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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 | Haemophilus parasuis: new trends on di- agnosis, epidemiology and control显示文摘 | Simone O Carlos P | 2004 | Veterinary Microbiology2004，99，1： | 1 |
| 3 | Impact of microvascular integrity and local viability on left ventricular remodelling after reperfused acute myocardial infarction显示文摘 | Pascal O Simon M | 2003 | Heart2003，89，4： | 1 |
| 4 | Effects of Acp26 on in vitro and in vivo productivity,pathogenesis and virulence of Autographa californica multiple nucleopolyhedrovirus显示文摘 | Simon O Williams T Caballero P | 2008 | Virus Res2008，136，12： | 1 |
| 5 | Time course and relation to local viability of microvascular function and volume after reperfused acute myocardial infarction显示文摘 | Garot P Pascal O Simon M | 2002 | Am J Cardiol2002，89，12： | 1 |
| 6 | Separation of the urea piperazine derivative of polyisocyanate monomers and prepolymers by normal-phase chromatography显示文摘 | Simon P Moulut O | 1988 | J Liq Chromatogr1988，11，910： | 1 |
| 7 | Roll Press design-influence of force feed systems on compaction显示文摘 | Guigon P Simon O | 2003 | Powder Tech nology2003，130，1： | 1 |
| 8 | Intra esophageal pH profiles and phannacokinetics of pantoprazole and esomeprezole: across over study in patients with gastro - esophageal reflux disease 显示文摘 | Simon B Muller P Paseu O | 2003 | Eur J Gastroenterol Hepatol2003，15，7： | 1 |
| 9 | Microscopy with self-reconstructing beams显示文摘 | Fahrbach F O Simon P Rohrbach A | | 0，，11： | 1 |
| 10 | Haemophilus parasuis:new trends on diagnosis, epidemiology and control 显示文摘 | Simone O Carlos P | 2004 | Vet Microbiol2004，99，1： | 1 |
| 11 | Arabidopsis and tobacco plants ectopically expressing the soybean antiquitin-like ALDH7 gene display enhanced tolerance to drought,salinity,and oxidative stress显示文摘 | Simone M R Maxuel O A Ana P S G Fabio M D Maria C B P Elizabeth P B F | | 0，，： | 1 |
| 12 | Dose and time-dependent effects of cyclooxygenase- 2 inhibition on fracture-healing 显示文摘 | Simon A M O'Connor J P | 2007 | :J Bone Joint Surg Am2007，89，3： | 1 |
| 13 | Effects of different iron, manganese, zinc and copper sources (sulphates, chelates, glycinates) on their bioavailability in early weaned piglets 显示文摘 | Manner K Simon O Schlegel P | 2006 | Tagung Schweine and geflugelemahrung2006，，： | 1 |
| 14 | Programmed cell death during the transition from muhicellular structures to globular embryos in barley androgenesis显示文摘 | DE SIMONE F M GAUSSAND A P ADELA O | 2005 | Planta2005，221，： | 1 |
| 15 | Haemophilus parasuis:new trends on diagnosis,epidemiology and control显示文摘 | Carlos P | 2004 | Vet Microbiol2004，2699，1： | 1 |
| 16 | Overview on Bayesian networks applications for dependability, risk analysis and maintenance areas显示文摘 | Weber P Medina O G Simon C | 2012 | Engineering Applications of Artificial Intelligence2012，25，4： | 1 |
| 17 | Soyasaponins lowered plasma cholesterol and increased fecal bile acids in female golden Syrian hamsters显示文摘 | Lee S O Simons A L Murphy P A | 2005 | Experimental Biology and Medicine2005，230，7： | 1 |
| 18 | Intra esophageal pH profiles and pharmacokinetics of pantoprazole and esomeprazole : across o- ver study in patients with gastro -esophageal reflux disease显示文摘 | Simon B Muller P Pascu O | 2003 | Eur J Gastroenterol Hepatol2003，15，7： | 1 |
| 19 | Haemophilus parasuis: new trends on diagnosis,epidemiology and control显示文摘 | Simone O Carlos P | 2004 | Vet Mierobiol2004，2699，1： | 1 |
| 20 | Overview on Bayesian networks applicatins for dependability, risk analysis and maintenance areas 显示文摘 | Weber P Medina O G Simon C | 2012 | Engineering Applications of Artificial Intelligence2012，25，4： | 1 |
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