 and connective tissue growth factor were significantly lower in the liver of the valine group 10 days after the last administration. These results indicate that L-valine treatment ameliorates liver fibrosis and restores thrombopoiesis in rats exposed to CCl(4). Therefore, L-valine supplementation may be helpful for patients with liver cirrhosis.

  12. Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model.

    Science.gov (United States)

    Karthikeyan, Swathi; Potter, James J; Geschwind, Jean-Francois; Sur, Surojit; Hamilton, James P; Vogelstein, Bert; Kinzler, Kenneth W; Mezey, Esteban; Ganapathy-Kanniappan, Shanmugasundaram

    2016-01-15

    Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis.

  13. Heat Killed Lactobacillus reuteri GMNL-263 Reduces Fibrosis Effects on the Liver and Heart in High Fat Diet-Hamsters via TGF-β Suppression

    Directory of Open Access Journals (Sweden)

    Wei-Jen Ting

    2015-10-01

    Full Text Available Obesity is one of the major risk factors for nonalcoholic fatty liver disease (NAFLD, and NAFLD is highly associated with an increased risk of cardiovascular disease (CVD. Scholars have suggested that certain probiotics may significantly impact cardiovascular health, particularly certain Lactobacillus species, such as Lactobacillus reuteri GMNL-263 (Lr263 probiotics, which have been shown to reduce obesity and arteriosclerosis in vivo. In the present study, we examined the potential of heat-killed bacteria to attenuate high fat diet (HFD-induced hepatic and cardiac damages and the possible underlying mechanism of the positive effects of heat-killed Lr263 oral supplements. Heat-killed Lr263 treatments (625 and 3125 mg/kg-hamster/day were provided as a daily supplement by oral gavage to HFD-fed hamsters for eight weeks. The results show that heat-killed Lr263 treatments reduce fatty liver syndrome. Moreover, heat-killed Lactobacillus reuteri GMNL-263 supplementation in HFD hamsters also reduced fibrosis in the liver and heart by reducing transforming growth factor β (TGF-β expression levels. In conclusion, heat-killed Lr263 can reduce lipid metabolic stress in HFD hamsters and decrease the risk of fatty liver and cardiovascular disease.

  14. Evaluation of Histological and non-Invasive Methods for the Detection of Liver Fibrosis: The Values of Histological and Digital Morphometric Analysis, Liver Stiffness Measurement and APRI Score.

    Science.gov (United States)

    Halász, Tünde; Horváth, Gábor; Kiss, András; Pár, Gabriella; Szombati, Andrea; Gelley, Fanni; Nemes, Balázs; Kenessey, István; Piurkó, Violetta; Schaff, Zsuzsa

    2016-01-01

    Prognosis and treatment of liver diseases mainly depend on the precise evaluation of the fibrosis. Comparisons were made between the results of Metavir fibrosis scores and digital morphometric analyses (DMA), liver stiffness (LS) values and aminotransferase-platelet ratio (APRI) scores, respectively. Liver biopsy specimens stained with Sirius red and analysed by morphometry, LS and APRI measurements were taken from 96 patients with chronic liver diseases (56 cases of viral hepatitis, 22 cases of autoimmune- and 18 of mixed origin). The strongest correlation was observed between Metavir score and DMA (r = 0.75 p < 0.05), followed in decreasing order by LS and Metavir (r = 0.61), LS and DMA (r = 0.47) LS and APRI (r = 0.35) and Metavir and APRI (r = 0.24), respectively. DMA is a helpful additional tool for the histopathological evaluation of fibrosis, even when the sample size is small and especially in case of advanced fibrosis. The non-invasive methods showed good correlation with the histopathological methods; LS proved to be more accurate than APRI. The stronger correlation between LS values and Metavir scores, as well as the results of DMA in case of appropriate sample size were remarkable. PMID:26189126

  15. Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats

    OpenAIRE

    B. Tang; Qiao, H.; Meng, F.; Sun, X.

    2007-01-01

    Massive hepatectomy associated with infection induces liver dysfunction, or even multiple organ failure and death. Glycyrrhizin has been shown to exhibit anti-oxidant and anti-inflammatory activities. The aim of the present study was to investigate whether glycyrrhizin could attenuate endotoxin-induced acute liver injury after partial hepatectomy. Male Wistar rats (6 to 8 weeks old, weighing 200-250 g) were randomly assigned to three groups of 24 rats each: sham, saline and glycyrrhizin. Rats...

  16. Evaluation of Fucosylated Haptoglobin and Mac-2 Binding Protein as Serum Biomarkers to Estimate Liver Fibrosis in Patients with Chronic Hepatitis C.

    Science.gov (United States)

    Tawara, Seiichi; Tatsumi, Tomohide; Iio, Sadaharu; Kobayashi, Ichizou; Shigekawa, Minoru; Hikita, Hayato; Sakamori, Ryotaro; Hiramatsu, Naoki; Miyoshi, Eiji; Takehara, Tetsuo

    2016-01-01

    Fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac-2 bp) are identified as cancer biomarkers, based on the results from a glyco-proteomic analysis. Recently, we reported that these glyco-biomarkers were associated with liver fibrosis and/or ballooning hepatocytes in patients with nonalcoholic fatty liver disease (NAFLD). We evaluated the ability of these glycoproteins to estimate liver fibrosis in 317 patients with chronic hepatitis C. We measured the serum Fuc-Hpt and Mac-2 bp levels using a lectin-antibody ELISA and ELISA, respectively. The serum levels of both Fuc-Hpt and Mac-2 bp increased with the progression of liver fibrosis. The multivariate analysis revealed that Mac-2 bp was an independent factor associated with moderate liver fibrosis (F ≥ 2). In contrast, Fuc-Hpt was an independent factor associated with advanced liver fibrosis (F ≥ 3). In terms of evaluating liver fibrosis, the serum levels of these glycomarkers were correlated with well-known liver fibrosis indexes, such as the aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis-4 (FIB4) index. An assay that combined the APRI or FIB4 index and the Fuc-Hpt or Mac-2 bp levels increased the AUC value for diagnosing hepatic fibrosis. Interestingly, the cumulative incidence of hepatocellular carcinoma (HCC) was significantly higher in the patients with elevated serum levels of Fuc-Hpt and Mac-2 bp. In conclusion, both Fuc-Hpt and Mac-2 bp could be useful glyco-biomarkers of liver fibrosis and predictors of HCC in patients with chronic hepatitis C.

  17. MR tracking of SPIO-labeled mesenchymal stem cells in rats with liver fibrosis could not monitor the cells accurately.

    Science.gov (United States)

    Zhou, Bin; Li, Dan; Qian, Jiesheng; Li, Zhengran; Pang, Pengfei; Shan, Hong

    2015-01-01

    Our previous study showed that in vivo magnetic resonance (MR) imaging is effective in tracking superparamagnetic iron oxide (SPIO)-labeled bone marrow mesenchymal stem cells (BMSCs) in rats with liver fibrosis. SPIO-labeling-induced signal reduction on MR images was completely reversed within 15 days after transplantation. It is still unclear whether the signal changes in MR imaging could reflect the number of transplanted cells in the liver. In the present study, BMSCs of male rats were doubly labeled with enhanced green fluorescent protein (EGFP) and SPIO and injected intravascularly into female rats with liver fibrosis. At different time points after injection, MR imaging was performed. The distribution of SPIO particles and EGFP-positive cells was determined by Prussian blue staining and EGFP immunohistochemistry, respectively. The distribution of transplanted BMSCs in various organs was assessed by detection of the SRY gene using real-time quantitative PCR. At 15 days post transplantation, the numbers of transplanted cells were significantly decreased in the lung, kidney, spleen and muscle, but not liver and heart, in comparison with those at 7 days after transplantation. EGFP staining-positive cells were observed in the liver intralobular parenchyma, while Prussian blue staining was negative at 42 days after transplantation. Taken together, SPIO particles and EGFP-labeled BMSCs show a different tissue distribution pattern in rats with liver fibrosis after a long-term period of monitoring. SPIO-based MR imaging may not be suitable for long-term tracking of transplanted BMSCs in vivo.

  18. MR tracking of SPIO-labeled mesenchymal stem cells in rats with liver fibrosis could not monitor the cells accurately.

    Science.gov (United States)

    Zhou, Bin; Li, Dan; Qian, Jiesheng; Li, Zhengran; Pang, Pengfei; Shan, Hong

    2015-01-01

    Our previous study showed that in vivo magnetic resonance (MR) imaging is effective in tracking superparamagnetic iron oxide (SPIO)-labeled bone marrow mesenchymal stem cells (BMSCs) in rats with liver fibrosis. SPIO-labeling-induced signal reduction on MR images was completely reversed within 15 days after transplantation. It is still unclear whether the signal changes in MR imaging could reflect the number of transplanted cells in the liver. In the present study, BMSCs of male rats were doubly labeled with enhanced green fluorescent protein (EGFP) and SPIO and injected intravascularly into female rats with liver fibrosis. At different time points after injection, MR imaging was performed. The distribution of SPIO particles and EGFP-positive cells was determined by Prussian blue staining and EGFP immunohistochemistry, respectively. The distribution of transplanted BMSCs in various organs was assessed by detection of the SRY gene using real-time quantitative PCR. At 15 days post transplantation, the numbers of transplanted cells were significantly decreased in the lung, kidney, spleen and muscle, but not liver and heart, in comparison with those at 7 days after transplantation. EGFP staining-positive cells were observed in the liver intralobular parenchyma, while Prussian blue staining was negative at 42 days after transplantation. Taken together, SPIO particles and EGFP-labeled BMSCs show a different tissue distribution pattern in rats with liver fibrosis after a long-term period of monitoring. SPIO-based MR imaging may not be suitable for long-term tracking of transplanted BMSCs in vivo. PMID:26153152

  19. Noninvasive assessment of macrovesicular liver steatosis in cadaveric donors based on computed tomography liver-to-spleen attenuation ratio.

    Science.gov (United States)

    Rogier, Julien; Roullet, Stéphanie; Cornélis, François; Biais, Matthieu; Quinart, Alice; Revel, Philippe; Bioulac-Sage, Paulette; Le Bail, Brigitte

    2015-05-01

    Fatty liver disease, including liver steatosis, is a major health problem worldwide. In liver transplantation, macrovesicular steatosis in donor livers is a major cause of graft failure and remains difficult to assess. On one hand, several imaging modalities can be used for the assessment of liver fat, but liver biopsy, which is still considered the gold standard, may be difficult to perform in this context. On the other hand, computed tomography (CT) is commonly used by teams managing cadaveric donors to assess donors and to minimize the risk of complications in recipients. The purpose of our study was to validate the use of CT as a semiquantitative method for assessing macrovesicular steatosis in cadaveric donors with liver biopsy as a reference standard. A total of 109 consecutive cadaveric donors were included between October 2009 and May 2011. Brain death was diagnosed according to French legislation. Liver biopsy and then CT were performed on the same day to determine the degree of macrovesicular steatosis. All liver biopsies and CT scans were analyzed in a double-blinded fashion by a senior pathologist and a senior radiologist, respectively. For CT, we used the liver-to-spleen (L/S) attenuation ratio, which is a validated method for determining 30% or greater steatosis in living liver donors. Fourteen of 109 biopsies exhibited macrovesicular steatosis > 30% upon histologic analysis. A receiver operating characteristic curve was generated for the L/S ratio to identify its ability to predict significant steatosis, which was defined as >30%. A cutoff value of 0.9 for the CT L/S ratio provided a sensitivity of 79% and a specificity of 97% to detect significant steatosis.

  20. Noninvasive assessment of macrovesicular liver steatosis in cadaveric donors based on computed tomography liver-to-spleen attenuation ratio.

    Science.gov (United States)

    Rogier, Julien; Roullet, Stéphanie; Cornélis, François; Biais, Matthieu; Quinart, Alice; Revel, Philippe; Bioulac-Sage, Paulette; Le Bail, Brigitte

    2015-05-01

    Fatty liver disease, including liver steatosis, is a major health problem worldwide. In liver transplantation, macrovesicular steatosis in donor livers is a major cause of graft failure and remains difficult to assess. On one hand, several imaging modalities can be used for the assessment of liver fat, but liver biopsy, which is still considered the gold standard, may be difficult to perform in this context. On the other hand, computed tomography (CT) is commonly used by teams managing cadaveric donors to assess donors and to minimize the risk of complications in recipients. The purpose of our study was to validate the use of CT as a semiquantitative method for assessing macrovesicular steatosis in cadaveric donors with liver biopsy as a reference standard. A total of 109 consecutive cadaveric donors were included between October 2009 and May 2011. Brain death was diagnosed according to French legislation. Liver biopsy and then CT were performed on the same day to determine the degree of macrovesicular steatosis. All liver biopsies and CT scans were analyzed in a double-blinded fashion by a senior pathologist and a senior radiologist, respectively. For CT, we used the liver-to-spleen (L/S) attenuation ratio, which is a validated method for determining 30% or greater steatosis in living liver donors. Fourteen of 109 biopsies exhibited macrovesicular steatosis > 30% upon histologic analysis. A receiver operating characteristic curve was generated for the L/S ratio to identify its ability to predict significant steatosis, which was defined as >30%. A cutoff value of 0.9 for the CT L/S ratio provided a sensitivity of 79% and a specificity of 97% to detect significant steatosis. PMID:25761371

  1. Association between thrombotic risk factors and extent of fibrosis in patients with non-alcoholic fatty liver diseases

    Institute of Scientific and Technical Information of China (English)

    N Assy; I Bekirov; Y Mejritsky; L Solomon; S Szvalb; O Hussein

    2005-01-01

    AIM: To evaluate the prevalence of genetic and acquired prothrombotic risk factors and their association with the extent of fibrosis and fatty infiltration in patients with non-alcoholic fatty liver disease (NAFLD).METHODS: Forty-four patients with chronic hepatitis (28 men and 16 women, with mean age of 45±11 and 49±12 years, respectively) constituted the patient population of this study. The groups were divided as follows: 15 patients with fatty liver (FL); 15 with non-alcoholic steatohepatitis (NASH); 14 with chronic viral hepatitis (CH) diagnosed by histology and liver technetium scan or ultrasound; and 10 healthy individuals. Thrombophilic, coagulation factors and genetic mutations were diagnosed by standard hemostatic and molecular coagulation assays.RESULTS: Activated protein C (APC) resistance and protein S were the most prevalent thrombotic risk factors (6% and 10% in NAFLD vs 21% and 14% in CH; P<0.01 and P<0.05, respectively). One thrombotic risk factor was identified in 41% of patients (23% mild fibrosis, 18% severe fibrosis) and two thrombotic risk factors in 6% of patients with NAFLD and severe fibrosis. While no differences in APC ratio, lupus anticoagulant, fibrinogen, factor V Leiden,prothrombin, and MTHFR mutation were found. Protein S levels were significantly lower in NASH patients than in patients with FL alone (92±19 vs106±2, P<0.01). Protein C levels were markedly higher in patients with NAFLD and mild or severe fibrosis as compared to the patients with CH, respectively (128±40 vs96±14, P<0.001 or 129±36 vs 88±13, P<0.01).CONCLUSION: Up to 46% of patients with NAFLD may have thrombotic risk factors, and the presence of thrombotic risk factors is correlated with the extent of hepatic fibrosis,suggesting a crucial role of the coagulation system in the pathogenesis of hepatic fibrosis.

  2. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    International Nuclear Information System (INIS)

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients

  3. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China); Zhu, Bo; Peng, Xiaomin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhou, Meiling, E-mail: meilingzhou2012@gmail.com [Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China)

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  4. Sampling variability of computer-aided fractal-corrected measures of liver fibrosis in needle biopsy specimens

    Institute of Scientific and Technical Information of China (English)

    Fabio Grizzi; Carlo Russo; Barbara Franceschini; Mariagrazia Di Rocco; Valter Torri; Emanuela Morenghi; Luigi Rainiero Fassati; Nicola Dioguardi

    2006-01-01

    AIM: To assess the sampling variability of computeraided, fractal-corrected measures of fibrosis in liver biopsies.METHODS: Samples were derived from six to eight different parts of livers removed from 12 patients with clinically and histologically proven cirrhosis undergoing orthotopic liver transplantation. Sirius red-stained sections with a thickness of 2 μm were digitized using a computer-aided image analysis system that automatically measures the surface of fibrosis, as well as its outline perimeter, fractal surface and outline dimensions,wrinkledness, and Hurst coefficient.RESULTS: We found a high degree of inter-sample variability in the measurements of the surface [coefficient of variation (CV) = 43% ± 13%] and wrinkledness (CV = 28% ± 9%) of fibrosis, but the inter-sample variability of Hurst's exponent was low (CV = 14% ± 2%).CONCLUSION: This study suggests that Hurst's exponent might be used in clinical practice as the best histological estimate of fibrosis in the whole organ,and evidences the fact that biopsy sections, which are fundamental for the qualitative diagnosis of chronic hepatitis, play a key role in the quantitative estimate of architectural changes in liver tissue.

  5. Long-chain PUFA in Granulocytes, Mononuclear Cells, and RBC in Patients With Cystic Fibrosis: Relation to Liver Disease

    DEFF Research Database (Denmark)

    Jorgensen, Marianne H.; Ott, Peter; Michaelsen, Kim F.;

    2012-01-01

    Background and Aim: Patients with cystic fibrosis (CF) have low levels of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) in plasma or red blood cells (RBC), as also seen in other chronic and acute liver diseases. The differences may be more pronounced in CF transmembrane conductance regu...

  6. Diagnostic Value of Conventional and Doppler Ultrasound Findings in Liver Fibrosis in Patients with Chronic Viral Hepatitis

    Directory of Open Access Journals (Sweden)

    Yasmin Davoudi

    2015-09-01

    Conclusion: Based on these findings, one can conclude that US may be an accurate, noninvasive alternative modality for the diagnosis of liver fibrosis, with fewer side effects than biopsy. It may be especially useful for repetitive follow-up of patients.

  7. Alpha-lipoic acid attenuates cardiac fibrosis in Otsuka Long-Evans Tokushima Fatty rats

    OpenAIRE

    Lee Jung Eun; Yi Chin-ok; Jeon Byeong Tak; Shin Hyun Joo; Kim Soo Kyoung; Jung Tae Sik; Choi Jun Young; Roh Gu Seob

    2012-01-01

    Abstract Background Hyperglycemia leads to cardiac oxidative stress and an imbalance in glucose homeostasis. Diabetic cardiomyopathy is characterised by cardiac hypertrophy and fibrosis. However, the underlying mechanisms of diabetic cardiomyopathy are not fully understood. This study aimed to investigate the effects of alpha-lipoic acid (ALA) on cardiac energy metabolism, antioxidant effect, and fibrosis in the hearts of Otsuka Long-Evans Tokushima fatty (OLETF) rats. Methods Animals were se...

  8. Effects of augmentation of liver regeneration recombinant plasmid on rat hepatic fibrosis

    Institute of Scientific and Technical Information of China (English)

    Qing Li; Dian-Wu Liu; Li-Mei Zhang; Bing Zhu; Yu-Tong He; Yong-Hong Xiao

    2005-01-01

    AIM: To investigate the effects of eukaryotic expression of plasmid on augmentation of liver regeneration (ALR) in rat hepatic fibrosis and to explore their mechanisms. METHODS: Ten rats were randomly selected from 50Wistar rats as normal control group. The rest were administered intraperitoneally with porcine serum twice weekly. After 8 wk, they were randomly divided into:model control group, colchicine group (Col), first ALR group (ALR1), second ALR group (ALR2). Then colchicine ALR recombinant plasmid were used to treat them respectively. At the end of the 4th wk, rats were killed.Serum indicators were detected and histopathological changes were graded. Expression of type Ⅰ, Ⅲ, collagen and TIMP-1 were detected by immunohisto-chemistry and expression of TIMP-1 mRNA was detected by semiquantified RT-PCR.RESULTS: The histologic examination showed that the degree of the rat hepatic fibrosis in two ALR groups was lower than those in model control group. Compared with model group, ALR significantly reduced the serum levels of ALT,AST, HA, LN, PCⅢ and Ⅳ (P<0.05). Immunohistochemical staining showed that expression of type Ⅰ, Ⅲ, collagen and TIMP-1 in two ALR groups was ameliorated dramatically compared with model group (Ⅰ collagen: 6.94±1.42, 5.80±1.66and 10.83±3.58 in ALR1, ALR2 and model groups, respectively;Ⅲ collagen: 7.18±1.95, 4.50±1.67 and 10.25±2.61,respectively; TIMP-1: 0.39±0.05, 0.20±0.06 and 0.53±0.12,respectively, P<0.05 or P<0.01). The expression level of TIMP-1 mRNA in the liver tissues was markedly decreased in two ALR groups compared with model group (TIMP-1mRNA/β-actin: 0.89±0.08, 0.65±0.11 and 1.36±0.11 in ALR1, ALR2 and model groups respectively, P<0.01).CONCLUSION: ALR recombinant plasmid has beneficial effects on rat hepatic fibrosis by enhancing regeneration of injured liver cells and inhibiting TIMP-1 expressions.

  9. Treatment of pig serum-induced rat liver fibrosis with Boschniakia rossica, oxymatrine and interferon-α

    Institute of Scientific and Technical Information of China (English)

    Chun-Song Wu; Xi-Xu Piao; Dong-Ming Piao; Yong-Ri Jin; Cheng-Hao Li

    2005-01-01

    AIM: To investigate the effect of Boschniakia rossica (BR),oxymatrine (OM) and interferon-alpha (IFN-α) 1b on the therapy of rat liver fibrosis and its mechanism.METHODS: By establishing a rat model of pig serum-induced liver fibrosis, liver/weight index and serum alanine transaminase (ALT) were observed to investigate the therapeutic effect of BR, OM and IFN-α. Radioimmunoassay was utilized to measure procollagen type Ⅲ (PCⅢ) and collagen type Ⅳ (CIV). RT-PCR was used to assay the expression of liver transforming growth factor- beta 1 (TGF-β1) mRNA. Immunohistochemistry of alpha-smooth muscle actin (α-SMA) and pathologic changes of liver tissues were also under investigation.RESULTS: Serum PCⅢ and CIV in BR, OM and IFN-α groups were significantly declined compared with those in model group, and their RT-PCR revealed that TGF-β1 mRNA expression was also reduced more than that in model group. Immunohistochemistry demonstrated that α-SMA also declined more than that in model group. Serum ALT in IFN-α, control and model groups was within normal level.Serum ALT in BR group had no significant difference from those of IFN-α, control and model groups. Serum ALT in OM group was significantly higher than those in BR, IFN-α,model, and control groups.CONCLUSION: BR, OM and IFN-α can prevent pig seruminduced liver rat fibrosis by inhibiting the activation of hepatic stellate cells and synthesizing collagen. OM has hepatotoxicity to rat liver fibrosis induced by pig serum.

  10. microRNA-222 modulates liver fibrosis in a murine model of biliary atresia

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Wen-jun; Dong, Rui; Chen, Gong, E-mail: chengongzlp@hotmail.com; Zheng, Shan

    2014-03-28

    Highlights: • The RRV infected group showed cholestasis, retardation and extrahepatic biliary atresia. • miR-222 was highly expressed, and PPP2R2A was inhibited in the murine biliary atresia model. • miR-222 profoundly modulated the process of fibrosis in the murine biliary atresia model. • miR-222 might represent a potential target for improving biliary atresia prognosis. - Abstract: microRNA-222 (miR-222) has been shown to initiate the activation of hepatic stellate cells, which plays an important role in the pathogenesis of liver fibrosis. The aim of our study was to evaluate the role of miR-22 in a mouse model of biliary atresia (BA) induced by Rhesus Rotavirus (RRV) infection. New-born Balb/c mice were randomized into control and RRV infected groups. The extrahepatic bile ducts were evaluated. The experimental group was divided into BA group and negative group based on histology. The expression of miR-222, protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), proliferating cell nuclear antigen (PCNA) and phospho-Akt were detected. We found that the experimental group showed signs of cholestasis, retardation and extrahepatic biliary atresia. No abnormalities were found in the control group. In the BA group, miR-222, PCNA and Akt were highly expressed, and PPP2R2A expression was significantly inhibited. Our findings suggest that miR-222 profoundly modulated the process of fibrosis in the murine BA model, which might represent a potential target for improving BA prognosis.

  11. Noninvasive assessment of liver fibrosis: Serum markers and transient elastography (FibroScan Evaluación no invasiva de fibrosis hepática: Marcadores séricos y elastografía transitoria (FibroScan

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    J. C. Marín-Gabriel

    2009-11-01

    Full Text Available Both the prognosis and potential treatment of chronic liver disease greatly depend on the progression of liver fibrosis, which is the ultimate outcome of chronic liver damage. Historically, liver biopsy has been instrumental in adequately assessing patients with chronic liver disease. Histological assessment allows clinicians both to obtain diagnostic information and initiate adequate therapy. However, the technique is not exempt of deleterious effects. Multiple diagnostic tests have been developed for the staging of fibrosis using noninvasive methods, most of them in the setting of chronic hepatitis C. The goal of this paper is to review available data on the staging and assessment of liver fibrosis with two methods: serum markers and transient elastography (FibroScan®.

  12. Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    Fin Stolze Larsen; Ben Vainer; Martin Eefsen; Peter Nissen Bjerring; Bent Adel Hansen

    2007-01-01

    AIM: To determine the efficacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis(AIH).METHODS: Retrospectively, clinical parameters,biochemistry and histology were obtained from patient records.RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P=0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P=0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P=0.032),respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P=0.016), while the degree of fibrosis tended to decrease (P=0.049).CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of fibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantialreduction of prednisone dose.

  13. Effects of Da Ding Feng Zhu Decoction in 30 Cases of Liver Fibrosis

    Institute of Scientific and Technical Information of China (English)

    李伟林; 王才党; 张君利

    2003-01-01

    To study the clinical effects of Da Ding Feng Zhu (大定风珠) Decoction on liver fibrosis. 56 patients withliver fibrosis due to chronic hepatitis B were randomly divided into a treatment group (30 cases treatedwith Da Ding Feng Zhu Decoction) and a control group (26 cases treated with colchicine). The serumlevels of hyaluronic acid (HA), procollagen Ⅲ (PC-Ⅲ), Ⅳ collagen (Ⅳ-C) and Laminin (LN) of thepatients were determined, compared and analyzed before treatment and after 3-month treatment in the twogroups. The results showed that in the treatment group, the levels of HA, PC-Ⅲ, Ⅳ-C and LN after3-month treatment were significantly lowered as compared to that before treatment (P<0.01). In thecontrol group, only the HA level was obviously lowered (P<0.05). There was an significant difference(P<0.05) in PC-Ⅲ and Ⅳ-C and a very significant difference (P<0.01) in HA after treatment between thetwo groups. It is therefore concluded that Da Ding Feng Zhu Decoction can lower serum indexes of liverfibrosis.

  14. Advancing the High Throughput Identification of Liver Fibrosis Protein Signatures Using Multiplexed Ion Mobility Spectrometry

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    Baker, Erin Shammel; Burnum-Johnson, Kristin E.; Jacobs, Jon M.; Diamond, Deborah L.; Brown, Roslyn N.; Ibrahim, Yehia M.; Orton, Daniel J.; Piehowski, Paul D.; Purdy, David E.; Moore, Ronald J.; Danielson, William F.; Monroe, Matthew E.; Crowell, Kevin L.; Slysz, Gordon W.; Gritsenko, Marina A.; Sandoval, John D.; Lamarche, Brian L.; Matzke, Melissa M.; Webb-Robertson, Bobbie-Jo M.; Simons, Brenna C.; McMahon, Brian J.; Bhattacharya, Renuka; Perkins, James D.; Carithers, Robert L.; Strom, Susan; Self, Steven; Katze, Michael G.; Anderson, Gordon A.; Smith, Richard D.

    2014-04-01

    Rapid diagnosis of disease states using less invasive, safer, and more clinically acceptable approaches than presently employed is an imperative goal for the field of medicine. While mass spectrometry (MS)-based proteomics approaches have attempted to meet these objectives, challenges such as the enormous dynamic range of protein concentrations in clinically relevant biofluid samples coupled with the need to address human biodiversity have slowed their employment. Herein, we report on the use of a new platform that addresses these challenges by coupling technical advances in rapid gas phase multiplexed ion mobility spectrometry (IMS) separations [1, 2] with liquid chromatography (LC) and MS to dramatically increase measurement sensitivity and throughput, further enabling future MS-based clinical applications. An initial application of the LC-IMS-MS platform for the analysis of blood serum samples from stratified post-liver transplant patients with recurrent fibrosis progression illustrates its potential utility for disease characterization and use in personalized medicine [3, 4].

  15. A network pharmacology approach to discover active compounds and action mechanisms of San-Cao Granule for treatment of liver fibrosis

    Science.gov (United States)

    Wei, Shizhang; Niu, Ming; Wang, Jian; Wang, Jiabo; Su, Haibin; Luo, Shengqiang; Zhang, Xiaomei; Guo, Yanlei; Liu, Liping; Liu, Fengqun; Zhao, Qingguo; Chen, Hongge; Xiao, Xiaohe; Zhao, Pan; Zhao, Yanling

    2016-01-01

    Ethnopharmacological relevance San-Cao Granule (SCG) has been used in patients with liver fibrosis for many years and has shown good effect. However, its mechanism of therapeutic action is not clear because of its complex chemical system. The purpose of our study is to establish a comprehensive and systemic method that can predict the mechanism of action of SCG in antihepatic fibrosis. Materials and methods In this study, a “compound–target–disease” network was constructed by combining the SCG-specific and liver fibrosis–specific target proteins with protein–protein interactions, and network pharmacology was used to screen out the underlying targets and mechanisms of SCG for treatment of liver fibrosis. Then, some key molecules of the enriched pathway were chosen to verify the effects of SCG on liver fibrosis induced by thioacetamide (TAA). Results This systematic approach had successfully revealed that 16 targets related to 11 SCG compounds were closely associated with liver fibrosis therapy. The pathway-enrichment analysis of them showed that the TGF-β1/Smad signaling pathway is relatively important. Animal experiments also proved that SCG could significantly ameliorate liver fibrosis by inhibiting the TGF-β1/Smad pathway. Conclusion SCG could alleviate liver fibrosis through the molecular mechanisms predicted by network pharmacology. Furthermore, network pharmacology could provide deep insight into the pharmacological mechanisms of Chinese herbal formulas. PMID:26929602

  16. Total Glucosides of Danggui Buxue Tang Attenuate BLM-Induced Pulmonary Fibrosis via Regulating Oxidative Stress by Inhibiting NOX4

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    Ping Zhao

    2015-01-01

    Full Text Available Pulmonary fibrosis (PF is a serious chronic lung disease with unknown pathogenesis. Researches have confirmed that oxidative stress which is regulated by NADPH oxidase-4 (NOX4, a main source of reactive oxygen species (ROS, is an important molecular mechanism underlying PF. Previous studies showed that total glucosides of Danggui Buxue Tang (DBTG, an extract from a classical traditional Chinese herbal formula, Danggui Buxue Tang (DBT, attenuated bleomycin-induced PF in rats. However, the mechanisms of DBTG are still not clear. We hypothesize that DBTG attenuates PF through regulating the level of oxidative stress by inhibiting NOX4. And we found that fibrosis indexes hydroxyproline (HYP and type I collagen (Col-I were lower in DBTG groups compared with the model group. In addition, the expression of transforming growth factor-β1 (TGF-β1 and expression of alpha smooth muscle actin (α-SMA were also much more decreased than the model group. For oxidative stress indicators, DBTG blunted the decrease of superoxide dismutase (SOD activity, total antioxidant capacity (T-AOC, and the increase in malondialdehyde (MDA, 8-iso-prostaglandin in lung homogenates. Treatment with DBTG restrained the expression of NOX4 compared to the model group. Present study confirms that DBTG inhibits BLM-induced PF by modulating the level of oxidative stress via suppressing NOX4.

  17. Association of MICA gene polymorphisms with liver fibrosis in schistosomiasis patients in the Dongting Lake region

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    Gong, Zheng; Luo, Qi-Zhi; Lin, Lin [Department of Immunology, College of Basic Medical Sciences, Central South University, Changsha, Hunan Province (China); Su, Yu-Ping; Peng, Hai-Bo [Central Blood Bank in Yueyang, Yueyang, Hunan Province (China); Du, Kun; Yu, Ping [Department of Immunology, College of Basic Medical Sciences, Central South University, Changsha, Hunan Province (China); Wang, Shi-Ping [Key Laboratory of Schistosomiasis in Hunan, Department of Parasitology, College of Basic Medical Sciences, Central South University, Changsha, Hunan Province (China)

    2012-03-02

    Major histocompatibility complex class I chain-related A (MICA) is a highly polymorphic gene located within the MHC class I region of the human genome. Expressed as a cell surface glycoprotein, MICA modulates immune surveillance by binding to its cognate receptor on natural killer cells, NKG2D, and its genetic polymorphisms have been recently associated with susceptibility to some infectious diseases. We determined whether MICA polymorphisms were associated with the high rate of Schistosoma parasitic worm infection or severity of disease outcome in the Dongting Lake region of Hunan Province, China. Polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing-based typing (SBT) were applied for high-resolution allele typing of schistosomiasis cases (N = 103, age range = 36.2-80.5 years, 64 males and 39 females) and healthy controls (N = 141, age range = 28.6-73.3 years, 73 males and 68 females). Fourteen MICA alleles and five short-tandem repeat (STR) alleles were identified among the two populations. Three (MICA*012:01/02, MICA*017 and MICA*027) showed a higher frequency in healthy controls than in schistosomiasis patients, but the difference was not significantly correlated with susceptibility to S. japonicum infection (Pc > 0.05). In contrast, higher MICA*A5 allele frequency was significantly correlated with advanced liver fibrosis (Pc < 0.05). Furthermore, the distribution profile of MICA alleles in this Hunan Han population was significantly different from those published for Korean, Thai, American-Caucasian, and Afro-American populations (P < 0.01), but similar to other Han populations within China (P > 0.05). This study provides the initial evidence that MICA genetic polymorphisms may underlie the severity of liver fibrosis occurring in schistosomiasis patients from the Dongting Lake region.

  18. "Liverscore" is predictive of both liver fibrosis and activity in chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Shoukat Ali Arain; Qamar Jamal; Amir Omair

    2011-01-01

    AIM: To formulate a noninvasive index predictive of severity of liver fibrosis and activity in chronic hepatitis C.METHODS: This cross sectional study was conducted on polymerase chain reaction positive, treatment na(i)ve patients. Fibrosis was staged on a five point scale from F0-F4 and activity was graded on a four point scale from A0-A3, according to the METAVIR system. Patients were divided into two overall severity groups, minimal disease (< F2 and < A2) and significant disease (≥ F2 or ≥ A2). Eleven markers were measured in blood. Statistically, the primary outcome variable was identification of minimal and significant overall disease. Indices were formulated using β regression values of different combinations of nine statistically significant factors.Diagnostic performance of these indices was assessed through receiver-operating characteristic curve analysis.RESULTS: A total of 98 patients were included and of these 46 had an overall clinically significant disease. Our final six marker index, Liverscore for Hepatitis C, consisted of age, alanine transaminase, gamma-glutamyl transpeptidase, apolipoprotein A-1, alpha-2 macroglobulin and hyaluronic acid. The area under the curve was found to be 0.813. On a 0-1 scale, negative predictive value at a cutoff level of ≤ 0.40 was 83%, while positive predictive value at ≥ 0.80 remained 89%. Altogether,61% of the patients had these discriminative scores.CONCLUSION: This index is discriminative of minimal and significant overall liver disease in a majority of chronic hepatitis C patients and can help in clinical decision making.

  19. Association of MICA gene polymorphisms with liver fibrosis in schistosomiasis patients in the Dongting Lake region

    International Nuclear Information System (INIS)

    Major histocompatibility complex class I chain-related A (MICA) is a highly polymorphic gene located within the MHC class I region of the human genome. Expressed as a cell surface glycoprotein, MICA modulates immune surveillance by binding to its cognate receptor on natural killer cells, NKG2D, and its genetic polymorphisms have been recently associated with susceptibility to some infectious diseases. We determined whether MICA polymorphisms were associated with the high rate of Schistosoma parasitic worm infection or severity of disease outcome in the Dongting Lake region of Hunan Province, China. Polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing-based typing (SBT) were applied for high-resolution allele typing of schistosomiasis cases (N = 103, age range = 36.2-80.5 years, 64 males and 39 females) and healthy controls (N = 141, age range = 28.6-73.3 years, 73 males and 68 females). Fourteen MICA alleles and five short-tandem repeat (STR) alleles were identified among the two populations. Three (MICA*012:01/02, MICA*017 and MICA*027) showed a higher frequency in healthy controls than in schistosomiasis patients, but the difference was not significantly correlated with susceptibility to S. japonicum infection (Pc > 0.05). In contrast, higher MICA*A5 allele frequency was significantly correlated with advanced liver fibrosis (Pc < 0.05). Furthermore, the distribution profile of MICA alleles in this Hunan Han population was significantly different from those published for Korean, Thai, American-Caucasian, and Afro-American populations (P < 0.01), but similar to other Han populations within China (P > 0.05). This study provides the initial evidence that MICA genetic polymorphisms may underlie the severity of liver fibrosis occurring in schistosomiasis patients from the Dongting Lake region

  20. Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice.

    Science.gov (United States)

    Peppler, Willem T; Anderson, Zachary G; Sutton, Charles D; Rector, R Scott; Wright, David C

    2016-05-15

    Sepsis induces an acute inflammatory response in the liver, which can lead to organ failure and death. Given the anti-inflammatory effects of exercise, we hypothesized that habitual physical activity could protect against acute sepsis-induced liver inflammation via mechanisms, including heat shock protein (HSP) 70/72. Male C57BL/6J mice (n = 80, ∼8 wk of age) engaged in physical activity via voluntary wheel running (VWR) or cage control (SED) for 10 wk. To induce sepsis, we injected (2 mg/kg ip) LPS or sterile saline (SAL), and liver was harvested 6 or 12 h later. VWR attenuated increases in body and epididymal adipose tissue mass, improved glucose tolerance, and increased liver protein content of PEPCK (P challenges. This study provides novel evidence that physical activity protects against the inflammatory cascade induced by LPS in the liver and that these effects may be mediated via HSP70/72. PMID:26887432

  1. Comparison of Histochemical Stainings in Evaluation of Liver Fibrosis and Correlation with Transient Elastography in Chronic Hepatitis

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    Daniela Cabibi

    2015-01-01

    Full Text Available Background and Aim. The best staining to evaluate liver fibrosis in liver hepatitis is still a debated topic. This study aimed to compare Masson’s trichrome (MT, Sirius Red (SR, and orcein stainings in evaluating liver fibrosis in chronic HCV hepatitis (CHC with semiquantitative and quantitative methods (Collagen Proportionate Area (CPA by Digital Image Analysis (DIA and correlate them with transient elastography (TE. Methods. Liver stiffness evaluation of 111 consecutive patients with CHC was performed by TE. Semiquantitative staging by Metavir score system and CPA by DIA were assessed on liver biopsy stained with MT, SR, and orcein. Results. MT, SR, and orcein staining showed concordant results in 89.6% of cases in staging CHC, without significant difference in both semiquantitative and quantitative evaluations of fibrosis. TE values were concordant with orcein levels in 86.5% of the cases and with MT/RS in 77.5% (P<0.001. No significant correlation between the grade of necroinflammatory activity and TE values was found. Conclusion. In CHC, SR/MT and orcein stainings are almost concordant and when discordant, orcein staining is better related to TE values than MT/RS. This suggests that elastic fibers play a more important role than reticular or collagenous ones in determining stiffness values in CHC.

  2. Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway.

    Science.gov (United States)

    Liu, Qingmei; Chu, Haiyan; Ma, Yanyun; Wu, Ting; Qian, Feng; Ren, Xian; Tu, Wenzhen; Zhou, Xiaodong; Jin, Li; Wu, Wenyu; Wang, Jiucun

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis. PMID:27278104

  3. Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway

    Science.gov (United States)

    Liu, Qingmei; Chu, Haiyan; Ma, Yanyun; Wu, Ting; Qian, Feng; Ren, Xian; Tu, Wenzhen; Zhou, Xiaodong; Jin, Li; Wu, Wenyu; Wang, Jiucun

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis. PMID:27278104

  4. The Role of Ultrasound Imaging in the Definition of the Stage of Liver Fibrosis in Patients with Chronic Hepatitis C

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    Dmitry Konstantinov

    2014-09-01

    Full Text Available The aim of this research was to develop a method for noninvasive staging of liver fibrosis (LF in patients with chronic hepatitis C (CHC based on ultrasound imaging (UI of the abdominal cavity. We examined 124 patients with CHC. The diagnosis was verified on the basis of clinical and epidemiological, serological and molecular biological data. Direct ultrasonic parameters of the structure and hemodynamics of liver and spleen were supplemented with estimated indicators: square of the expected cross-section of the lobes of the liver and spleen, as well as their ratio. On the basis of the discriminant analysis of the survey data of 82 patients, we developed an analytical model (with predictive value of 95.2% for interval estimation of the fibrosis degree in CHC patients. We have concluded that UI performed on modern equipment, including Doppler, is able to determine the degree of LF without resorting to histological verification.

  5. Genetically Attenuated Plasmodium berghei Liver Stages Persist and Elicit Sterile Protection Primarily via CD8 T Cells

    OpenAIRE

    Mueller, Ann-Kristin; Deckert, Martina; Heiss, Kirsten; Goetz, Kristin; Matuschewski, Kai; Schlüter, Dirk

    2007-01-01

    Live-attenuated Plasmodium liver stages remain the only experimental model that confers complete sterile protection against malaria. Irradiation-attenuated Plasmodium parasites mediate protection primarily by CD8 T cells. In contrast, it is unknown how genetically attenuated liver stage parasites provide protection. Here, we show that immunization with uis3(−) sporozoites does not cause breakthrough infection in T and B-cell-deficient rag1−/− and IFN-γ−/− mice. However, protection was abolish...

  6. Study on the Anti-Liver Fibrosis Effect of Benefit Liver Granule (益肝冲剂) and Its Mechanism in Rats

    Institute of Scientific and Technical Information of China (English)

    姚希贤; 崔东来; 孙玉凤; 冯丽英; 孙泽民; 宋梅

    2002-01-01

    Objective:To explore the effect of Benefit Liver Granule (BLG), a traditional Chinese medical preparation, in antagonizing liver fibrosis and its possible mechanism. Methods:Carbon tetrachloride was used to establish the experimental liver fibrosis model of rat. The model rats were randomly divided into 4 groups and BLG, Astragalus (As), Salvia (Sa) and normal saline (for control) respectively were given to them by gastrogavage. Changes of serum alanine transaminase (ALT), aspartate aminotransferase (AST), transforming growth factor α(TGF-α), interleukine-6 (IL-6), liver content of hydroxyproline (Hyp), superoxide dismutase (SOD), malonyldialdehyde (MDA) as well as liver pathology after treatment were observed. A normal control group was also established for control.Results: Pathological examination showed that in the saline group, the structure of normal hepatic lobuli was destroyed with swelled liver cells, focal necrosis, extensive fatty degeneration, and focal inflammatory cell infiltration. Small amounts of proliferated fiber tissue were found in the intra-lobular area, peri-central vein area, portal area and limiting plate area, and formation of pseudolobuli was also seen. In the 3 treated groups, the serum ALT, AST, TGF-α and IL-6 as well as liver content of Hyp, and MDA were lower and SOD were higher than those in the control group significantly, P<0.05 or P<0.01.Conclusion: BLG, As and Sa have the action of anti-liver fibrosis, while BLG has the best effect. The mechanisms are probably related to their effects in regulating TGF-α and IL-6, reducing collagen fiber synthesis, promoting free radical scavenge and anti-lipid peroxidation.

  7. Fibroscan Compared to FIB-4, APRI, and AST/ALT Ratio for Assessment of Liver Fibrosis in Saudi Patients With Nonalcoholic Fatty Liver Disease

    Science.gov (United States)

    Fallatah, Hind I.; Akbar, Hisham O.; Fallatah, Alyaa M.

    2016-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as a cause of chronic liver disease. It has also been associated with devastating outcomes such as decompensated liver cirrhosis and hepatocellular carcinoma, as well as diabetes and metabolic syndrome. Objectives This study was conducted in order to assess liver fibrosis using Fibroscan, and to compare these results to the use of Fibrosis-4 (FIB-4) scores, AST platelet ratio index (APRI scores), and the AST/ALT ratios on NAFLD patients. Patients and Methods A cross sectional study was conducted on NAFLD patients who underwent Fibroscan examinations between September 1, 2011 and June 30, 2014. Demographic data was collected, including sex, age, and nationality; serum alanine aminotransferase levels (ALT, 30 - 65 U/L), serum aspartate aminotransferase levels (AST, 15 - 37 U/L), and platelet counts (150 - 400 k/μL) were also determined. The stages of fibrosis (F0 1 - 6, F1 6.1 - 7, F2 7 - 9, F3 9.1 - 10.3, and F4 ≥ 10.4) were defined in kPa. For each patient, the AST/ALT ratio was also measured. The results of APRI and FIB-4 were compared with the Fibroscan fibrosis scores. Results The results of 122 patients were analyzed, including 65 (53.3%) males with a mean age of 50.2 years (SD: 13.7; range: 18 - 86). The males were significantly younger than the females (48.7 years (SD: 16.03) versus 51.8 years (SD: 10.3 P = 0.05), respectively). The mean stiffness score was 12.02 (SD: 12.7) kPa. Forty-four patients (36%) had advanced fibrosis. The mean platelet and serum ALT levels were normal. There was a significant positive correlation between the Fibroscan results and the AST/ALT ratios, the APRI scores, and the FIB-4 results. Similarly, there was a significant positive correlation between age and fibrosis score, and a significant negative correlation between platelet count and stiffness score. Conclusions The data showed that more than one-third of the cohort exhibited advanced

  8. Evaluation of Liver Fibrosis Using Texture Analysis on Combined-Contrast-Enhanced Magnetic Resonance Images at 3.0T

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    Takeshi Yokoo

    2015-01-01

    Full Text Available Purpose. To noninvasively assess liver fibrosis using combined-contrast-enhanced (CCE magnetic resonance imaging (MRI and texture analysis. Materials and Methods. In this IRB-approved, HIPAA-compliant prospective study, 46 adults with newly diagnosed HCV infection and recent liver biopsy underwent CCE liver MRI following intravenous administration of superparamagnetic iron oxides (ferumoxides and gadolinium DTPA (gadopentetate dimeglumine. The image texture of the liver was quantified in regions-of-interest by calculating 165 texture features. Liver biopsy specimens were stained with Masson trichrome and assessed qualitatively (METAVIR fibrosis score and quantitatively (% collagen stained area. Using L1 regularization path algorithm, two texture-based multivariate linear models were constructed, one for quantitative and the other for quantitative histology prediction. The prediction performance of each model was assessed using receiver operating characteristics (ROC and correlation analyses. Results. The texture-based predicted fibrosis score significantly correlated with qualitative (r=0.698, P<0.001 and quantitative (r=0.757, P<0.001 histology. The prediction model for qualitative histology had 0.814–0.976 areas under the curve (AUC, 0.659–1.000 sensitivity, 0.778–0.930 specificity, and 0.674–0.935 accuracy, depending on the binary classification threshold. The prediction model for quantitative histology had 0.742–0.950 AUC, 0.688–1.000 sensitivity, 0.679–0.857 specificity, and 0.696–0.848 accuracy, depending on the binary classification threshold. Conclusion. CCE MRI and texture analysis may permit noninvasive assessment of liver fibrosis.

  9. Vitamin D Attenuates Kidney Fibrosis via Reducing Fibroblast Expansion, Inflammation, and Epithelial Cell Apoptosis.

    Science.gov (United States)

    Arfian, Nur; Muflikhah, Khusnul; Soeyono, Sri Kadarsih; Sari, Dwi Cahyani Ratna; Tranggono, Untung; Anggorowati, Nungki; Romi, Muhammad Mansyur

    2016-01-01

    Kidney fibrosis is the common final pathway of chronic kidney diseases (CKD). It is characterized by myofibroblast formation, inflammation, and epithelial architecture damage. Vitamin D is known as a renoprotective agent, although the precise mechanism is not well understood. This study aimed to elucidate the effect of vitamin D in fibroblast expansion, inflammation, and apoptosis in kidney fibrosis. We performed unilateral ureteral obstruction (UUO) in male Swiss-Webster background mice (3 months, 30-40 grams) to induce kidney fibrosis. The mice (n=25) were divided into five groups: UUO, 3 groups treated with different oral vitamin D doses (0.125 µg/kg (UUO+VD1), 0.25 µg/kg (UUO+VD2), and 0.5 µg/kg (UUO+VD3), and a Sham operation (SO) group with ethanol 0.2% supplementation. We sacrificed the mice on day14 after the operation and harvested the kidney. We made paraffin sections for histological analysis. Tubular injury and fibrosis were quantified based on periodic acid-Schiff (PAS) and Sirius Red (SR) staining. Immunostaining was done for examination of myofibroblasts (αSMA), fibroblasts (PDGFRβ), TLR4, and apoptosis (TUNEL). We did RNA extraction and cDNA for Reverse transcriptase PCR (RT-PCR) experiment for measuring MCP-1, ICAM-1, TLR4, and collagen 1 expression. TGFβ1 level was quantified using ELISA. We observed a significantly lower levels of fibrosis (pexpression of collagen1, as well as inflammation-mediator expression (MCP-1, ICAM-1, TLR4) in the UUO+VD-1 group compared with the SO group. Vitamin D reduces kidney fibrosis through inhibition of fibroblast activation, and ameliorates epithelial cell architecture. PMID:27578035

  10. Exacerbating effects of human parvovirus B19 NS1 on liver fibrosis in NZB/W F1 mice.

    Directory of Open Access Journals (Sweden)

    Tsai-Ching Hsu

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disorder with unknown etiology that impacts various organs including liver. Recently, human parvovirus B19 (B19 is recognized to exacerbate SLE. However, the effects of B19 on liver in SLE are still unclear. Herein we aimed to investigate the effects of B19 on liver in NZB/W F1 mice by injecting subcutaneously with PBS, recombinant B19 NS1, VP1u or VP2, respectively. Our experimental results revealed that B19 NS1 protein significantly enhanced the TGF-β/Smad fibrotic signaling by increasing the expressions of TGF-β, Smad2/3, phosphorylated Smad2/3, Smad4 and Sp1. The consequent fibrosis-related proteins, PAI-1 and α-SMA, were also significantly induced in livers of NZB/W F1 mice receiving B19 NS1 protein. Accordingly, markedly increased collagen deposition was also observed in livers of NZB/W F1 mice receiving B19 NS1 protein. However, no significant difference was observed in livers of NZB/W F1 mice receiving B19 VP1u or VP2 as compared to the controls. These findings indicate that B19 NS1 plays a crucial role in exacerbating liver fibrosis in NZB/W F1 mice through enhancing the TGF-â/Smad fibrotic signaling.

  11. Accelerated CCl4-induced liver fibrosis in Hjv-/- mice, associated with an oxidative burst and precocious profibrogenic gene expression.

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    Giada Sebastiani

    Full Text Available Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronic liver diseases aggravates liver injury. To uncover underlying molecular mechanisms, hemochromatotic hemojuvelin knockout (Hjv-/- mice and wild type (wt controls were intoxicated with CCl(4. Hjv-/- mice developed earlier (by 2-4 weeks and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF and, notably, the iron-regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv-/- animals. Even though livers of naïve Hjv-/- mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards α-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2-3 fold vs. wt, p<0.05 levels of α1-(I-collagen, TGF-β1, endothelin-1 and PDGF mRNAs, indicative of early fibrogenesis. Our data suggest that hepatic iron overload in parenchymal cells promotes oxidative stress and triggers premature profibrogenic gene expression, contributing to accelerated onset and precipitous progression of liver fibrogenesis.

  12. Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis.

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    Young Eun Chon

    Full Text Available Transient elastography (TE, a non-invasive tool that measures liver stiffness, has been evaluated in meta-analyses for effectiveness in assessing liver fibrosis in European populations with chronic hepatitis C (CHC. However, these data cannot be extrapolated to populations in Asian countries, where chronic hepatitis B (CHB is more prevalent. In this study, we performed a meta-analysis to assess the overall performance of TE for assessing liver fibrosis in patients with CHB.Studies from the literature and international conference abstracts which enrolled only patients with CHB or performed a subgroup analysis of such patients were enrolled. Combined effects were calculated using area under the receiver operating characteristic curves (AUROC and diagnostic accuracy values of each study.A total of 18 studies comprising 2,772 patients were analyzed. The mean AUROCs for the diagnosis of significant fibrosis (F2, severe fibrosis (F3, and cirrhosis (F4 were 0.859 (95% confidence interval [CI], 0.857-0.860, 0.887 (95% CI, 0.886-0.887, and 0.929 (95% CI, 0.928-0.929, respectively. The estimated cutoff for F2 was 7.9 (range, 6.1-11.8 kPa, with a sensitivity of 74.3% and specificity of 78.3%. For F3, the cutoff value was determined to be 8.8 (range, 8.1-9.7 kPa, with a sensitivity of 74.0% and specificity of 63.8%. The cutoff value for F4 was 11.7 (range, 7.3-17.5 kPa, with a sensitivity of 84.6% and specificity of 81.5%.TE can be performed with good diagnostic accuracy for quantifying liver fibrosis in patients with CHB.

  13. Separation of advanced from mild fibrosis in diffuse liver disease using {sup 31}P magnetic resonance spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Noren, Bengt [Department of Radiology, Linkoeping University, SE-581 85 Linkoeping (Sweden); Dahlqvist, Olof [Department of Radiation Physics, Linkoeping University, SE-581 85 Linkoeping (Sweden); Center for Medical Image Science and Visualization (CMIV), Linkoeping University, SE-581 85 Linkoeping (Sweden); Lundberg, Peter [Department of Radiology, Linkoeping University, SE-581 85 Linkoeping (Sweden); Department of Radiation Physics, Linkoeping University, SE-581 85 Linkoeping (Sweden); Center for Medical Image Science and Visualization (CMIV), Linkoeping University, SE-581 85 Linkoeping (Sweden)], E-mail: Peter.Lundberg@imv.liu.se; Almer, Sven [Department of Gastroenterology and Hepatology, Linkoeping University, SE-581 85 Linkoeping (Sweden); Kechagias, Stergios [Department of Internal Medicine, Linkoeping University, SE-581 85 Linkoeping (Sweden); Ekstedt, Mattias [Department of Gastroenterology and Hepatology, Linkoeping University, SE-581 85 Linkoeping (Sweden); Franzen, Lennart [Medilab, SE-183 53 Taeby Sweden (Sweden); Wirell, Staffan [Department of Radiology, Linkoeping University, SE-581 85 Linkoeping (Sweden); Smedby, Orjan [Department of Radiology, Linkoeping University, SE-581 85 Linkoeping (Sweden); Center for Medical Image Science and Visualization (CMIV), Linkoeping University, SE-581 85 Linkoeping (Sweden)

    2008-05-15

    {sup 31}P-MRS using DRESS was used to compare absolute liver metabolite concentrations (PME, Pi, PDE, {gamma}ATP, {alpha}ATP, {beta}ATP) in two distinct groups of patients with chronic diffuse liver disorders, one group with steatosis (NAFLD) and none to moderate inflammation (n = 13), and one group with severe fibrosis or cirrhosis (n = 16). All patients underwent liver biopsy and extensive biochemical evaluation. A control group (n = 13) was also included. Absolute concentrations and the anabolic charge, AC = {l_brace}PME{r_brace}/({l_brace}PME{r_brace} + {l_brace}PDE{r_brace}), were calculated. Comparing the control and cirrhosis groups, lower concentrations of PDE (p = 0.025) and a higher AC (p < 0.001) were found in the cirrhosis group. Also compared to the NAFLD group, the cirrhosis group had lower concentrations of PDE (p = 0.01) and a higher AC (p = 0.009). No significant differences were found between the control and NAFLD group. When the MRS findings were related to the fibrosis stage obtained at biopsy, there were significant differences in PDE between stage F0-1 and stage F4 and in AC between stage F0-1 and stage F2-3. Using a PDE concentration of 10.5 mM as a cut-off value to discriminate between mild, F0-2, and advanced, F3-4, fibrosis the sensitivity and specificity were 81% and 69%, respectively. An AC cut-off value of 0.27 showed a sensitivity of 93% and a specificity of 54%. In conclusion, the results suggest that PDE is a marker of liver fibrosis, and that AC is a potentially clinically useful parameter in discriminating mild fibrosis from advanced.

  14. Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis

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    Friedrich-Rust Mireen

    2010-09-01

    Full Text Available Abstract Background FibroTest (FT is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoproteinA1, haptoglobin, GGT, bilirubin. The Enhanced Liver Fibrosis (ELF test consists of an algorithm of three fibrosis markers (hyaluronic acid, amino-terminal propeptide-of-type-III-collagen, tissue-inhibitor of matrix-metaloproteinase-1. While a systematic review has shown comparable results for both individual markers, there has been no direct comparison of both markers. Methods In the present study, the ELF-test was analyzed retrospectively in patients with chronic liver disease, who received a liver biopsy, transient elastography (TE and the FibroTest using histology as the reference method. Histology was classified according to METAVIR and the Ludwig's classification (F0-F4 for patients with chronic hepatitis C and B virus (HCV, HBV infection and primary biliary cirrhosis (PBC, respectively. Results Seventy-four patients were analysed: 36 with HCV, 10 with HBV, and 28 with PBC. The accuracy (AUROC for the diagnosis of significant fibrosis (F≥2 for ELF and FibroTest was 0.78 (95%CI:0.67-0.89 and 0.69 (95%-CI:0.57-0.82, respectively (difference not statistically significant, n.s.. The AUROC for the diagnosis of liver cirrhosis was 0.92 (95%CI:0.83-1,00, and 0.91 (95%CI:0.83-0.99, respectively (n.s.. For 66 patients with reliable TE measurements the AUROC for the diagnosis of significant fibrosis (cirrhosis for TE, ELF and FT were 0.80 (0.94, 0.76 (0.92, and 0.67 (0.91, respectively (n.s.. Conclusion FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography.

  15. Magnetic resonance-based total liver volume and magnetic resonance-diffusion weighted imaging for staging liver fibrosis in mini-pigs

    Institute of Scientific and Technical Information of China (English)

    Hang Li; Tian-Wu Chen; Xiao-Li Chen; Xiao-Ming Zhang; Zhen-Lin Li; Nan-Lin Zeng; Li Zhou

    2012-01-01

    AIM:TO determine whether and how magnetic resonance imaging (MRI)-based total liver volume (TLV) and diffusion weighted imaging (DWI) could predict liver fibrosis.METHODS:Sixteen experimental mature mini-pigs (6 males,10 females),weighing between 20.0 and 24.0 kg were prospectively used to model liver fibrosis induced by intraperitoneal injection of 40% CCl4 dissolved in fat emulsion twice a week for 16 wk,and by feeding 40% CCl4 mixed with maize flour twice daily for the subsequent 5 wk.All the survival animals underwent percutaneous liver biopsy and DWI using b =300,500 and 800 s/mm2 followed by abdominal gadolinium-enhanced MRI at the 0,5th,9th,16th and 21st weekend after beginning of the modeling.TLV was obtained on enhanced MRI,and apparent diffusion coefficient (ADC) was obtained on DWI.Hepatic tissue specimens were stained with hematoxylin and Masson's trichrome staining for staging liver fibrosis.Pathological specimens were scored using the human METAVIR classification system.Statistical analyses were performed to determine whether and how the TLV and ADC could be used to predict the stage of liver fibrosis.RESULTS:TLV increased from stage 0 to 2 and decreased from stage 3 (r =0.211; P < 0.001).There was a difference in TLV between stage 0-1 and 2-4 (P =0.03) whereas no difference between stage 0-2 and 3-4 (P =0.71).TLV could predict stage ≥ 2 [area under receiver operating characteristic curve (AUC) =0.682].There was a decrease in ADC values with increasing stage of fibrosis for b =300,500 and 800s/mm2 (r =-0.418,-0.535 and-0.622,respectively;all P < 0.001).Differences were found between stage 0-1 and 2-4 in ADC values for b =300,500 and 800 s/mm2,and between stage 0-2 and 3-4 for b =500 or 800 s/mm2 (all P < 0.05).For predicting stage ≥ 2 and ≥ 3,AUC was 0.803 and 0.847 for b =500 s/mm2,and 0.848 and 0.887 for b =800 s/mm2,respectively.CONCLUSION:ADC for b =500 or 800 s/mm2 could be better than TLV and ADC for b =300 s/mm2 to predict

  16. Unhealthy alcohol use, HIV infection and risk of liver fibrosis in drug users with hepatitis C.

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    Roberto Muga

    Full Text Available AIM: To analyze alcohol use, clinical data and laboratory parameters that may affect FIB-4, an index for measuring liver fibrosis, in HCV-monoinfected and HCV/HIV-coinfected drug users. PATIENTS AND METHODS: Patients admitted for substance abuse treatment between 1994 and 2006 were studied. Socio-demographic data, alcohol and drug use characteristics and clinical variables were obtained through hospital records. Blood samples for biochemistry, liver function tests, CD4 cell count, and serology of HIV and HCV infection were collected at admission. Multivariate linear regression was used to analyze the predictors of FIB-4 increase. RESULTS: A total of 472 (83% M, 17% F patients were eligible. The median age at admission was 31 years (Interquartile range (IQR 27-35 years, and the median duration of drug use was 10 years (IQR 5.5-15 years. Unhealthy drinking (>50 grams/day was reported in 32% of the patients. The FIB-4 scores were significantly greater in the HCV/HIV-coinfected patients (1.14, IQR 0.76-1.87 than in the HCV-monoinfected patients (0.75, IQR 0.56-1.11 (p<0.001. In the multivariate analysis, unhealthy drinking (p = 0.034, lower total cholesterol (p = 0.042, serum albumin (p<0.001, higher GGT (p<0.001 and a longer duration of addiction (p = 0.005 were independently associated with higher FIB-4 scores in the HCV-monoinfected drug users. The effect of unhealthy drinking on FIB-4 scores disappeared in the HCV/HIV-coinfected patients, whereas lower serum albumin (p<0.001, a lower CD4 cell count (p = 0.006, higher total bilirubin (p<0.001 and a longer drug addiction duration (p<0.001 were significantly associated with higher FIB-4 values. CONCLUSIONS: Unhealthy alcohol use in the HCV-monoinfected patients and HIV-related immunodeficiency in the HCV/HIV-coinfected patients are important risk factors associated with liver fibrosis in the respective populations.

  17. Transient and 2-Dimensional Shear-Wave Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis

    DEFF Research Database (Denmark)

    Thiele, Maja; Detlefsen, Sönke; Møller, Linda Maria Sevelsted;

    2016-01-01

    BACKGROUND & AIMS: Alcohol abuse causes half of all deaths from cirrhosis in the West, but few tools are available for noninvasive diagnosis of alcoholic liver disease. We evaluated 2 elastography techniques for diagnosis of alcoholic fibrosis and cirrhosis; liver biopsy with Ishak score...... and collagen-proportionate area were used as reference. METHODS: We performed a prospective study of 199 consecutive patients with ongoing or prior alcohol abuse, but without known liver disease. One group of patients had a high pretest probability of cirrhosis because they were identified at hospital liver...... predictive value for cirrhosis was >66% in the high-risk group vs approximately 50% in the low-risk group. Evidence of alcohol-induced damage to cholangiocytes, but not ongoing alcohol abuse, affected liver stiffness. The collagen-proportionate area correlated with Ishak grades and accurately identified...

  18. Novel matrine derivative MD-1 attenuates hepatic fibrosis by inhibiting EGFR activation of hepatic stellate cells.

    Science.gov (United States)

    Feng, Yi; Ying, Hai-Yan; Qu, Ying; Cai, Xiao-Bo; Xu, Ming-Yi; Lu, Lun-Gen

    2016-09-01

    Matrine (MT), the effective component of Sophora flavescens Ait, has been shown to have anti-inflammation, immune-suppressive, anti-tumor, and anti-hepatic fibrosis activities. However, the pharmacological effects of MT still need to be strengthened due to its relatively low efficacy and short half-life. In the present study, we report a more effective thio derivative of MT, MD-1, and its inhibitory effects on the activation of hepatic stellate cells (HSCs) in both cell culture and animal models. Cytological experiments showed that MD-1 can inhibit the proliferation of HSC-T6 cells with a half-maximal inhibitory concentration (IC50) of 62 μmol/L. In addition, MD-1 more strongly inhibits the migration of HSC-T6 cells compared to MT and can more effectively induce G0/G1 arrest and apoptosis. Investigating the biological mechanisms underlying anti-hepatic fibrosis in the presence of MD-1, we found that MD-1 can bind the epidermal growth factor receptor (EGFR) on the surface of HSC-T6 cells, which can further inhibit the phosphorylation of EGFR and its downstream protein kinase B (Akt), resulting in decreased expression of cyclin D1 and eventual inhibition of the activation of HSC-T6 cells. Furthermore, in rats with dimethylnitrosamine (DMN)-induced hepatic fibrosis, MD-1 slowed the development and progression of hepatic fibrosis, protecting hepatic parenchymal cells and improving hepatic functions. Therefore, MD-1 is a potential drug for anti-hepatic fibrosis.

  19. Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet.

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    Komal Sodhi

    Full Text Available Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD, obesity and cardiovascular disease (CVD. Heme Oxygenase-1 (HO-1 is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1 belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox.We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction.We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05. Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05. Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose. These beneficial effects of CoPP were reversed by SnMP.Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates

  20. A novel fibrosis index comprising a non-cholesterol sterol accurately predicts HCV-related liver cirrhosis.

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    Magdalena Ydreborg

    Full Text Available Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5-6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI in the paper, was based on the model: Log-odds (predicting cirrhosis = -12.17+ (age × 0.11 + (BMI (kg/m(2 × 0.23 + (D7-lathosterol (μg/100 mg cholesterol×(-0.013 + (Platelet count (x10(9/L × (-0.018 + (Prothrombin-INR × 3.69. The area under the ROC curve (AUROC for prediction of cirrhosis was 0.91 (95% CI 0.86-0.96. The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82-0.98. In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.

  1. A quantitative index measured on 99mTc GSA SPECT/CT 3D fused images to evaluate severe fibrosis in patients with chronic liver disease

    International Nuclear Information System (INIS)

    We compared quantitative indices estimated by use of technetium-99m galactosyl human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT)/computed tomography (CT) fused imaging and hepatic fibrosis in patients with chronic liver disease. On the basis of pathological findings we divided 161 patients into non-severe and severe fibrosis groups (n=81 and n=80, respectively). We measured 2 indices by 99mTc-GSA SPECT/CT fused imaging: liver uptake value (LUV) = [radioactivity (whole liver)/radioactivity (injected)] x 100/body surface area, and functional liver index (FLI)=[radioactivity (hepatocytes)/radioactivity (injected)] x 100/liver volume. We compared these indices with biochemical and histopathological results. Univariate and multivariate analyses showed that FLI, LUV, liver and heart ROIs at 15 min post-injection (LHL15), and prothrombin time were significant independent predictors of severe fibrosis. On the basis of receiver operating characteristics analysis, the areas under curve values of FLI, LUV, LHL15, and prothrombin time for predicting severe fibrosis were 0.83, 0.73, 0.69, and 0.68, respectively. Using an FLI value of 0.053, it was possible to predict severe fibrosis with 65% sensitivity, 88% specificity, and 76% accuracy. Assessment of functional hepatocytes by use of 99mTc-GSA SPECT/CT fused images is useful for identifying pathological liver fibrosis. (author)

  2. Peroxiredoxin 2: a potential biomarker for early diagnosis of Hepatitis B Virus related liver fibrosis identified by proteomic analysis of the plasma

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    Wang Haijian

    2010-10-01

    Full Text Available Abstract Background Liver fibrosis is a middle stage in the course of chronic Hepatitis B virus (HBV infection, which will develop into cirrhosis and eventually hepatocellular carcinoma (HCC if not treated at the early stage. Considering the limitations and patients' reluctance to undergo liver biopsy, a reliable, noninvasive diagnostic system to predict and assess treatment and prognosis of liver fibrosis is needed. The aim of this study was to identify biomarkers for early diagnosis of HBV related liver fibrosis. Method Plasma samples from 7 healthy volunteers and 27 HBV infected patients with different stages of fibrosis were selected for 2-DIGE proteomic screening. One-way ANOVA analysis was used to assess differences in protein expression among all groups. The alteration was further confirmed by western blotting. Plasma levels of 25 serological variables in 42 healthy volunteers and 68 patients were measured to establish a decision tree for the detection of various stages fibrosis. Result The up-regulated proteins along with fibrosis progress included fibrinogen, collagen, macroglobulin, hemopexin, antitrypsin, prealbumin and thioredoxin peroxidase. The down-regulated proteins included haptoglobin, serotransferrin, CD5 antigen like protein, clusterin, apolipoprotein and leucine-rich alpha-2-glycoprotein. For the discrimination of milder stage fibrosis, the area under curve for Prx II was the highest. Four variables (PT, Pre, HA and Prx II were selected from the 25 variables to construct the decision tree. In a training group, the correct prediction percentage for normal control, milder fibrosis, significant fibrosis and early cirrhosis was 100%, 88.9%, 95.2% and 100%, respectively, with an overall correct percent of 95.9%. Conclusion This study showed that 2-D DIGE-based proteomic analysis of the plasma was helpful in screening for new plasma biomarkers for liver disease. The significant up-expression of Prx II could be used in the early

  3. Predictive value of liver enzymes and inflammatory biomarkers for the severity of liver fibrosis stage in HIV/HCV co-infected patients.

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    Charlotte Charpentier

    Full Text Available OBJECTIVE: The aim of our study was to assess a possible association between plasma inflammatory biomarkers (CRP, IL-6, soluble CD14 and the extent of fibrosis or cirrhosis using a FibroScan® in HIV/HCV co-infected patients. METHODS: This cross-sectional study assessed 60 HIV/HCV co-infected patients who had paired plasma samples and FibroScan® values available. All included patients were controlled for HIV infection (HIV-1 RNA <50 copies/mL and had detectable HCV RNA levels. Levels of three biomarkers were measured in all samples using commercial ELISA kits. Multivariate logistic regression models identified factors associated with the METAVIR stages of fibrosis (F0-F2 vs. F3-F4. RESULTS: In univariate logistic regression analyses, in addition to sCD14 (odds ratio [OR] = 3.23, 95% confidence interval [95%CI] = 1.30-7.97, P = 0.01, aspartate aminotransferase (AST, alanine aminotransferase, platelet counts, and CD4 cell counts were associated with the stage of liver fibrosis and, thus, were introduced into the model. However, only AST (OR = 1.06, 95%CI = 1.02-1.10, P = 0.0009 was independently associated with F3-F4 stage liver fibrosis. CONCLUSIONS: In our study of HIV/HCV co-infected patients, sCD14 plasma level, a biomarker of monocyte activation, was not independently associated with the F3-F4 stage of liver fibrosis. We hypothesize that the higher levels of inflammation markers observed in HIV/HCV co-infected patients, compared to HCV mono-infected patients, prevent this association being observed within this population.

  4. MicroRNA-21 is associated with fibrosis in a rat model of nonalcoholic steatohepatitis and serves as a plasma biomarker for fibrotic liver disease.

    Science.gov (United States)

    Takeuchi-Yorimoto, Ayano; Yamaura, Yu; Kanki, Masayuki; Ide, Tetsuya; Nakata, Ayumi; Noto, Takahisa; Matsumoto, Masahiro

    2016-09-01

    Evidence indicates that hepatic fibrosis is the initial lesion of cirrhosis or hepatocellular carcinoma in diseases such as nonalcoholic steatohepatitis (NASH). To induce NASH, we fed rats a choline-deficient and iron-supplemented L-amino acid-defined (CDAA) diet. Histopathological examination revealed that fibrosis appeared from week 4 and progressed to bridging fibrosis from week 12. Using qRT-PCR assays, we detected increased expression of miR-21, Mmp-9, and Timp-1 in liver that peaked during week 4, when fibrosis was first detected. The expression pattern of miR-21 in plasma paralleled that in liver. Fibrosis tended to be resolved within 12 weeks of a recovery period after 12 weeks of feeding, and the expression of miR-21, Timp-1, and Mmp-9 decreased in liver. Comprehensive analyses of miRNA and mRNA expression in the liver using samples acquired at week 4 detected 16 miRNAs and 11 mRNAs that are mutually-interacting fibrosis-related factors. We therefore conclude that miR-21 was closely associated with fibrosis in a rat model of NASH and has potential as a plasma biomarker for hepatic fibrosis. PMID:27320964

  5. The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis

    DEFF Research Database (Denmark)

    Sandahl, T D; McGrail, R; Møller, H J;

    2016-01-01

    BACKGROUND: Noninvasive identification of significant portal hypertension in patients with cirrhosis is needed in hepatology practice. AIM: To investigate whether the combination of sCD163 as a hepatic inflammation marker and the fibrosis markers of the Enhanced Liver Fibrosis score (ELF) can pre...

  6. Role of the Aspartate Transaminase and Platelet Ratio Index in Assessing Hepatic Fibrosis and Liver Inflammation in Adolescent Patients with HBeAg-Positive Chronic Hepatitis B

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    Yu Zhijian

    2015-01-01

    Full Text Available This study described an index of aspartate aminotransferase-to-platelet ratio index (APRI to assess hepatic fibrosis with limited expense and widespread availability compared to the liver biopsy in adolescent patients with CHB.

  7. Rapamycin ameliorates CCl4-induced liver fibrosis in mice through reciprocal regulation of the Th17/Treg cell balance.

    Science.gov (United States)

    Gu, Lei; Deng, Wen-Sheng; Sun, Xiao-Fei; Zhou, Hong; Xu, Qing

    2016-08-01

    Previous investigations have suggested that the activation of Th17 cells and/or deficiency of regulatory T cells (Tregs) are involved in the pathogenesis of liver fibrosis. The aim of the present study was to investigate the effect of rapamycin on immune responses in a carbon tetrachloride (CCl4)-induced murine liver fibrosis model. Liver fibrosis was induced by intraperitoneal administration with CCl4. Following injection of CCl4, the mice were treated intraperitoneally with rapamycin (1.25 mg/kg/day) for 8 weeks. Hematoxylin and eosin staining and Masson's trichrome staining were used for histological examination. The protein levels of forkhead/winged helix transcription factor P3, retinoic-acid-related orphan receptor (ROR)‑γt in liver tissue were determined by western blotting, the frequency of Th17 and Treg cells in the liver was evaluated by flow cytometry, and a suppression assay was measured by incorporating [3H]‑thymidine. In addition, to explore the effect of Tregs expanded with rapamycin on hepatic stellate cells (HSC), HSCs were co‑cultured with Tregs from rapamycin or phosphate‑buffered saline‑treated mice. It was found that rapamycin treatment led to a significant reduction in the number of Th17 cells and in the expression levels of ROR‑γt in the liver tissues. Simultaneously, the results of the present study showed a significant increase in the frequency of Tregs and a marked enhancement in the expression of forkhead/winged helix transcription factor P3 in the rapamycin‑treated mice. Furthermore, the Tregs in rapamycin‑treated mice had significantly higher suppressive effects, compared with the cells from mice treated with phospphate‑buffered saline. Consequently, rapamycin treatment prevented the development of CCl4-induced hepatic fibrosis, which was shown by its histological appearances. These results suggested that the immunosuppressive effect of rapamycin on liver fibrosis was associated with the suppression of hepatic

  8. Efficacy of Chinese medicine Yi-gan-kang granule in prophylaxis and treatment of liver fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    Xi-Xian Yao; Sbu-Lin Jiang; You-Wei Tang; Dong-Mei Yao; Xin Yao

    2005-01-01

    AIM: To investigate the efficacy of a Chinese medicine, Yi-gan-kang granule (granules for benefiting the liver), in prophylaxis and treatment of liver fibrosis in rats and its possible mechanism.METHODS: One hundred and forty Sprague-Dawley rats were randomly divided into seven groups (20 each): group 1, blank control group without any interference during the study; group 2, CCl4-induced liver fibrosis group; group 3, pig serum-induced liver fibrosis group; group 4, prophylaxis group of CCl4-induced liver fibrosis by Yi-gan-kang, group 5,prophylaxis group of pig serum-induced liver fibrosis by Yi-gan-kang, group 6, treatment group of CCl4-induced liver fibrosis by Yi-gan-kang, group 7, treatment group of CCl4-induced liver fibrosis by Yi-gan-kang. At wk 6, 10, 14 and 20(baseline for CCl4 or big serum induction), five rats in each group were anesthetized and their livers were removed for pathological studies including immunohistochemicalstudies for α-SMA, type Ⅰ collagen and in situ hybridization of tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA of hepatic stellate cells (HSCs). Anti-lipid peroxidation in isolated mitochondria and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay for proliferation and terminal deoxynucleotidyl transferasemedicated dUTP-biotin nick end-labeling (TUNEL), flow cytometry and electron microscopy for apoptosis in isolated HSCs were also studied.RESULTS: The mean number of pseudolobuli at wk 10,14 and 20 in the prophylaxis group was significantly less than that in the control group (P<0.05 or 0.01). The effectof prophylaxis at wk 14 in CCl4 rats and at wk 10 in pig serum-induced rats was much better than that of treatment group (P<0.01). The thickness (in μm) of fibers both in pig serum-induced prophylaxis and in treatment groups at wk 14 and. 20 was significantly less than that in control group (P<0.05). The number of fibers both in prophylaxis and in treatment groups from wk 10 or 14

  9. Disruption of Calcium Signaling in Fibroblasts and Attenuation of Bleomycin-Induced Fibrosis by Nifedipine.

    Science.gov (United States)

    Mukherjee, Subhendu; Ayaub, Ehab A; Murphy, James; Lu, Chao; Kolb, Martin; Ask, Kjetil; Janssen, Luke J

    2015-10-01

    Fibrotic lung disease afflicts millions of people; the central problem is progressive lung destruction and remodeling. We have shown that external growth factors regulate fibroblast function not only through canonical signaling pathways but also through propagation of periodic oscillations in Ca(2+). In this study, we characterized the pharmacological sensitivity of the Ca(2+)oscillations and determined whether a blocker of those oscillations can prevent the progression of fibrosis in vivo. We found Ca(2+) oscillations evoked by exogenously applied transforming growth factor β in normal human fibroblasts were substantially reduced by 1 μM nifedipine or 1 μM verapamil (both L-type blockers), by 2.7 μM mibefradil (a mixed L-/T-type blocker), by 40 μM NiCl2 (selective at this concentration against T-type current), by 30 mM KCl (which partially depolarizes the membrane and thereby fully inactivates T-type current but leaves L-type current intact), or by 1 mM NiCl2 (blocks both L- and T-type currents). In our in vivo study in mice, nifedipine prevented bleomycin-induced fibrotic changes (increased lung stiffness, overexpression of smooth muscle actin, increased extracellular matrix deposition, and increased soluble collagen and hydroxyproline content). Nifedipine had little or no effect on lung inflammation, suggesting its protective effect on lung fibrosis was not due to an antiinflammatory effect but rather was due to altering the profibrotic response to bleomycin. Collectively, these data show that nifedipine disrupts Ca(2+) oscillations in fibroblasts and prevents the impairment of lung function in the bleomycin model of pulmonary fibrosis. Our results provide compelling proof-of-principle that interfering with Ca(2+) signaling may be beneficial against pulmonary fibrosis.

  10. Dasatinib Attenuates Pressure Overload Induced Cardiac Fibrosis in a Murine Transverse Aortic Constriction Model.

    Directory of Open Access Journals (Sweden)

    Sundaravadivel Balasubramanian

    Full Text Available Reactive cardiac fibrosis resulting from chronic pressure overload (PO compromises ventricular function and contributes to congestive heart failure. We explored whether nonreceptor tyrosine kinases (NTKs play a key role in fibrosis by activating cardiac fibroblasts (CFb, and could potentially serve as a target to reduce PO-induced cardiac fibrosis. Our studies were carried out in PO mouse myocardium induced by transverse aortic constriction (TAC. Administration of a tyrosine kinase inhibitor, dasatinib, via an intraperitoneally implanted mini-osmotic pump at 0.44 mg/kg/day reduced PO-induced accumulation of extracellular matrix (ECM proteins and improved left ventricular geometry and function. Furthermore, dasatinib treatment inhibited NTK activation (primarily Pyk2 and Fak and reduced the level of FSP1 positive cells in the PO myocardium. In vitro studies using cultured mouse CFb showed that dasatinib treatment at 50 nM reduced: (i extracellular accumulation of both collagen and fibronectin, (ii both basal and PDGF-stimulated activation of Pyk2, (iii nuclear accumulation of Ki67, SKP2 and histone-H2B and (iv PDGF-stimulated CFb proliferation and migration. However, dasatinib did not affect cardiomyocyte morphologies in either the ventricular tissue after in vivo administration or in isolated cells after in vitro treatment. Mass spectrometric quantification of dasatinib in cultured cells indicated that the uptake of dasatinib by CFb was greater that that taken up by cardiomyocytes. Dasatinib treatment primarily suppressed PDGF but not insulin-stimulated signaling (Erk versus Akt activation in both CFb and cardiomyocytes. These data indicate that dasatinib treatment at lower doses than that used in chemotherapy has the capacity to reduce hypertrophy-associated fibrosis and improve ventricular function.

  11. Curcumin Attenuates Radiation-Induced Inflammation and Fibrosis in Rat Lungs

    OpenAIRE

    Cho, Yu Ji; Yi, Chin Ok; Jeon, Byeong Tak; Jeong, Yi Yeong; Kang, Gi Mun; Lee, Jung Eun; Roh, Gu Seob; Lee, Jong Deog

    2013-01-01

    A beneficial radioprotective agent has been used to treat the radiation-induced lung injury. This study was performed to investigate whether curcumin, which is known to have anti-inflammatory and antioxidant properties, could ameliorate radiation-induced pulmonary inflammation and fibrosis in irradiated lungs. Rats were given daily doses of intragastric curcumin (200 mg/kg) prior to a single irradiation and for 8 weeks after radiation. Histopathologic findings demonstrated that macrophage acc...

  12. Hirsutella sinensis mycelium attenuates bleomycin-induced pulmonary inflammation and fibrosis in vivo.

    Science.gov (United States)

    Huang, Tsung-Teng; Lai, Hsin-Chih; Ko, Yun-Fei; Ojcius, David M; Lan, Ying-Wei; Martel, Jan; Young, John D; Chong, Kowit-Yu

    2015-01-01

    Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1β and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment with HSM inhibits TGF-β1-induced expression of fibronectin and α-SMA in lung fibroblasts. HSM also restores superoxide dismutase expression in TGF-β1-treated lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Furthermore, HSM pretreatment markedly reduces bleomycin-induced lung injury and fibrosis in mice. Accordingly, HSM reduces inflammatory cell accumulation in bronchoalveolar lavage fluid and proinflammatory cytokines levels in lung tissues. The HSM extract also significantly reduces TGF-β1 in lung tissues, and this effect is accompanied by decreased collagen 3α1 and α-SMA levels. Moreover, HSM reduces expression of the NLRP3 inflammasome and P2X7R in lung tissues, whereas it enhances expression of superoxide dismutase. These findings suggest that HSM may be used for the treatment of pulmonary inflammation and fibrosis. PMID:26497260

  13. Pentraxin 3 Is a Predictor for Fibrosis and Arterial Stiffness in Patients with Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Kadir Ozturk

    2016-01-01

    Full Text Available Objective. The aim of the present study was to investigate whether pentraxin 3 (PTX3 can be a new noninvasive marker for prediction of liver fibrosis in patients with NAFLD. We also aimed to evaluate the relationship between PTX3 and atherosclerosis in patients with NAFLD. Method. Fifty-four male patients with biopsy-proven NAFLD and 20 apparently healthy male volunteers were included. PTX3 levels were determined, using an ELISA method (R&D Sysytems, Quantikine ELISA, USA. To detect the presence of subclinical atherosclerosis in NAFLD, measurements of CIMT, FMD, and cf-PWV levels were performed. Results. PTX3 levels in NAFLD patients with fibrosis were higher than both NAFLD patients without fibrosis and controls (P=0.032 and P=0.028, respectively, but there was no difference between controls and NAFLD patients without fibrosis in terms of PTX3 levels (P=0.903. PTX3 levels were strongly correlated with cf-PWV (r=0.359, P=0.003, whereas no significant correlation was found with other atherosclerosis markers, CIMT and FMD. Conclusion. Elevated plasma PTX3 levels are associated with the presence of fibrosis in patients with NAFLD, independently of metabolic syndrome components. This study demonstrated that for the first time there is a close association between elevated PTX3 levels and increased arterial stiffness in patients with NAFLD.

  14. Effect of compound rhodiola sachalinensis A Bor on CCl4-induced liver fibrosis in rats and its probable molecular mechanisms

    Institute of Scientific and Technical Information of China (English)

    Xiao-Ling Wu; Wei-Zheng Zeng; Pi-Long Wang; Chun-Tao Lei; Ming-De Jiang; Xiao-Bin Chen; Yong Zhang; Hui Xu; Zhao Wang

    2003-01-01

    AIM: To explore the anti-fibrotic effect of a traditional Chinese medicine, compound rhodiola sachalinensis A Bor on CCl4-induced liver fibrosis in rats and its probable molecular mechanisms.METHODS: Ninety healthy male SD rats were randomly divided into three groups: normal group (n=10), treatment group of compound rhodiola sachalinensis A Bor (n=40) and CCl4-induced model group (n=40). The liver fibrosis was induced by CCl4 subcutaneous injection. Treatment group was administered with compound rhodiola sachalinensis A Bor (0.5 g/kg) once a day at the same time. Then the activities of several serum fibrosis-associated enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST),N-acetyl-beta-D-glucosaminidase (β-NAG) and the levels of serum procollagen Ⅲ (PCⅢ), collagen IV (CIV), hyaluronic acid (HA) were assayed. The histopathological changes were observed with HE, VG and Masson stain. The expression of TGF-β1 mRNA, α1 (I) mRNA and Na+/Ca2+ exchanger (NCX)mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR) in situ.RESULTS: Compound rhodiola sachalinensis A Bor significantly reduced serum activities of ALT, AST, β-NAG and decreased the levels of PCⅢ, CIV, HA, improved the liver histopathological changes, inhibited the expression of TGFβ1 mRNA, α(I) mRNA and Na+/Ca2+ exchanger mRNA in rats.CONCLUSION: Compound rhodiola sachalinensis A Bor can intervene in CCl4-induced liver fibrosis in rats, in which potential mechanisms may be decreasing the production of TGF-β1, reducing the production of collagen, preventing the activation of hepatic stellate cell (HSC) and inhibiting the expression of TGF-β1 mRNA, α1(I) mRNA and Na+/Ca2+exchanger mRNA.

  15. Protective Effect of the Total Saponins from Rosa laevigata Michx Fruit against Carbon Tetrachloride-Induced Liver Fibrosis in Rats

    OpenAIRE

    Deshi Dong; Lianhong Yin; Yan Qi; Lina Xu; Jinyong Peng

    2015-01-01

    In this study, the protective effect of the total saponins from Rosa laevigata Michx (RLTS) against liver fibrosis induced by carbon tetrachloride (CCl4) in rats was evaluated. The results showed that RLTS significantly rehabilitated the levels of alanine aminotransferase, aspartate aminotransferase, malondialdehyde, glutathione, glutathione peroxidase, catalase, superoxide dismutase, hydroxyproline, α-smooth muscle actin, collagen I, collagen III and fibronectin, which were confirmed using ...