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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 | Feasibility of radical sigmoid colectomy performed as natural orifice translumenal endoscopic surgery (NOTES) using transanal endoscopic microsurgery显示文摘 | M. H. Whiteford P. M. Denk L. L. Swanstr?m | 2007 | Surgical Endoscopy2007，，10： | 3 |
| 3 | Results of a Summer Academy to Increase Minority Student Access to Allied Health and Other Health Professions显示文摘 | Thomson W A Denk J P Miller L M | 1991 | J Allied Health1991，21，1： | 1 |
| 4 | Residual stress fields in surface- treated silicon carbide for space industry-comparison of biaxial and triaxial analysis using differebt X-ray methods显示文摘 | Genzel CH KLAUS M DENKS I | 2005 | Materials Science and Engineering2005，390，： | 1 |
| 5 | Induction of apoptosis in human papillomaviruspositive cancer cells by peptide aptamers targeting the viral E6 oncoprotein 显示文摘 | Butz K Denk C Ullmann A Scheffner M | 2000 | Proc Natl Acad Sci USA2000，97，12： | 1 |
| 6 | Prognostic factors for swallowing rehabilitation following head and neck cancer surgery显示文摘 | Denk D M Swoboda H Schima W | 1997 | Acta Otolaryngol1997，117，5： | 1 |
| 7 | Light efficient, quntum-limited interferometric wavefront estimation by virtual mode sensing显示文摘 | Lauterbach M A Ruckel M Denk M | 2006 | Opt Exrpress2006，14，9： | 1 |
| 8 | Correlation between glaucomatous hemifield scotomas in white---on-white perimetry and blue-on-yellow perimetry using the oculus twinfield perimeter显示文摘 | Denk PO Markovic M Knorr M | 2004 | Klin Monatsbl Augenheilkd2004，221，2： | 1 |
| 9 | Loss of maspin expression contributes to a more invasive potential in malignant melanoma显示文摘 | Denk AE Bettstetter M Wild PJ | | 0，，02： | 1 |
| 10 | Comparison of the effects of medium-chain triacylglycerols, palm oil, and high oleic acid sunflower oil on plasma triacylglycerol fatty acids and lipid and lipoprotein concentrations in humans显示文摘 | Cater N B Heller H J Denke M A | 1997 | American Journal of Clinical Nutrition1997，65，： | 1 |
| 11 | Advantages of recurrent laryngeal nerve identification inthyroidectomy and parathy- roidectomy and the importance of preoperative and postop- erative laryngoscopoc examination in more than 1 000 nerves at risk显示文摘 | Steurer M Passler C Denk D M | 2002 | Laryngoscope2002，112，1： | 1 |
| 12 | Transanal Endoscopic Microsurgical Platform for Natural Orifice Surgery显示文摘 | Denk P M Swanstrom L L Whiteford MH | 2008 | Gastrointest Endosc2008，68，5： | 1 |
| 13 | Regional glycoprotein expression in the chicken lens显示文摘 | Denk PO Breipohl W Naib-Majani W Knorr M | 1997 | Curr Eye Res1997，16，6： | 1 |
| 14 | The IKK- 2/I kappa B alpha/NF- kappa B pathway plays a key role in the regulation of CCR3 and eotaxin - 1 in fibroblasts :a critical link to dermatitis in I kappa B alpha - deficient mice 显示文摘 | Huber M A Denk A Peter R U | 2002 | J Biol Chem2002，277，2： | 1 |
| 15 | Dietary influences on serum lipids and lipoproteins 显示文摘 | GRUNDY S M DENKE M A | 1990 | Journal of Lipid Research1990，31，7： | 1 |
| 16 | Activation of NF-κB via the IκB kinase complex is both essential and sufficient for proinflammatory gene expression in primary endothelial cells显示文摘 | Denk A Goebeler M Sybille S | 2001 | J Biol Chem2001，276，28： | 1 |
| 17 | Differential regulation of expression of PDGF receptors on corneal epithelial cells 显示文摘 | Denk PO Knorr M | 2002 | Ophthalmologe2002，99，1： | 1 |
| 18 | Loss of maspin ex-pression contributes to a more invasive potential in malig-nant melanoma显示文摘 | Denk AE Bettstetter M Wild PJ | | 0，，02： | 1 |
| 19 | ULtrasounD Diagnosis of cervicaL LymPh node tubercuLosis显示文摘 | Winkelbauer F Denk DM Ammann M | 1993 | ULtraschaLL MeD(Eng Abstr)[ArticLe in German]1993，14，1： | 1 |
| 20 | Superimposed high-frequency jet ventilation (SHFJV) for endoscopic laryngotracheal surgery in more than 1 500 patients显示文摘 | Rezaie-Majd A Bigenzahn W Denk D M | 2006 | Br J Anaesth2006，96，5： | 1 |
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