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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 | 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 |
| 5 | 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 |
| 6 | Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis显示文摘 | Gernot Zollner Peter Fickert Dagmar Silbert Andrea Fuchsbichler Hanns-Ulrich Marschall Kurt Zatloukal Helmut Denk Michael Trauner | 2003 | Journal of Hepatology2003，，6： | 1 |
| 7 | 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 |
| 8 | Mdr2 ( Abcb4 )-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes显示文摘 | Yury Popov Eleonora Patsenker Peter Fickert Michael Trauner Detlef Schuppan | 2005 | Journal of Hepatology2005，，6： | 1 |
| 9 | Farnesoid X Receptor Critically Determines the Fibrotic Response in Mice but Is Expressed to a Low Extent in Human Hepatic Stellate Cells and Periductal Myofibroblasts显示文摘 | Peter Fickert Andrea Fuchsbichler Tarek Moustafa Martin Wagner Gernot Zollner Emina Halilbasic Ulrike St?ger Marco Arrese Margarita Pizarro Nancy Solís Gonzalo Carrasco Alessandra Caligiuri Martina Sombetzki Emil Reisinger Oleksiy Tsybrovskyy Kurt Zatlouk | 2009 | The American Journal of Pathology2009，，6： | 1 |
| 10 | 24- nor Ursodeoxycholic Acid Is Superior to Ursodeoxycholic Acid in the Treatment of Sclerosing Cholangitis in Mdr2 (Abcb4) Knockout Mice显示文摘 | Peter Fickert Martin Wagner Hanns–Ulrich Marschall Andrea Fuchsbichler Gernot Zollner Oleksiy Tsybrovskyy Kurt Zatloukal Jie Liu Michael P. Waalkes Cathleen Cover Helmut Denk Alan F. Hofmann Hartmut Jaeschke Michael Trauner | 2006 | Gastroenterology2006，，2： | 1 |
| 11 | Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases显示文摘 | Michael Trauner Peter Fickert Emina Halilbasic Tarek Moustafa | 2008 | Wiener Medizinische Wochenschrift . 2008 (19-2)2008，，19： | 1 |
| 12 | Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases显示文摘 | Gernol Zoliner Peter Fickert Rainer Zenz | 2001 | Hepatology2001，33，： | 1 |
| 13 | Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice显示文摘 | Min Yang Anup Ramachandran Hui-Min Yan Benjamin L. Woolbright Bryan L. Copple Peter Fickert Michael Trauner Hartmut Jaeschke | 2014 | Toxicology Letters2014，，2： | 1 |
| 14 | Bile acids trigger cholemic nephropathy in common bile‐duct–ligated mice显示文摘 | Peter Fickert Elisabeth Krones Marion J. Pollheimer Andrea Thueringer Tarek Moustafa Dagmar Silbert Emina Halilbasic Min Yang Hartmut Jaeschke Geurt Stokman Rebecca G. Wells Kathrin Eller Alexander R. Rosenkranz Gosta Eggertsen Carsten A. Wagner Cord Lang | 2013 | Hepatology2013，，6： | 1 |
| 15 | 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 |
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