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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 | Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial显示文摘 | Gunnar Folprecht Thomas Gruenberger Wolf O Bechstein Hans-Rudolf Raab Florian Lordick J?rg T Hartmann Hauke Lang Andrea Frilling Jan Stoehlmacher Jürgen Weitz Ralf Konopke Christian Stroszczynski Torsten Liersch Detlev Ockert Thomas Herrmann Eray Goekkurt | 2010 | Lancet Oncology2010，，1： | 3 |
| 3 | A fuzzy vector valued KNN-algorithm for auto- matic outlier detection 显示文摘 | RALF O | 2009 | Applied Soft Computing2009，9，： | 1 |
| 4 | Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition显示文摘 | Jana O Kerstin A Ralf PB | 2004 | Hypertension2004，44，： | 1 |
| 5 | THA 1-oading arising from increased femoral antever stress显示文摘 | Ralf U Kleeman A Markus O | 2003 | Orthop Res2003，21，11： | 1 |
| 6 | Indicators for the sustainability assessment of wastewater treatment systems 显示文摘 | ANNELIES J B HEINZ A P RALF O | 2002 | Urban Water2002，，4： | 1 |
| 7 | From EST to IHC: human antibody pipeline for target research显示文摘 | Christian F Bodo B Ralf O | 2003 | J Immunol Methods2003，75，： | 1 |
| 8 | Cleavage of the SARS Coronavirus Spike Glycoprotein by Airway Proteases Enhances Virus Entry into Human Bronchial Epithelial Cells In Vitro显示文摘 | Yiu-Wing K Yuushi O Hiroshi K Lisa FP Ng Roberto B Ralf A | | 0，，11： | 1 |
| 9 | The Causal Relationship between Real Estate and Stock Markets显示文摘 | John O kunev Patrick Wilson Ralf Zurbruegg | 2000 | Joumal of Real Estate Finance and Economics2000，21，3： | 1 |
| 10 | Ureaplasma urealyticum-harmless commensal or underestimated enemy of human reproduction? 显示文摘 | Thorsten V Ralf O Brigitte P | 2005 | Arch Gynecol Obstet2005，273，3： | 1 |
| 11 | Ureaplasma urealyticum-harm- less commensal or underestimated enemy of human repmducfion 显示文摘 | Thorsten V Ralf O Brigitte P | 2005 | Arch Gynecol Obstet2005，273，3： | 1 |
| 12 | The endo- phytic fungus Piriformospora indica reprograms barley to salt- stress tolerance, disease resistance, and higher yield 显示文摘 | RALF O ACHATZ B RALTRUSCHAT H | 2005 | Pro- ceedings of the National Academy of Science of the United States of America2005，102，13： | 1 |
| 13 | Long-term bond between dual-polymerizing cementing agents and human hard dental tissue显示文摘 | Andree P Ralf B Peter O | 2007 | Dent Mater2007，23，2： | 1 |
| 14 | From EST to IHC: human antibody pipeline for target research显示文摘 | Christian F Bodo B Ralf O | 2003 | J Immunol Methods2003，75，： | 1 |
| 15 | information theoretical probe selection for hybridisation experiments显示文摘 | Ralf Herwig Armin O Schmitt Matthias Steinfath John O'Brien Henrik Seidel Sebastian Meier- Ewert Hans Lehrach and Uwe Radelof | 2000 | Bioinformatics2000，16，10： | 1 |
| 16 | From EST to IHC:human antibody pipeline for target research显示文摘 | Christian F Bodo B Ralf O | 2003 | Immunol Methods2003，75，： | 1 |
| 17 | Potential of a new cw 2 μm laser scalpel for laparoscopic surgery显示文摘 | DIRK T K VERENA O RALF B | 2007 | Medical Laser Application2007，22，： | 1 |
| 18 | Ureap lasma urealyticum-harmlesscommensal or underestimated enemy of human reproduction显示文摘 | Thorsten V Ralf O Brigitte P | 2005 | Arch Gynecol Obstet2005，273，3： | 1 |
| 19 | SSL/TLS session-aware user authentication-or how to effectively thwart the man-in-the-middle 显示文摘 | ROLF O RALF H DAVID B | 2006 | Computer Communications2006，29，： | 1 |
| 20 | Determination of nitrate in municipal waste water by UV spectroscopy显示文摘 | Mikael Karlsson Bo Karlberg Ralf J O Olsson | 1995 | Anal Chim Acta1995，312，： | 1 |
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