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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 | Progression in lacuna stroke is related to elevated acute phase parameters显示文摘 | AUDEBERT H J PELLKOFER T S WIMMER M L | 2004 | Eur Neurol2004，51，3： | 1 |
| 3 | 7-Deoxy-desulfocylindrospermopsin and 7-deoxy-desulfo-12-acetylcylindrospermopsin:Two new cylindrospermopsin analogs isolated from a Thai strain of Cylindrospermopsisraciborskii显示文摘 | Wimmer K M Strangman W K Wright J L C | 2014 | Harmful Algae2014，，20： | 1 |
| 4 | The Role of Associative Strength in Children' s False Memory Illusions显示文摘 | Howe M L Wimmer M C Blease K | 2009 | Memory2009，11，： | 1 |
| 5 | Comparison and evaluation of methods for liver segmentation from CT datasets显示文摘 | Heimann T van Ginneken B Styner MA Arzhaeva Y Aurich V Bauer C Beck A Becket C Beichel R Bekes G Bello F Binnig G Bischof H Bornik A Cashman PM Chi Y Cordova A Dawant BM Fidrich M Furst JD Furukawa D Grenacher L Hornegger J Kainmuller D Kitney RI Kobatake H Lamecker H Lange T Lee J Lennon B Li R Li S Meinzer HP Nemeth G Raicu DS Rau AM van Rikxoort EM Rousson M Rusko L Saddi KA Schmidt G Seghers D Shimizu A Slagmolen P Sorantin E Soza G Susomboon R Waite JM Wimmer A Wolf I | 2009 | IEEE Transactions on Medical Imaging2009，28，8： | 1 |
| 6 | An Associative Activation Theory of Children's and Adults' Memory Illusions 显示文摘 | Howe M L Wimmer M C Gagnon N | 2009 | Journal of Memory and Language2009，60，： | 1 |
| 7 | Intemal ribosomal entry site substitution eliminates neurovirulence in intergeneric polio- virus recombinants 显示文摘 | Gromeier M Alexander L Wimmer E | 1996 | Proc Natl Acad Sci USA1996，93，6： | 1 |
| 8 | Progreession in lacunar stroke is related to elevated acute phase parameters显示文摘 | Audeber H J Pellkofer T S Wimmer M L | 2004 | Eur Neurot2004，51，3： | 1 |
| 9 | Progression in lacunar显示文摘 | Audeber H J Pellkofer T S Wimmer M L | 2004 | Stroke2004，51，3： | 1 |
| 10 | Isotopic and elemental data for tracing the origin of European olive oils显示文摘 | Camin F Larcher R Nicolini G Bontempo L Bertoldi D Perini M Schlicht C Schellenberg A Thomas F Heinrich K Voerkelius S Horacek M Ueckermann H Froeschl H Wimmer B Heiss G Baxter M Rossmann A HoogewerffJ | 2010 | Journal of Agricultural and Food Chemistry2010，58，1： | 1 |
| 11 | Relationship between pain and medial knee joint loading in mild radio- graphic knee osteoarthritis 显示文摘 | Thorp L E Sumner D R Wimmer M A | 2007 | Arthritis Rheum2007，57，7： | 1 |
| 12 | Evaluation of HDRtone mapping methods using essential perceptual attributes 显示文摘 | Cadik M Wimmer M Neumann L | 2008 | Computers &Graphics2008，32，3： | 1 |
| 13 | An associative-activation theory of children's and adults' memory illusions 显示文摘 | HOWE M L WIMMER M C GAGNON N | 2009 | Journal of Memory and Language2009，，60： | 1 |
| 14 | A survey of urban reconstruction显示文摘 | MUSIALSKI P WONKA P A sc liaga D G WIMMER M GOOL L PURGATHOFER W | 2013 | Computer Graphics Forum2013，32，6： | 1 |
| 15 | Relationship between pain and medial knee joint loading in mild radiographic knee osteoar-thritis显示文摘 | THORP L E SUMNER D R WIMMER M A | 2007 | Arthritis care & research2007，57，7： | 1 |
| 16 | Progression in lacunarstroke is related to elevated acute phase parameters 显示文摘 | Audebert H J Pellkofer T S Wimmer M L | 2004 | Eur Neurol2004，，： | 1 |
| 17 | Progression in Lacunar Stroke Is Related to Elevated Acute Phase Parameters显示文摘 | Pellkofer T S Wimmer M L | 2004 | Eur Neurol2004，51，3： | 1 |
| 18 | Combining isotopic signatures of n ( ^87 Sr)/n( ^86 Sr) and light stable elements ( C, N, O, S) with multi-elemental profiling for the authentication of provenance of European cereal samples显示文摘 | Asfaha D G Quatel C R Thomas F Horacek M Wimmer B Heiss G Dekant C Deters-hzelsberger P Hoelzl S Rummel S Brach-Papa C Bocxstaele M V Jamin E Baxter M Heinrich K Kelly S Bertoldi D Bontempo L Camin F Larcher R Perini M Rossmann A Schellenberg A Schlicht C Froeschl H Hoogewerff J Uechkermann H | 2011 | Journal of Cereal Science2011，53，2： | 1 |
| 19 | Evaluation of HDR tone mapping methods using essential perceptual attributes显示文摘 | Cadik M Wimmer M Neumann L | 2008 | Computers & Graphics2008，32，3： | 1 |
| 20 | Re- lationship between pain and medial knee joint loading in mild radiographic knee osteoarthritis 显示文摘 | THORP L E SUMNER D R WIMMER M A | 2007 | Arthritis and Rheumatism2007，57，7： | 1 |
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