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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 | Surgery for Ductal Adenocarcinoma of the Pancreatic Head: Staging, Complications, and Survival after Regional versus Extended Lymphadenectomy显示文摘 | Doris Henne-Bruns Ilka Vogel Jutta Lüttges Günter Kl?ppel Bernd Kremer | 2000 | World Journal of Surgery2000，，5： | 2 |
| 3 | Counting the dead and what they died from,an assessment of the global status of cause of death data显示文摘 | Golin DM Doris MF Mie L | 2005 | Bull WHO2005，83，： | 1 |
| 4 | Ozonation of high strength segregated effluents from a woollen textile dyeing and finishing plant显示文摘 | Ahmet B Ayfer Y Doris L | 2003 | Dyes and Pigments2003，58，： | 1 |
| 5 | In vitro fluconazole sus- ceptibility of 1565 clinical isolates of Candida species evaluated by the disk diffusion method performed using NCCLS M44-A guidelines 显示文摘 | Testore GP Dori L Buonomini AR | 2004 | Diagn Microbiol and Infect Dis2004，50，3： | 1 |
| 6 | Purification of a 41kDa cod-allergenic protein显示文摘 | Galland A V Dory D Pons L | | 0，，： | 1 |
| 7 | From raster to vectors: extracting visual information from line drawings显示文摘 | WENYIN L DORI D | 1999 | Pattern Analysis & Applications1999，2，1： | 1 |
| 8 | Specifying Model Transformations at the Metamodel Level显示文摘 | Sheena R Judson Robert B France Doris L Carver | 2003 | Proc of the Workshop in Software Model Engineering2003，，： | 1 |
| 9 | LES of spatially developing 3D compressible mixing Iayer 显示文摘 | DORIS L CHRISTIAN T PHUOC L T | 2000 | Computational Fluid Mechanics2000，328，7： | 1 |
| 10 | Transient hyperphosphatasemia in children revisited显示文摘 | Dori N Levi L Stam T | 2010 | Pediatr Int2010，52，6： | 1 |
| 11 | Generation of mechanically mixed layers (MMLs) during sliding contact and the effects of lubricant thereon显示文摘 | Young John L Jr Kuhlmann-Wilsdorf Doris Hull R | 2000 | Wear2000，246，12： | 1 |
| 12 | Free amino acid content of chicken muscle from broilers and hens显示文摘 | Julius H M Dawson L E Doris H B | 1965 | Jouenal of Food Science1965，30，3： | 1 |
| 13 | Olfactory and Its Alteration by Nasal Obstruction Rhinitis and Rhinosinusitis显示文摘 | Richard L Dory Anupam Mishra | 2001 | Laryngoscope2001，111，3： | 1 |
| 14 | Hyperbaric oxygen reduces the progression and acelerates the regression of atherescleresis in rabbits 显示文摘 | Kudhodkar BJ Wilson J Laeko A Dory L | 2000 | Arterioscler Thremb Vasc Biol2000，20，6： | 1 |
| 15 | Rates of degradation of malathion by bacteria isolated from aquatic system显示文摘 | Doris F Paris David L Lewis Wolfe N Lee | 1979 | Environmentalscience & Technology1979，9，2： | 1 |
| 16 | A CO2 -switchable polymer brush for reversible capture and release of proteins 显示文摘 | KUMAR S TONG X DORY Y L | 2013 | Chemical Communications2013，49，： | 1 |
| 17 | Sens Actuators B显示文摘 | Guidi V Cardinali G C Dori L | 1998 | 49(1-2):88-921998，49，12： | 1 |
| 18 | Differentiation of green fluorescent protein-labeled embryonic stem cell-derived neural precursor cells into Thy-1-positive neurons and glia after transplantation into adult rat striatum 显示文摘 | Stefan A Doris L Klaus KB | 2000 | J Neurosug2000，93，12： | 1 |
| 19 | Permeated porous silicon for hydrocarbon sensor fabrication显示文摘 | Poggi A Dori L | 1999 | Sensors and Actuators1999，74，： | 1 |
| 20 | Counting the dead and what they died from:an assessment of the global status of cause of death data显示文摘 | Colin D M Doris M F Mie l | 2005 | Bull WHO2005，83，3： | 1 |
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