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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 | The Importance of Medial Support in Locked Plating of Proximal Humerus Fractures显示文摘 | Michael J Gardner Yoram Weil Joseph U Barker Bryan T Kelly David L Helfet Dean G Lorich | 2007 | Journal of Orthopaedic Trauma2007，，3： | 2 |
| 3 | The β-lactam antibiotic, ceftriaxone, dramatically improves survival, increases glutamate uptake and induces neurotrophins in stroke显示文摘 | Christa Th?ne-Reineke Christian Neumann Pawel Namsolleck Kristin Schmerbach Maxim Krikov Jan H Schefe Kristin Lucht Heide H?rtnagl Michael Godes Susanne Müller Kay Rumschüssel Heiko Funke-Kaiser Arno Villringer U Muscha Steckelings Thomas Unger | 2008 | Journal of Hypertension2008，，12： | 2 |
| 4 | To catch a killer. What can mycobacterial models teach us about Mycobacterium tuberculosis pathogenesis?显示文摘 | Michael U Shiloh Patricia A DiGiuseppe Champion | 2009 | Current Opinion in Microbiology2009，，1： | 2 |
| 5 | A new SURE approach to im- age denoising: interscale othonormal wavelet thresholding 显示文摘 | Flofian L Thierry B Michael U | 2007 | IEEE Transactions on hnage Processing2007，16，3： | 1 |
| 6 | Studies on nodal integral methods for the convec- tion-diffusion heat equation显示文摘 | MICHAEL E P E DORNING J J RIZWAN U | 2001 | Nuclear Science and Engineering2001，137，3： | 1 |
| 7 | The Phase Transformations in Starch During Gelatiniza- tion:a Liquid Crystalline Approach 显示文摘 | THOMAS A W MICHAEL J G BEMARD U K | 2000 | CarbohydrateResearch2000，328，2： | 1 |
| 8 | cDNA cloning of cyto- plasmic ribosomal protein S7 of winter rye(Secale cereale) and its expression in low-temperature-treated leaves显示文摘 | THOMAS B MICHAEL U JU'RGEN F | 2000 | Biochim Biophys Acta2000，1492，1： | 1 |
| 9 | Capsule contraction syndrome with haptic deformation and flexion显示文摘 | Michael K O′Colmain U Vallance JH | 2010 | J Cataract Refract Surg2010，36，4： | 1 |
| 10 | What is their benefit in the identification of infection, severity assessment, and management of community-acquired pneumonia显示文摘 | Shweta U Michael S Niederman B | 2013 | In fect Dis Clin N Am2013，27，1： | 1 |
| 11 | Effects of fungicide and insecticide mix-tures on apple tree canopy photosynthesis,dark respiration andcarbon economy显示文摘 | Ralf U Michael M B | 2004 | Crop Protection2004，23，： | 1 |
| 12 | Interleukin 26 and Tumor Necrosis Factor2a production after acute psychological stress,exercise,and infused isoproterenol:differential effects and pathways显示文摘 | Marion U G Paul J M Michael R I | 2000 | Psychosomatic Medicine2000，62，： | 1 |
| 13 | Dynamic electric behavior and open-cir- cuit-voltage modeling of LiFePO4-based lithium ion secondarybattefies显示文摘 | Michael A R Dirk U S | 2011 | J Power Sources2011，196，1： | 1 |
| 14 | Molecular analysis of FRIGIDA,a major determinant of natural variation in Arabidopsis flowering time显示文摘 | Johanson U West J Lister C Michaels S Amasino R Dean C | | 0，，5490： | 1 |
| 15 | Endomorphism Spectra of Graphs 显示文摘 | Michael Bottcher Knauer U | 1992 | Discrete Mathematies1992，109，13： | 1 |
| 16 | The membrane form of the type Ⅱ IL-1 receptor accounts for inhibitory function显示文摘 | Detlef N Christian K Michael U | 2000 | J Immunol2000，165，6： | 1 |
| 17 | Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: A U.S.–Canadian multicenter study显示文摘 | Norbert Br?u Rena K. Fox Peiying Xiao Kristen Marks Zeenat Naqvi Lynn E. Taylor Anita Trikha Morris Sherman Mark S. Sulkowski Douglas T. Dieterich Michael O. Rigsby Teresa L. Wright Maria D. Hernandez Mamta K. Jain Gajendra K. Khatri Richard K. Sterling M | 2007 | Journal of Hepatology2007，，4： | 1 |
| 18 | Comparison of the usefulness of the MTT,ATP,and calcein assays to predict the potency of cytotoxic agents in various hum an cancer cell lines显示文摘 | Henrik Mueller Matthias U Kassack Michael Wiese | | 0，，： | 1 |
| 19 | Capsule contraction syndrome with haptic deformation and flexion显示文摘 | Michael K O'Colmain U Vallance JH | 2010 | J Cataract Refract Surg2010，36，： | 1 |
| 20 | Modeling Cryptosporidium parvum oocyst inactivation and bromate in a flow-through ozone contactor treating natural water显示文摘 | Kima J H Michael S E Guntenc U | 2007 | Water Research2007，41，： | 1 |
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