Experimental liver fibrosis research: update on animal models, legal issues and translational aspects

Fibrogenesis & Tissue Repair

Ralf Weiskirchen²  Jonel Trebicka⁴  Christian Trautwein³  René Tolba¹  Frank Tacke³  Konrad Streetz³  David Scholten³  Tilman Sauerbruch⁴  Tom Luedde³  Christian Liedtke³ 

[1] Institute of Laboratory Animal Science, RWTH University Hospital Aachen, Aachen, Germany;Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Aachen D-52074, Germany;Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany;Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany

关键词: Translational medicine;    Liver immunology;    Hepatocellular carcinoma;    Hepatic stellate cells;    Fibrosis;    EU-Directive 2010/63;    Cirrhosis;    Cholestasis;    Animal welfare;    Animal models;   

Others  :  802889
DOI  :  10.1186/1755-1536-6-19

 received in 2013-08-09, accepted in 2013-09-11,  发布年份 2013

【 摘 要 】

Liver fibrosis is defined as excessive extracellular matrix deposition and is based on complex interactions between matrix-producing hepatic stellate cells and an abundance of liver-resident and infiltrating cells. Investigation of these processes requires in vitro and in vivo experimental work in animals. However, the use of animals in translational research will be increasingly challenged, at least in countries of the European Union, because of the adoption of new animal welfare rules in 2013. These rules will create an urgent need for optimized standard operating procedures regarding animal experimentation and improved international communication in the liver fibrosis community. This review gives an update on current animal models, techniques and underlying pathomechanisms with the aim of fostering a critical discussion of the limitations and potential of up-to-date animal experimentation. We discuss potential complications in experimental liver fibrosis and provide examples of how the findings of studies in which these models are used can be translated to human disease and therapy. In this review, we want to motivate the international community to design more standardized animal models which might help to address the legally requested replacement, refinement and reduction of animals in fibrosis research.

【 授权许可】

   
2013 Liedtke et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH: The morphology of cirrhosis: definition, nomenclature, and classification. Bull World Health Organ 1977, 55:521-540.
• [2]Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH: The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 1978, 31:395-414.
• [3]Hernandez-Gea V, Friedman SL: Pathogenesis of liver fibrosis. Annu Rev Pathol 2011, 6:425-456.
• [4]Gressner AM, Weiskirchen R: Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-β as major players and therapeutic targets. J Cell Mol Med 2006, 10:76-99.
• [5]Friedman SL: Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008, 88:125-172.
• [6]Tacke F, Weiskirchen R: Update on hepatic stellate cells: pathogenic role in liver fibrosis and novel isolation techniques. Expert Rev Gastroenterol Hepatol 2012, 6:67-80.
• [7]Ramachandran P, Iredale JP: Liver fibrosis: a bidirectional model of fibrogenesis and resolution. QJM 2012, 105:813-817.
• [8]Consolo M, Amoroso A, Spandidos DA, Mazzarino MC: Matrix metalloproteinases and their inhibitors as markers of inflammation and fibrosis in chronic liver disease. Int J Mol Med 2009, 24:143-152.
• [9]Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R: Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 2007, 282:23337-23347.
• [10]Wells RG: The epithelial-to-mesenchymal transition in liver fibrosis: here today, gone tomorrow? Hepatology 2010, 51:737-740.
• [11]Scholten D, Weiskirchen R: Questioning the challenging role of epithelial-to-mesenchymal transition in liver injury. Hepatology 2011, 53:1048-1051.
• [12]Chu AS, Diaz R, Hui JJ, Yanger K, Zong Y, Alpini G, Stanger BZ, Wells RG: Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis. Hepatology 2011, 53:1685-1695.
• [13]Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M, Brenner DA: Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 2010, 51:1027-1036.
• [14]Li Y, Wang J, Asahina K: Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial-mesenchymal transition in liver injury. Proc Natl Acad Sci U S A 2013, 110:2324-2329.
• [15]Zimmermann HW, Tacke F: Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm Allergy Drug Targets 2011, 10:509-536.
• [16]Herrmann J, Gressner AM, Weiskirchen R: Immortal hepatic stellate cell lines: useful tools to study hepatic stellate cell biology and function? J Cell Mol Med 2007, 11:704-722.
• [17]Hooijmans CR, Leenaars M, Ritskes-Hoitinga M: A gold standard publication checklist to improve the quality of animal studies, to fully integrate the three Rs, and to make systematic reviews more feasible. Altern Lab Anim 2010, 38:167-182.
• [18]Russell WMS, Burch R: The Principles of Humane Experimental Technique. London: Methuen; 1959.
• [19]Rollin BE: The regulation of animal research and the emergence of animal ethics: a conceptual history. Theor Med Bioeth 2006, 27:285-304.
• [20]Rollin BE: Animal research: a moral science: Talking Point on the use of animals in scientific research. EMBO Rep 2007, 8:521-525.
• [21]Gannon F: Animal rights, human wrongs? Introduction to the Talking Point on the use of animals in scientific research. EMBO Rep 2007, 8:519-520.
• [22]Scholten D, Österreicher CH, Scholten A, Iwaisako K, Gu G, Brenner DA, Kisseleva T: Genetic labeling does not detect epithelial-to-mesenchymal transition (EMT) of cholangiocytes in liver fibrosis in mice. Gastroenterology 2010, 139:987-998.
• [23]Kirkland JG, Godfrey CB, Garrett R, Kakar S, Yeh BM, Corvera CU: Reversible surgical model of biliary inflammation and obstructive jaundice in mice. J Surg Res 2010, 164:221-227.
• [24]Heinrich S, Georgiev P, Weber A, Vergopoulos A, Graf R, Clavien PA: Partial bile duct ligation in mice: a novel model of acute cholestasis. Surgery 2011, 149:445-451.
• [25]Aller MA, Arias N, Prieto I, Agudo S, Gilsanz C, Lorente L, Arias JL, Arias J: A half century (1961–2011) of applying microsurgery to experimental liver research. World J Hepatol 2012, 4:199-208.
• [26]Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E: The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Semin Liver Dis 2010, 30:134-146.
• [27]Mauad TH, van Nieuwkerk CMJ, Dingemans KP, Smit JJM, Schinkel AH, Notenboom RGE, van den Berg Weerman MA, Verkruisen RP, Groen AK, Oude Elferink RPJ, van der Valk MA, Borst P, Offerhaus GJA: Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol 1994, 145:1237-1245.
• [28]Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, Ridgway WM, Ansari AA, Coppel RL, Li MO, Flavell RA, Kronenberg M, Mackay IR, Gershwin ME: Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-β receptor II dominant-negative mice. J Immunol 2006, 177:1655-1660.
• [29]Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH, Yang GX, Ridgway W, Ueno Y, Ansari AA, Coppel RL, Mackay IR, Gershwin ME: IL-2 receptor α-/- mice and the development of primary biliary cirrhosis. Hepatology 2006, 44:1240-1249.
• [30]Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I, Oude Elferink RP, Prieto J, Medina JF: Ae2a, b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology 2008, 134:1482-1493.
• [31]Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R, Peterson LB, Leung PSC, Cheng C, Mackay IR, Gershwin ME, Ridgway WM: NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006, 203:1209-1219.
• [32]Wu SJ, Yang YH, Tsuneyama K, Leung PS, Illarionov P, Gershwin ME, Chuang YH: Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology 2011, 53:915-925.
• [33]Fickert P, Stöger U, Fuchsbichler A, Moustafa T, Marschall HU, Weighlein AH, Tsybrovskyy O, Jaeschke H, Zatloukal K, Denk H, Trauner M: A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. Am J Pathol 2007, 171:525-536.
• [34]Eliakim M, Eisner M, Ungar H: Experimental intrahepatic obstructive jaundice following ingestion of alphanaphthyl-iso-thiocyanate. Bull Res Counc Isr Sect E Exp Med 1959, 8E:7-17.
• [35]Dietrich CG, de Waart DR, Ottenhoff R, Schoots IG, Elferink RP: Increased bioavailability of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in MRP2-deficient rats. Mol Pharmacol 2001, 59:974-980.
• [36]Sullivan BP, Cui W, Copple BL, Luyendyk JP: Early growth response factor-1 limits biliary fibrosis in a model of xenobiotic-induced cholestasis in mice. Toxicol Sci 2012, 126:267-274.
• [37]Connolly AK, Price SC, Connelly JC, Hinton RH: Early changes in bile duct lining cells and hepatocytes in rats treated with α-naphthylisothiocyanate. Toxicol Appl Pharmacol 1988, 93:208-219.
• [38]Popov Y, Patsenker E, Stickel F, Jonczyk A, Goodman SL, Schuppan D: Integrin αvβ6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol 2008, 48:453-464.
• [39]Sullivan BP, Weinreb PH, Violette SM, Luyendyk JP: The coagulation system contributes to αVβ6 integrin expression and liver fibrosis induced by cholestasis. Am J Pathol 2010, 177:2837-2849.
• [40]Domenicali M, Caraceni P, Giannone F, Baldassarre M, Lucchetti G, Quarta C, Patti C, Catani L, Nanni C, Lernoli RM, Bernardi M: A novel model of CCl4-induced cirrhosis with ascites in the mouse. J Hepatol 2009, 51:991-999.
• [41]McLean EK, McLean AEM, Sutton PM: Instant cirrhosis: an improved method for producing cirrhosis of the liver in rats by simultaneous administration of carbon tetrachloride and phenobarbitone. Br J Exp Pathol 1969, 50:502-506.
• [42]Hillebrandt S, Goos C, Matern S, Lammert F: Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15. Gastroenterology 2002, 123:2041-2051.
• [43]Slater TF, Cheeseman KH, Ingold KU: Carbon tetrachloride toxicity as a model for studying free-radical mediated liver injury. Philos Trans R Soc Lond B Biol Sci 1985, 311:633-645.
• [44]Shi J, Aisaki K, Ikawa Y, Wake K: Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am J Pathol 1998, 153:515-525.
• [45]Heindryckx F, Colle I, van Vlierberghe H: Experimental mouse models for hepatocellular carcinoma research. Int J Exp Pathol 2009, 90:367-386.
• [46]Nevzorova YA, Bangen JM, Hu W, Haas U, Weiskirchen R, Gassler N, Huss S, Tacke F, Sicinski P, Trautwein C, Liedtke C: Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice. Hepatology 2012, 56:1140-1149.
• [47]Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJ: Mechanisms of spontaneous resolution of rat liver fibrosis: hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998, 102:538-549.
• [48]Kisseleva T, Cong M, Paik Y, Scholten D, Jiang C, Benner C, Iwaisako K, Moore-Morris T, Scott B, Tsukamoto H, Evans SM, Dillmann W, Glass C, Brenner DA: Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A 2012, 109:9448-9453.
• [49]Dashti H, Jeppsson B, Hägerstrand I, Hultberg B, Srinivas U, Abdulla M, Bengmark S: Thioacetamide- and carbon tetrachloride-induced liver cirrhosis. Eur Surg Res 1989, 21:83-91.
• [50]Müller A, Machnik F, Zimmermann T, Schubert H: Thioacetamide-induced cirrhosis-like liver lesions in rats: usefulness and reliability of this animal model. Exp Pathol 1988, 34:229-236.
• [51]Muñoz Torres E, Paz Bouza JI, López Bravo A, Abad Hernández MM, Carrascal Marino E: Experimental thioacetamide-induced cirrhosis of the liver. Histol Histopathol 1991, 6:95-100.
• [52]Hajovsky H, Hu G, Koen Y, Sarma D, Cui W, Moore DS, Staudinger JL, Hanzlik RP: Metabolism and toxicity of thioacetamide and thioacetamide S-oxide in rat hepatocytes. Chem Res Toxicol 2012, 25:1955-1963.
• [53]Chilakapati J, Korrapati MC, Shankar K, Hill RA, Warbritton A, Latendresse JR, Mehendale HM: Role of CYP2E1 and saturation kinetics in the bioactivation of thioacetamide: effects of diet restriction and phenobarbital. Toxicol Appl Pharmacol 2007, 219:72-84.
• [54]Kang JS, Wanibuchi H, Morimura K, Wongpoomchai R, Chusiri Y, Gonzalez FJ, Fukushima S: Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity. Toxicol Appl Pharmacol 2008, 228:295-300.
• [55]Ding Z, Zhuo L: Attenuation of hepatic fibrosis by an imidazolium salt in thioacetamide-induced mouse model. J Gastroenterol Hepatol 2013, 28:188-201.
• [56]Zaldivar MM, Pauels K, von Hundelshausen P, Erres ML, Schmitz P, Bornemann J, Kowalska MA, Gassler N, Streetz KL, Weiskirchen R, Trautwein C, Weber C, Wasmuth HE: CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology 2010, 51:1345-1353.
• [57]Salguero Palacios R, Roderfeld M, Hemmann S, Rath T, Atanasova S, Tschuschner A, Gressner OA, Weiskirchen R, Graf J, Roeb E: Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice. Lab Invest 2008, 88:1192-1203.
• [58]Jenkins SA, Grandison A, Baxter JN, Day DW, Taylor I, Shields R: A dimethylnitrosamine-induced model of cirrhosis and portal hypertension in the rat. J Hepatol 1985, 1:489-499.
• [59]Kitamura K, Nakamoto Y, Akiyama M, Fujii C, Kondo T, Kobayashi K, Kaneko S, Mukaida N: Pathogenic roles of tumor necrosis factor receptor p55-mediated signals in dimethylnitrosamine-induced murine liver fibrosis. Lab Invest 2002, 82:571-583.
• [60]Farrell GC, Larter CZ: Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006, 43(2 Suppl 1):S99-S112.
• [61]Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M: Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003, 37:917-923.
• [62]Day CP, James OF: Steatohepatitis: a tale of two "hits"? Gastroenterology 1998, 114:842-845.
• [63]Ribeiro PS, Cortez-Pinto H, Solá S, Castro RE, Ramalho RM, Baptista A, Moura MC, Carmilo ME, Rodrigues CM: Hepatocyte apoptosis, expression of death receptors, and activation of NF-κB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am J Gastroenterol 2004, 99:1708-1717.
• [64]Singh R, Czaja MJ: Regulation of hepatocyte apoptosis by oxidative stress. J Gastroenterol Hepatol 2007, 22(Suppl 1):S45-S48.
• [65]Pessayre D, Berson A, Fromenty B, Mansouri A: Mitochondria in steatohepatitis. Semin Liver Dis 2001, 21:57-69.
• [66]Browning JD, Horton JD: Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004, 114:147-152.
• [67]Zou C, Ma J, Wang X, Guo L, Zhu Z, Stoops J, Eaker AE, Johnson CJ, Strom S, Michalopoulos GK, DeFrances MC, Zarnegar R: Lack of Fas antagonism by Met in human fatty liver disease. Nat Med 2007, 13:1078-1085.
• [68]Dixon LJ, Berk M, Thapaliya S, Papouchado BG, Feldstein AE: Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis. Lab Invest 2012, 92:713-723.
• [69]Hebbard L, George J: Animal models of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2011, 8:35-44.
• [70]Nishikawa S, Yasoshima A, Doi K, Nakayama H, Uetsuka K: Involvement of sex, strain and age factors in high fat diet-induced obesity in C57BL/6J and BALB/cA mice. Exp Anim 2007, 56:263-272.
• [71]Xu ZJ, Fan JG, Ding XD, Qiao L, Wang GL: Characterization of high-fat, diet-induced, non-alcoholic steatohepatitis with fibrosis in rats. Dig Dis Sci 2010, 55:931-940.
• [72]Romestaing C, Piquet MA, Bedu E, Rouleau V, Dautresme M, Hourmand-Ollivier I, Filippi C, Duchamp C, Sibille B: Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutr Metab (Lond) 2007, 4:4.
• [73]Lieber CS, Jones DP, Decarli LM: Effects of prolonged ethanol intake: production of fatty liver despite adequate diets. J Clin Invest 1965, 44:1009-1021.
• [74]Gao B, Bataller R: Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011, 141:1572-1585.
• [75]Bertola A, Mathews S, Ki SH, Wang H, Gao B: Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc 2013, 8:627-637.
• [76]Sahai A, Malladi P, Pan X, Paul R, Melin-Aldana H, Green RM, Whitington PF: Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol Gastrointest Liver Physiol 2004, 287:G1035-G1043.
• [77]Dela Peña A, Leclercq I, Field J, George J, Jones B, Farrell G: NF-κB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. Gastroenterology 2005, 129:1663-1674.
• [78]Vance JE, Vance DE: The role of phosphatidylcholine biosynthesis in the secretion of lipoproteins from hepatocytes. Can J Biochem Cell Biol 1985, 63:870-881.
• [79]Yao ZM, Vance DE: The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J Biol Chem 1988, 263:2998-3004.
• [80]Rizki G, Arnaboldi L, Gabrielli B, Yan J, Lee GS, Ng RK, Turner SM, Badger TM, Pitas RE, Maher JJ: Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1. J Lipid Res 2006, 47:2280-2290.
• [81]Larter CZ, Yeh MM, Williams J, Bell-Anderson KS, Farrell GC: MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes. J Hepatol 2008, 49:407-416.
• [82]Oz HS, Im HJ, Chen TS, de Villiers WJ, McClain CJ: Glutathione-enhancing agents protect against steatohepatitis in a dietary model. J Biochem Mol Toxicol 2006, 20:39-47.
• [83]Rangnekar AS, Lammert F, Igolnikov A, Green RM: Quantitative trait loci analysis of mice administered the methionine-choline deficient dietary model of experimental steatohepatitis. Liver Int 2006, 26:1000-1005.
• [84]Galastri S, Zamara E, Milani S, Novo E, Provenzano A, Delogu W, Vizzutti F, Sutti S, Locatelli I, Navari N, Vivoli E, Caligiuri A, Pinzani M, Albano E, Parola M, Marra F: Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis. Clin Sci (Lond) 2012, 123:459-471.
• [85]Kirsch R, Clarkson V, Shephard EG, Marais DA, Jaffer MA, Woodburne VE, Kirsch RE, de la M Hall P: Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J Gastroenterol Hepatol 2003, 18:1272-1282.
• [86]Leclercq IA, Farrell GC, Schriemer R, Robertson GR: Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol 2002, 37:206-213.
• [87]Rinella ME, Green RM: The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol 2004, 40:47-51.
• [88]Fujita K, Nozaki Y, Yoneda M, Wada K, Takahashi H, Kirikoshi H, Inamori M, Saito S, Iwasaki T, Terauchi Y, Maeyama S, Nakajima A: Nitric oxide plays a crucial role in the development/progression of nonalcoholic steatohepatitis in the choline-deficient, L-amino acid-defined diet-fed rat model. Alcohol Clin Exp Res 2010, 34(Suppl 1):S18-S24.
• [89]Veteläinen R, van Vliet A, van Gulik TM: Essential pathogenic and metabolic differences in steatosis induced by choline or methione-choline deficient diets in a rat model. J Gastroenterol Hepatol 2007, 22:1526-1533.
• [90]Kroy DC, Beraza N, Tschaharganeh DF, Sander LE, Erschfeld S, Giebeler A, Liedtke C, Wasmuth HE, Trautwein C, Streetz KL: Lack of interleukin-6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice. Hepatology 2010, 51:463-473.
• [91]Lindström P: The physiology of obese-hyperglycemic mice [ob/ob mice]. ScientificWorldJournal 2007, 7:666-685.
• [92]Brix AE, Elgavish A, Nagy TR, Gower BA, Rhead WJ, Wood PA: Evaluation of liver fatty acid oxidation in the leptin-deficient obese mouse. Mol Genet Metab 2002, 75:219-226.
• [93]Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM: Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A 1997, 94:2557-2562.
• [94]Honda H, Ikejima K, Hirose M, Yoshikawa M, Lang T, Enomoto N, Kitamura T, Takei Y, Saton N: Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology 2002, 36:12-21.
• [95]Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y, Sato N: Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology 2001, 34:288-297.
• [96]Bataller R, Brenner DA: Liver fibrosis. J Clin Invest 2005, 115:209-218.
• [97]Adams DH, Ju C, Ramaiah SK, Uetrecht J, Jaeschke H: Mechanisms of immune-mediated liver injury. Toxicol Sci 2010, 115:307-321.
• [98]Tiegs G: Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury [in English and German]. Z Gastroenterol 2007, 45:63-70.
• [99]Christen U, Hintermann E, Jaeckel E: New animal models for autoimmune hepatitis. Semin Liver Dis 2009, 29:262-272.
• [100]Hardtke-Wolenski M, Fischer K, Noyan F, Schlue J, Falk CS, Stahlhut M, Woller N, Kuehnel F, Taubert R, Manns MP, Jaeckel E: Genetic predisposition and environmental danger signals initiate chronic autoimmune hepatitis driven by CD4+ T cells. Hepatology 2013, 58:718-728.
• [101]Mederacke I: Liver fibrosis: mouse models and relevance in human liver diseases [in English and German]. Z Gastroenterol 2013, 51:55-62.
• [102]Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, López CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG, Inflammation and Host Response to Injury, Large Scale Collaborative Research Program: Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 2013, 110:3507-3512.
• [103]Racanelli V, Rehermann B: The liver as an immunological organ. Hepatology 2006, 43(2 Suppl 1):S54-S62.
• [104]Zimmermann HW, Seidler S, Gassler N, Nattermann J, Luedde T, Trautwein C, Tacke F: Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis. PLoS One 2011, 6:e21381.
• [105]Ingersoll MA, Spanbroek R, Lottaz C, Gautier EL, Frankenberger M, Hoffmann R, Lang R, Haniffa M, Collin M, Tacke F, Habenicht AJ, Ziegler-Heitbrock L, Randolph GJ: Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 2010, 115:e10-e19.
• [106]Weber S, Gressner OA, Hall R, Grünhage F, Lammert F: Genetic determinants in hepatic fibrosis: from experimental models to fibrogenic gene signatures in humans. Clin Liver Dis 2008, 12:747-757.
• [107]Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, Romanelli RG, Laffi G, Gentilini P: Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol 1998, 152:423-430.
• [108]Marra F, Romanelli RG, Giannini C, Failli P, Pastacaldi S, Arrighi MC, Pinzani M, Laffi G, Montalto P, Gentilini P: Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells. Hepatology 1999, 29:140-148.
• [109]Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N, Huss S, Klussmann S, Eulberg D, Luedde T, Trautwein C, Tacke F: Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 2012, 61:416-426.
• [110]Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F: Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009, 50:261-274.
• [111]Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, Schwabe RF, Brenner DA: CCR2 promotes hepatic fibrosis in mice. Hepatology 2009, 50:185-197.
• [112]Mitchell C, Couton D, Couty JP, Anson M, Crain AM, Bizet V, Rénia L, Pol S, Mallet V, Gilgenkrantz H: Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am J Pathol 2009, 174:1766-1775.
• [113]Liaskou E, Zimmermann HW, Li KK, Oo YH, Suresh S, Stamataki Z, Qureshi O, Lalor PF, Shaw J, Syn WK, Curbishley SM, Adams DH: Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 2013, 57:385-398.
• [114]Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zernecke A, Tischendorf JJ, Luedde T, Weiskirchen R, Trautwein C, Tacke F: Functional contribution of elevated circulating and hepatic non-classical CD14+CD16+ monocytes to inflammation and human liver fibrosis. PLoS One 2010, 5:e11049.
• [115]Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, Ramachandran P, Van Deemter M, Hume DA, Iredale JP, Forbes SJ: Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 2011, 53:2003-2015.
• [116]Houlihan DD, Hopkins LJ, Suresh SX, Armstrong MJ, Newsome PN: Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology 2011, 54:1891-1892.
• [117]De Minicis S, Seki E, Uchinami H, Kluwe J, Zhang Y, Brenner DA, Schwabe RF: Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology 2007, 132:1937-1946.
• [118]Seki E, De Minicis S, Österreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF: TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat Med 2007, 13:1324-1332.
• [119]Gur C, Doron S, Kfir-Erenfeld S, Horwitz E, Abu-Tair L, Safadi R, Mandelboim O: NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 2012, 61:885-893.
• [120]Muhanna N, Abu-Tair L, Doron S, Amer J, Azzeh M, Mahamid M, Friedman S, Safadi R: Amelioration of hepatic fibrosis by NK cell activation. Gut 2011, 60:90-98.
• [121]Safadi R, Ohta M, Alvarez CE, Fiel MI, Bansal M, Mehal WZ, Friedman SL: Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes. Gastroenterology 2004, 127:870-882.
• [122]Bonacchi A, Petrai I, Defranco RM, Lazzeri E, Annunziato F, Efsen E, Cosmi L, Romagnani P, Milani S, Failli P, Batignani G, Liotta F, Laffi G, Pinzani M, Gentilini P, Marra F: The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 2003, 125:1060-1076.
• [123]Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH: Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999, 163:6236-6243.
• [124]Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F: Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 1998, 187:129-134.
• [125]Seki E, De Minicis S, Gwak GY, Kluwe J, Inokuchi S, Bursill CA, Llovet JM, Brenner DA, Schwabe RF: CCR1 and CCR5 promote hepatic fibrosis in mice. J Clin Invest 2009, 119:1858-1870.
• [126]Wasmuth HE, Lammert F, Zaldivar MM, Weiskirchen R, Hellerbrand C, Scholten D, Berres ML, Zimmermann H, Streetz KL, Tacke F, Hillebrandt S, Schmitz P, Keppeler H, Berg T, Dahl E, Gassler N, Friedman SL, Trautwein C: Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology 2009, 137:309-319. 319.e301–319.e303
• [127]Oo YH, Banz V, Kavanagh D, Liaskou E, Withers DR, Humphreys E, Reynolds GM, Lee-Turner L, Kalia N, Hubscher SG, Klenerman P, Eksteen B, Adams DH: CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J Hepatol 2012, 57:1044-1051.
• [128]Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M, Iwaisako K, Liu X, Zhang M, Österreicher CH, Stickel F, Ley K, Brenner DA, Kisseleva T: Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012, 143:765-776. e776.e1–776.e3
• [129]Hammerich L, Heymann F, Tacke F: Role of IL-17 and Th17 cells in liver diseases. Clin Dev Immunol 2011, 2011:345803.
• [130]Rajewsky K, Gu H, Kühn R, Betz UA, Müller W, Roes J, Schwenk F: Conditional gene targeting. J Clin Invest 1996, 98:600-603.
• [131]Kellendonk C, Opherk C, Anlag K, Schütz G, Tronche F: Hepatocyte-specific expression of Cre recombinase. Genesis 2000, 26:151-153.
• [132]Streetz KL, Tacke F, Leifeld L, Wüstefeld T, Graw A, Klein C, Kamino K, Spengler U, Kreipe H, Kubicka S, Müller W, Manns MP, Trautwein C: Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases. Hepatology 2003, 38:218-229.
• [133]Hernández-Gea V, Ghiassi-Nejad Z, Rozenfeld R, Gordon R, Fiel MI, Yue Z, Czaja MJ, Friedman SL: Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 2012, 142:938-946.
• [134]Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, Zhao Z, Thapar V, Joyce JA, Krizhanovsky V, Lowe SW: Non-cell-autonomous tumor suppression by p53. Cell 2013, 153:449-460.
• [135]Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF: Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 2012, 143:1073-1083. 1083.e1–1083.e22
• [136]Tacke F: Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo. Fibrogenesis Tissue Repair 2012, 5(Suppl 1):S27.
• [137]Clausen BE, Burkhardt C, Reith W, Renkawitz R, Förster I: Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res 1999, 8:265-277.
• [138]Copple BL, Kaska S, Wentling C: Hypoxia-inducible factor activation in myeloid cells contributes to the development of liver fibrosis in cholestatic mice. J Pharmacol Exp Ther 2012, 341:307-316.
• [139]Zhang Z, Zhang F, An P, Guo X, Shen Y, Tao Y, Wu Q, Zhang Y, Yu Y, Ning B, Nie G, Knutson MD, Anderson GJ, Wang F: Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 2011, 118:1912-1922.
• [140]Schaller E, Macfarlane AJ, Rupec RA, Gordon S, McKnight AJ, Pfeffer K: Inactivation of the F4/80 glycoprotein in the mouse germ line. Mol Cell Biol 2002, 22:8035-8043.
• [141]Li F, Wang JY: Targeted delivery of drugs for liver fibrosis. Expert Opin Drug Deliv 2009, 6:531-541.
• [142]Poelstra K, Schuppan D: Targeted therapy of liver fibrosis/cirrhosis and its complications. J Hepatol 2011, 55:726-728.
• [143]Popov Y, Schuppan D: Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 2009, 50:1294-1306.
• [144]Beljaars L, Olinga P, Molema G, de Bleser P, Geerts A, Groothuis GM, Meijer DK, Poelstra K: Characteristics of the hepatic stellate cell-selective carrier mannose 6-phosphate modified albumin (M6P28-HSA). Liver 2001, 21:320-328.
• [145]Klein S, van Beuge MM, Granzow M, Beljaars L, Schierwagen R, Kilic S, Heidari I, Huss S, Sauerbruch T, Poelstra K, Trebicka J: HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects. J Hepatol 2012, 57:1220-1227.
• [146]Kinnman N, Goria O, Wendum D, Gendron MC, Rey C, Popon R, Housset C: Hepatic stellate cell proliferation is an early platelet-derived growth factor-mediated cellular event in rat cholestatic liver injury. Lab Invest 2001, 81:1709-1716.
• [147]Bansal R, Prakash J, de Ruijter M, Beljaars L, Poelstra K: Peptide-modified albumin carrier explored as a novel strategy for a cell-specific delivery of interferon γ to treat liver fibrosis. Mol Pharm 2011, 8:1899-1909.
• [148]Bosch J, García-Pagán JC: Complications of cirrhosis. I. Portal hypertension. J Hepatol 2000, 32(1 Suppl):141-156.
• [149]Trebicka J, Hennenberg M, Schulze Pröbsting A, Laleman W, Klein S, Granzow M, Nevens F, Zaagsma J, Heller J, Sauerbruch T: Role of β3-adrenoceptors for intrahepatic resistance and portal hypertension in liver cirrhosis. Hepatology 2009, 50:1924-1935.
• [150]Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology 2008, 134:1655-1669.
• [151]Abraldes JG, Pasarín M, García-Pagán JC: Animal models of portal hypertension. World J Gastroenterol 2006, 12:6577-6584.
• [152]Wiest R: Splanchnic and systemic vasodilation: the experimental models. J Clin Gastroenterol 2007, 41(Suppl 3):S272-S287.
• [153]Kisseleva T, Brenner DA: Anti-fibrogenic strategies and the regression of fibrosis. Best Pract Res Clin Gastroenterol 2011, 25:305-317.
• [154]Pinzani M, Rosselli M, Zuckermann M: Liver cirrhosis. Best Pract Res Clin Gastroenterol 2011, 25:281-290.
• [155]Groszmann RJ, Abraldes JG: Portal hypertension: from bedside to bench. J Clin Gastroenterol 2005, 39(4 Suppl 2):S125-S130.
• [156]Hennenberg M, Trebicka J, Sauerbruch T, Heller J: Mechanisms of extrahepatic vasodilation in portal hypertension. Gut 2008, 57:1300-1314.
• [157]Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J: Angiogenesis in liver disease. J Hepatol 2009, 50:604-620.
• [158]Heller J, Trebicka J, Shiozawa T, Schepke M, Neef M, Hennenberg M, Sauerbruch T: Vascular, hemodynamic and renal effects of low-dose losartan in rats with secondary biliary cirrhosis. Liver Int 2005, 25:657-666.
• [159]Trebicka J, Leifeld L, Hennenberg M, Biecker E, Eckhardt A, Fischer N, Pröbsting AS, Clemens C, Lammert F, Sauerbruch T, Heller J: Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology 2008, 47:1264-1276.
• [160]Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, Schepke M, Nevens F, Sauerbruch T, Heller J: Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007, 46:242-253.
• [161]Lee SS, Girod C, Braillon A, Hadengue A, Lebrec D: Hemodynamic characterization of chronic bile duct-ligated rats: effect of pentobarbital sodium. Am J Physiol 1986, 251:G176-G180.
• [162]Hennenberg M, Trebicka J, Fischer HP, Heller J, Sauerbruch T: Hepatic VASP upregulation in rats with secondary biliary cirrhosis by expression in the peribiliary vascular plexus. Microvasc Res 2009, 78:235-240.
• [163]Biecker E, Neef M, Sägesser H, Shaw S, Koshy A, Reichen J: Nitric oxide synthase 1 is partly compensating for nitric oxide synthase 3 deficiency in nitric oxide synthase 3 knock-out mice and is elevated in murine and human cirrhosis. Liver Int 2004, 24:345-353.
• [164]Castañeda B, Morales J, Lionetti R, Moitinho E, Andreu V, Pérez-Del-Pulgar S, Pizcueta P, Rodés J, Bosch J: Effects of blood volume restitution following a portal hypertensive-related bleeding in anesthetized cirrhotic rats. Hepatology 2001, 33:821-825.
• [165]Cho JJ, Hocher B, Herbst H, Jia JD, Ruehl M, Hahn EG, Riecken EO, Schuppan D: An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology 2000, 118:1169-1178.
• [166]Sigal M, Siebert N, Zechner D, Menschikow E, Abshagen K, Vollmar B, Eipel C: Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice. Lab Invest 2010, 90:1447-1456.
• [167]Burns RC, Wu Y, Sitzmann JV: Role of cirrhosis in the hemodynamic response to hemorrhage in portal hypertension. Surgery 1995, 117:488-493.
• [168]Proctor E, Chatamra K: High yield micronodular cirrhosis in the rat. Gastroenterology 1982, 83:1183-1190.
• [169]Constandinou C, Henderson N, Iredale JP: Modeling liver fibrosis in rodents. Methods Mol Med 2005, 117:237-250.
• [170]Moleda L, Trebicka J, Dietrich P, Gäbele E, Hellerbrand C, Straub RH, Sauerbruch T, Schoelmerich J, Wiest R: Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction. Gut 2011, 60:1122-1132.
• [171]Stock MK, Hammerich L, do O NT, Berres ML, Alsamman M, Heinrichs D, Nellen A, Trautwein C, Tacke F, Wasmuth HE, Sahin H: Met-CCL5 modifies monocyte subpopulations during liver fibrosis regression. Int J Clin Exp Pathol 2013, 6:678-685.
• [172]Okuyama H, Nakamura H, Shimahara Y, Uyama N, Kwon YW, Kawada N, Yamaoka Y, Yodoi J: Overexpression of thioredoxin prevents thioacetamide-induced hepatic fibrosis in mice. J Hepatol 2005, 42:117-123.
• [173]Laleman W, Vander Elst I, Zeegers M, Servaes R, Libbrecht L, Roskams T, Fevery J, Nevens F: A stable model of cirrhotic portal hypertension in the rat: thioacetamide revisited. Eur J Clin Invest 2006, 36:242-249.
• [174]Luo B, Liu L, Tang L, Zhang J, Ling Y, Fallon MB: ET-1 and TNF-α in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. Am J Physiol Gastrointest Liver Physiol 2004, 286:G294-G303.
• [175]Yeh CN, Maitra A, Lee KF, Jan YY, Chen MF: Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis 2004, 25:631-636.
• [176]Tsukamoto H, Matsuoka M, French SW: Experimental models of hepatic fibrosis: a review. Semin Liver Dis 1990, 10:56-65.
• [177]Nanji AA: Animal models of nonalcoholic fatty liver disease and steatohepatitis. Clin Liver Dis 2004, 8:559-574.
• [178]Chuang SC, La Vecchia C, Boffetta P: Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett 2009, 286:9-14.
• [179]Sherman M: Epidemiology of hepatocellular carcinoma. Oncology 2010, 78(Suppl 1):7-10.
• [180]Sherman M: Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 2010, 30:3-16.
• [181]Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359:378-390.
• [182]Villanueva A, Llovet JM: Targeted therapies for hepatocellular carcinoma. Gastroenterology 2011, 140:1410-1426.
• [183]Zender L, Villanueva A, Tovar V, Sia D, Chiang DY, Llovet JM: Cancer gene discovery in hepatocellular carcinoma. J Hepatol 2010, 52:921-929.
• [184]Vucur M, Roderburg C, Bettermann K, Tacke F, Heikenwalder M, Trautwein C, Luedde T: Mouse models of hepatocarcinogenesis: What can we learn for the prevention of human hepatocellular carcinoma? Oncotarget 2010, 1:373-378.
• [185]Verna L, Whysner J, Williams GM: N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacol Ther 1996, 71:57-81.
• [186]Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, Wagner EF: Liver tumor development: c-Jun antagonizes the proapoptotic activity of p53. Cell 2003, 112:181-192.
• [187]Lee JS, Chu IS, Mikaelyan A, Calvisi DF, Heo J, Reddy JK, Thorgeirsson SS: Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 2004, 36:1306-1311.
• [188]Lim IK: Spectrum of molecular changes during hepatocarcinogenesis induced by DEN and other chemicals in Fisher 344 male rats. Mech Ageing Dev 2003, 124:697-708.
• [189]Hann B, Balmain A: Building 'validated’ mouse models of human cancer. Curr Opin Cell Biol 2001, 13:778-784.
• [190]Luedde T, Schwabe RF: NF-κB in the liver––linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011, 8:108-118.
• [191]Luedde T, Trautwein C: Intracellular survival pathways in the liver. Liver Int 2006, 26:1163-1174.
• [192]Roderburg C, Gautheron J, Luedde T: TNF-dependent signaling pathways in liver cancer: promising targets for therapeutic strategies? Dig Dis 2012, 30:500-507.
• [193]Maeda S, Kamata H, Luo JL, Leffert H, Karin M: IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005, 121:977-990.
• [194]Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, Khiabanian H, Adeyemi A, Bataller R, Lefkowitch JH, Bower M, Friedman R, Sartor RB, Rabadan R, Schwabe RF: Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012, 21:504-516.
• [195]Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y: NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 2004, 431:461-466.
• [196]Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, Roskams T, Trautwein C, Pasparakis M: Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 2007, 11:119-132.
• [197]Bettermann K, Vucur M, Haybaeck J, Koppe C, Janssen J, Heymann F, Weber A, Weiskirchen R, Liedtke C, Gassler N, Müller M, de Vos R, Wolf MJ, Boege Y, Seleznik GM, Zeller N, Erny D, Fuchs T, Zoller S, Cairo S, Buendia MA, Prinz M, Akira S, Tacke F, Heikenwalder M, Trautwein C, Luedde T: TAK1 suppresses a NEMO-dependent but NF-κB-independent pathway to liver cancer. Cancer Cell 2010, 17:481-496.
• [198]Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, Bremer J, Iezzi G, Graf R, Clavien PA, Thimme R, Blum H, Nedospasov SA, Zatloukal K, Ramzan M, Ciesek S, Pietschmann T, Marche PN, Karin M, Kopf M, Browning JL, Aguzzi A, Heikenwalder M: A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 2009, 16:295-308.
• [199]Directive 2010/63/EU of the European Parliament and of the Council on the protection of animals used for scientific purposes Official Journal of the European Union 2010. L276/33–L276/79 (22 September 2010). http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:276:0033:0079:en:PDF webcite
• [200]Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG: Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010, 8:e1000412.
• [201]Stenkamp-Strahm C, Patterson S, Boren J, Gericke M, Balemba O: High-fat diet and age-dependent effects on enteric glial cell populations of mouse small intestine. Auton Neurosci 2013, 177:199-210.
• [202]Faculty of Veterinary Medicine, Utrecht University: Humane endpoints in laboratory animal experimentation. http://www.humane-endpoints.info/eng/index.php?lang=en webcite
• [203]Canadian Council on Animal Care (CCAC) Guidelines Committee: Guidelines Committee: Guidelines on Choosing an Appropriate Endpoint in Experiments Using Animals for Research, Teaching and Testing. Ottawa, ON, Canada; 1998. Available at http://www.ccac.ca/Documents/Standards/Guidelines/Appropriate_endpoint.pdf webcite (accessed 18 September 2013)
• [204]Hendriksen CFM, Morton DB: Humane endpoints in animal experiments for biomedical research. In Proceedings of the International Conference 22–25 November 1998, Zeist, the Netherlands. London: Royal Society of Medicine Press; 1999.
• [205]Wallace J: Humane endpoints in cancer research. ILAR J 2000, 41:87-93.
• [206]Ullman-Culleré MH, Foltz CJ: Body condition scoring: a rapid and accurate method for assessing health status in mice. Lab Anim Sci 1999, 49:319-323.
• [207]Schuppli CA, Fraser D, McDonald M: Expanding the three Rs to meet new challenges in humane animal experimentation. Altern Lab Anim 2004, 32:525-532.
• [208]Wehr A, Baeck C, Heymann F, Niemietz PM, Hammerich L, Martin C, Zimmermann HW, Pack O, Gassler N, Hittatiya K, Ludwig A, Luedde T, Trautwein C, Tacke F: Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J Immunol 2013, 190:5226-5236.
• [209]Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, Krause R, Lammert F, Langner C, Zatloukal K, Marschall HU, Denk H, Trauner M: Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2004, 127:261-274.
• [210]Hochrath K, Krawczyk M, Goebel R, Langhirt M, Rathkolb B, Micklich K, Rozman J, Horsch M, Beckers J, Klingenspor M, Fuchs H, Gailus-Durner V, Wolf E, Acalovschi M, Volmer DA, Hrabě de Angelis M, Lammert F: The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis. FASEB J 2012, 26:5081-5091.
• [211]Nevzorova YA, Hu W, Cubero FJ, Haas U, Freimuth J, Tacke F, Trautwein C, Liedtke C: Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis. Biochim Biophys Acta 1832, 2013:1765-1775.
• [212]Nevzorova YA, Tschaharganeh D, Gassler N, Geng Y, Weiskirchen R, Sicinski P, Trautwein C, Liedtke C: Aberrant cell cycle progression and endoreplication in regenerating livers of mice that lack a single E-type cyclin. Gastroenterology 2009, 137:691-703. 703.e1–703.e6
• [213]Borkham-Kamphorst E, van de Leur E, Zimmermann HW, Karlmark KR, Tihaa L, Haas U, Tacke F, Berger T, Mak TW, Weiskirchen R: Protective effects of lipocalin-2 (LCN2) in acute liver injury suggest a novel function in liver homeostasis. Biochim Biophys Acta 1832, 2013:660-673.
• [214]Labbus K, Henning M, Borkham-Kamphorst E, Geisler C, Berger T, Mak TW, Knüchel R, Meyer HE, Weiskirchen R, Henkel C: Proteomic profiling in lipocalin 2 deficient mice under normal and inflammatory conditions. J Proteomics 2013, 78:188-196.
• [215]Møller S, Bendtsen F, Henriksen JH: Splanchnic and systemic hemodynamic derangement in decompensated cirrhosis. Can J Gastroenterol 2001, 15:94-106.
• [216]Trebicka J, Hennenberg M, Odenthal M, Shir K, Klein S, Granzow M, Vogt A, Dienes HP, Lammert F, Reichen J, Heller J, Sauerbruch T: Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol 2010, 53:702-712.
• [217]Santos RAS, AC S e S, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T: Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A 2003, 100:8258-8263.
• [218]Grace JA, Klein S, Herath CB, Granzow M, Schierwagen R, Masing N, Walther T, Sauerbruch T, Burrell LM, Angus PW, Trebicka J: Activation of the Mas receptor by angiotensin-(1–7) in the renin–angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterologyin press. doi:10.1053/j.gastro.2013.06.036
• [219]Pornwilard MM, Weiskirchen R, Gassler N, Bosserhoff AK, Becker JS: Novel bioimaging techniques of metals by laser ablation inductively coupled plasma mass spectrometry for diagnosis of fibrotic and cirrhotic liver disorders. PLoS One 2013, 8:e58702.
• [220]Pornwilard MM, Merle U, Weiskirchen R, Becker JS: Bioimaging of copper deposition in Wilson’s diseases mouse liver by laser ablation inductively coupled plasma mass spectrometry imaging (LA-ICP-MSI). Int J Mass Spectromin press. doi:10.1016/j.ijms.2013.07.006