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| 1 | Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4^(-/-) mouse model显示文摘AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse model.METHODS: Female and male Abcb4^(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m L IL-1β with or without 2.5 μg/m L Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4^(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4^(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; MannWhitney U-test) and lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P < 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4^(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4^(-/-) mice. | Florian P Reiter Ralf Wimmer Lena Wottke Renate Artmann Jutta M Nagel Manuel O Carranza Doris Mayr Christian Rust Peter Fickert Michael Trauner Alexander L Gerbes Simon Hohenester Gerald U Denk | 2016 | World Journal of Hepatology2016，8，8： | 3 |
| 2 | Hepatotoxicity of NONI juice: Report of two cases显示文摘NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses.No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice.A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acutehepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice. | Vanessa Stadlbauer Peter Fickert Carolin Lackner Jutta Schmerlaib Peter Krisper Michael Trauner Rudolf E Stauber | 2005 | World Journal of Gastroenterology2005，11，30： | 3 |
| 3 | Pathogenesis of primary sclerosing cholangitis显示文摘 | Marion J. Pollheimer Emina Halilbasic Peter Fickert Michael Trauner | 2011 | Best Practice & Research Clinical Gastroenterology2011，，6： | 1 |
| 4 | Assessment of the diagnostic value of dual-energy CT and MRI in the detection of iatrogenically induced injuries of anterior cruciate ligament in a porcine model显示文摘 | Fickert S Niks M Dinter DJ | 2013 | Skeletal Radiol2013，42，3： | 1 |
| 5 | Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 ( Abcb4 ) knockout mice显示文摘 | Peter Fickert Andrea Fuchsbichler Martin Wagner Gernot Zollner Arthur Kaser Herbert Tilg Robert Krause Frank Lammert Cord Langner Kurt Zatloukal Hanns-Ulrich Marschall Helmut Denk Michael Trauner | 2004 | Gastroenterology2004，，1： | 1 |
| 6 | Molecular regulation of hepatobiliary transport systems:clinical implications for understanding and treating cholestasis显示文摘 | Trauner M Wagner M Fickert P | 2005 | J Clin Gastroenterol2005，39，412： | 1 |
| 7 | Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles 显示文摘 | Fickert P Zollner G Fuchsbichler A | 2002 | Gastroenterology2002，123，4： | 1 |
| 8 | Oncosis represents the main type of cell death in mouse models of cholestasis显示文摘 | Fickert P Trauner M Fuchsbichler A | 2005 | J Hepatol2005，42，3： | 1 |
| 9 | Role of nuclear receptors andhepatocyte-enriched transcription factors for Ntcp repression inbiliary obstruction in mouse liver显示文摘 | Zollner G Wagner M Fickert P | 2005 | Am J Physiol GastrointestLiver Physiol2005，289，5： | 1 |
| 10 | Role of nuclear bile acid receptor FXR in adaptive ABC transporter regulation by cholic and ursodexycholic acid in mouse liver kidney and intestine 显示文摘 | Zollner G Fickert P Fuchsbichler A et a1 | 2003 | J Hepatol2003，39，4： | 1 |
| 11 | Oncosis represents the main type of cell death in mouse models of cholestasis 显示文摘 | Fickert P Trauner M Fuchsbichler A | 2005 | J Hepatol2005，42，3： | 1 |
| 12 | Bile acids as regulators of hepatic lipid and glucose metabolism显示文摘 | Trauner M Claudel T Fickert P Moustafa T Wagner M | 2010 | Dig Dis2010，28，1： | 1 |
| 13 | Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice显示文摘 | Fickert P Fuchsbichler A Wagner M | 2004 | Gastroenterology2004，127，1： | 1 |
| 14 | Identification of subpopulations with characteristics of mesenchymal progenitor cells from human osteoarthritic cartilage using triple staining for cell surface markers 显示文摘 | Fickert S Fiedler J Brenner RE | 2004 | Arthritis Res Ther2004，6，： | 1 |
| 15 | MDR3 (ABCB4) defects:a paradigm for the genetics of adult cholestatic syndromes显示文摘 | Tranner M Fickert P Wagner M | | 0，，01： | 1 |
| 16 | Mechanisms of disease : mecha- nisms and clinical implications of cholestasis in sepsis 显示文摘 | Geier A Fickert P Tranner M | 2006 | Nat Clin Pract Gastroenterol Hepatol2006，3，10： | 1 |
| 17 | Mechanisms of disease: mechan- isms and clinical implications of cholestasis in sepsis显示文摘 | Geier A Fickert P Trauner M | 2006 | Nat Clin Pract Gastroenterol Hepatol2006，3，10： | 1 |
| 18 | Hepatobiliary transporter expression in percutaneous liver biopsies of patients with choles- tatic liver diseases 显示文摘 | Zollner G Fickert P Zenz R | 2001 | Hepatology2001，33，3： | 1 |
| 19 | Chronic cholestatic liver diseases: Clues from histopathology for pathogenesis显示文摘 | Marion J. Pollheimer Peter Fickert Bruno Stieger | 2014 | Molecular Aspects of Medicine2014，，： | 1 |
| 20 | Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases显示文摘 | Zollner G Fickert P Zenz R | 2001 | Hepatology2001，33，3： | 1 |
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