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In vivo Experimental Models for hepatotoxin Induced Fibrosis – A Toxicological View
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Liver fibrosis is common sequel of chronic liver injury regardless of any etiology. The experimental animal models of hepatic fibrosis remain hallmark for the evaluation of antifibrotic agents prior to clinical studies. Accumulating evidence indicates that carbon tetrachloride, N-nitrosodimethylamine, thioacetamide, ethanol and bile duct ligation models are commonly employed and these models have been extensively studied for their potency of inducing hepatic fibrosis and for the evaluation of various antifibrotic agents in experimental animals. However, none of these experimental models reproduces exactly human liver fibrosis, each model has its own limitation and disadvantages i.e., development of ascites, extra hepatic toxicity, mortality etc. The development, progression and resolution of hepatic fibrosis induced by these hepatotoxins in experimental animals varying on the routes of their administration, frequency (intermittent/chronic) of administration, dose, species, and strain. Nevertheless, over past three decades knowledge gained from these hepatotoxin induced fibrosis models has advanced our understanding of the pathophysiology, molecular mechanisms and wide spectrum of signaling pathways associated with hepatic fibrosis. This article reviews some of the most studied hepatic fibrosis experimental models.
Keywords
Carbon Tetrachloride, Ethanol, Liver Fibrosis, Oxidative Stress, Thioacetamide.
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- Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: A translational success story. Gut 2015; 64(5):830–41.
- Mormone E, George J, Nieto N. Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem Biol Interact. 2011; 193(3):225–31.
- Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008; 214(2):199–10.
- Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, et al. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology. 2003; 125(6):1796–07.
- Wang JH, Choi MK, Shin JW, Hwang SY, Son CG. Antifibrotic effects of Artemisia capillaris and Artemisia iwayomogi in a carbon tetrachloride-induced chronic hepatic fibrosis animal model. J Ethnopharmacol. 2012; 140(1):179–85.
- Zhao Y, Ma X, Wang J, He X, Hu Y, et al. Curcumin protects against CCl4-induced liver fibrosis in rats by inhibiting HIF-1α through an ERK-dependent pathway. Molecules. 2014; 19(11):18767–80.
- Rivera CA, Bradford BU, Hunt KJ, Adachi Y, Schrum LW, et al. Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol. 2001; 281(1):G200-7.
- Fujii T, Fuchs BC, Yamada S, Lauwers GY, Kulu Y, et al. Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterol. 2010; 10:79.
- Ezhilarasan D, Karthikeyan S, Vivekanandan P. Ameliorative effect of silibinin against N-nitrosodimethylamine-induced hepatic fibrosis in rats. Environ Toxicol Pharmacol. 2012; 34(3):1004–13.
- Kim SK, Seo JM, Chae YR, Jung YS, Park JH, et al. Alleviation of dimethylnitrosamine-induced liver injury and fibrosis by betaine supplementation in rats. Chem Biol Interact. 2009; 177(3):204–11.
- Tanaka H, Ueda H, Fukuchi H, Ichinose M. Antifibrotic effect of edaravone in rat liver cirrhosis induced by dimethylnitrosamine. Clin Exp Med. 2009; 9(3):229–33.
- Kadir FA, Kassim NM, Abdulla MA, Kamalidehghan B, Ahmadipour F, et al. PASS-predicted hepatoprotective activity of Caesalpinia sappan in thioacetamide-induced liver fibrosis in rats. ScientificWorld Journal. 2014; 2014:301879.
- Parajuli DR, Zhao YZ, Jin H, Chi JH, Li SY, et al. Anti-fibrotic effect of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, in thioacetamide-induced experimental rats liver fibrosis. Arch Pharm Res. 2015; 38(4):549–55.
- Geng J, Peng W, Huang Y, Fan H, Li S. Ginsenoside-Rg1 from Panax notoginseng prevents hepatic fibrosis induced by thioacetamide in rats. Eur J Pharmacol. 2010; 634(1-3):162–9.
- Bruck R, Genina O, Aeed H, Alexiev R, Nagler A, et al. Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats. Hepatology. 2001; 33(2):379–86.
- Chheda TK, Shivakumar P, Sadasivan SK, Chanderasekharan H, Moolemath Y, et al. Fast food diet with CCl4micro-dose induced hepatic-fibrosis--a novel animal model. BMC Gastroenterol. 2014; 10(14):89.
- Tamayo RP. Is cirrhosis of the liver experimentally produced by CCl4 and adequate model of human cirrhosis? Hepatology. 1983; 3(1):112–20.
- Jeong DH, Lee GP, Jeong WI, Do SH, Yang HJ, et al. Alterations of mast cells and TGF-beta1 on the silymarin treatment for CCl(4)-induced hepatic fibrosis. World J Gastroenterol. 2005; 11(8):1141–8.
- Fu Y, Zheng S, Lin J, Ryerse J, Chen A. Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol. 2008; 73(2):399–409.
- Burk RF, Lane JM, Patel K. Relationship of oxygen and glutathione in protection against carbon tetrachloride-induced hepatic microsomal lipid peroxidation and covalent binding in the rat. Rationale for the use of hyperbaric oxygen to treat carbon tetrachloride ingestion. J Clin Invest. 1984; 74:1996–01.
- Constandinou C, Henderson N, Iredale JP. Modeling liver fibrosis in rodents. Methods Mol Med. 2005; 117:237–50.
- Ma JQ, Ding J, Zhang L, Liu CM. Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway. Clin Res Hepatol Gastroenterol. 2015; 39(2):188–97.
- Clichici S, Olteanu D, Nagy AL, Oros A, Filip A, et al. Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl4-treated rats. J Med Food. 2015; 18(3):290–8.
- Schuppan D, Krebs A, Bauer M, Hahn EG. Hepatitis C and liver fibrosis. Cell Death Differ. 2003; 10 Suppl 1:S59–67.
- Tsai JH, Liu JY, Wu TT, Ho PC, Huang CY, et al. Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats. J Viral Hepat. 2008; 15(7):508–14.
- Muriel P, Moreno MG, Hernández Mdel C, Chávez E, Alcantar LK Resolution of liver fibrosis in chronic CCl4 administration in the rat after discontinuation of treatment: effect of silymarin, silibinin, colchicine and trimethylcolchicinic acid. Basic Clin Pharmacol Toxicol. 2005; 96(5):375–80.
- Chavez E, Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, et al. Resveratrol prevents fibrosis, NF-kappaB activation and TGF-beta increases induced by chronic CCl4 treatment in rats. J Appl Toxicol. 2008; 28(1):35–43.
- Heeba GH, Mahmoud ME. Therapeutic potential of morin against liver fibrosis in rats: modulation of oxidative stress, cytokine production and nuclear factor kappa B. Environ Toxicol Pharmacol. 2014; 37(2):662–71.
- Galicia-Moreno M, Rodríguez-Rivera A, Reyes-Gordillo K, Segovia J, Shibayama M, et al. N-acetylcysteine prevents carbon tetrachloride-induced liver cirrhosis: Role of liver transforming growth factor-beta and oxidative stress. Eur J Gastroenterol Hepatol. 2009; 21(8):908–14.
- San-Miguel B, Crespo I, Sánchez DI, González-Fernández B, Ortiz de Urbina JJ, et al. Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis. J Pineal Res. 2015. DOI: 10.1111/jpi.12247.
- Fang HL, Lai JT, Lin WC. Inhibitory effect of olive oil on fibrosis induced by carbon tetrachloride in rat liver. Clin Nutr. 2008; 27(6):900–7.
- Magee PN. Toxic liver injury; the metabolism of dimethylnitrosamine. Biochem J. 1956; 64(4):676–82.
- Ezhilarasan D, Karthikeyan S. Silibinin alleviates N-nitrosodimethylamineinduced glutathione dysregulation and hepatotoxicity in rats. Chin J Nat Med. 2016; 14(1):40–7.
- Jezequel AM, Mancini R, Rinaldesi ML, Macarri G, Venturini C, et al. Morphological study of the early stages of hepatic fibrosis induced by low doses of dimethylnitrosamine in the rat. J Hepatol. 1987; 5(2):174–81.
- George J. Ascorbic acid concentrations in dimethylnitrosamineinduced hepatic fibrosis in rats. Clin Chim Acta. 2003; 335(1-2):39–47.
- Vendemiale G, Grattagliano I, Caruso ML, Serviddio G, Valentini AM, et al. Increased oxidative stress in dimethylnitrosamineinduced liver fibrosis in the rat: Effect of N-acetylcysteine and interferon-alpha. Toxicol Appl Pharmacol. 2001; 175(2):130–9.
- Kang JS, Wanibuchi H, Morimura K, Gonzalez FJ, Fukushima S. Role of CYP2E1 in diethylnitrosamine-induced hepatocarcinogenesis in vivo. Cancer Res. 2007; 67(23):11141–6.
- Liedtke C, Luedde T, Sauerbruch T, Scholten D, Streetz K, et al. Experimental liver fibrosis research: Update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair. 2013; 6(1):19.
- Chen JY, Chen HL, Cheng JC, Lin HJ, Tung YT, et al. A Chinese herbal medicine, Gexia-Zhuyu Tang (GZT), prevents dimethylnitrosamine-induced liver fibrosis through inhibition of hepatic stellate cells proliferation. J Ethnopharmacol. 2012; 142(3):811–8.
- Hu QW, Liu GT. Effects of bicyclol on dimethylnitrosamineinduced liver fibrosis in mice and its mechanism of action. Life Sci. 2006; 79(6):606–12.
- Weerawatanakorn M, Lee YL, Tsai CY, Lai CS, Wan X, et al. Protective effect of the aflavin-enriched black tea extracts against dimethylnitrosamine-induced liver fibrosis in rats. Food Funct. 2015. DOI: 10.1039/C5FO00126A.
- Ahmad A, Ahmad R. Resveratrol mitigate structural changes and hepatic stellate cell activation in N-nitrosodimethylamineinduced liver fibrosis via restraining oxidative damage. Chem Biol Interact. 2014; 221:1–12.
- Elshazly SM, Mahmoud AA. Antifibrotic activity of hesperidin against dimethylnitrosamine-induced liver fibrosis in rats. Naunyn Schmiedebergs Arch Pharmacol. 2014; 387(6):559–67.
- Xu L, Zheng N, He Q, Li R, Zhang K, et al. Puerarin, isolated from Pueraria lobata (Willd.), protects against hepatotoxicity via specific inhibition of the TGF-β1/Smad signaling pathway, thereby leading to anti-fibrotic effect. Phytomedicine. 2013; 20(13):1172–9.
- Shin DS, Kim KW, Chung HY, Yoon S, Moon JO. Effect of sinapic acid against dimethylnitrosamine-induced hepatic fibrosis in rats. Arch Pharm Res. 2013; 36(5):608–18.
- Li S, Wang L, Yan X, Wang Q, Tao Y, et al. Salvianolic acid B attenuates rat hepatic fibrosis via downregulating angiotensin IIS ignaling. Evid Based Complement Alternat Med. 2012; 2012:160726.
- Heindryckx F, Colle I, Van Vlierberghe H. Experimental mouse models for hepatocellular carcinoma research. Int J Exp Pathol. 2009; 90(4):367–86.
- Koen YM, Sarma D, Hajovsky H, Galeva NA, Williams TD, et al. Protein targets of thioacetamide metabolites in rat hepatocytes. Chem Res Toxicol. 2013; 26(4):564–74.
- Stankova P, Kucera O, Lotkova H, Roušar T, Endlicher R, et al. The toxic effect of thioacetamide on rat liver in vitro. Toxicol In Vitro. 2010; 24(8):2097–103.
- Spira B, Raw I. The effect of thioacetamide on the activity and expression of cytosolic rat liver glutathione-S-transferase. Mol Cell Biochem. 2000; 211:103–10.
- Palacios RS, Roderfeld M, Hemmann S, Rath T, Atanasova S, et al. Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice. Lab Invest. 2008; 88(11):1192–203.
- Wasmuth HE, Lammert F, Zaldivar MM, Weiskirchen R, Hellerbrand C, et al. Trautwein C. Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology. 2009; 137(1):309–19.
- Schnur J, Olah J, Szepesi A, Nagy P, Thorgeirsson SS. Thioacetamideinduced hepatic fibrosis in transforming growth factor beta-1 transgenic mice. Eur J Gastroenterol Hepatol. 2004; 16(2):127–33.
- Spira G, Mawasi N, Paizi M, Anbinder N, Genina O, et al. Halofuginone, a collagen type I inhibitor improves liver regeneration in cirrhotic rats. J Hepatol. 2002; 37(3):331–9.
- Lieber CS, DeCarli LM. Liquid diet technique of ethanol administration: 1989 update. Alcohol Alcohol. 1989; 24(3):197–11.
- Lieber CS, DeCarli LM. Animal models of chronic ethanol toxicity. Methods Enzymol. 1994; 233:585–94.
- Rigamonti C, Mottaran E, Reale E, Rolla R, Cipriani V, et al. Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology. 2003; 38(1):42–9.
- Casini A, Cunningham M, Rojkind M, Lieber CS. Acetaldehyde increases procollagen type I and fibronectin gene transcription in cultured rat fat-storing cells through a protein synthesis-dependent mechanism. Hepatology. 1991; 13(4):758–65.
- Moshage H, Casini A, Lieber CS. Acetaldehyde selectively stimulates collagen production in cultured rat liver fat-storing cells but not in hepatocytes. Hepatology. 1990; 12(3 Pt 1):511–8.
- Fontana L, Jerez D, Rojas-Valencia L, Solís-Herruzo JA, Greenwel P, et al. Ethanol induces the expression of alpha 1(I) procollagen mRNA in a co-culture system containing a liver stellate cell-line and freshly isolated hepatocytes. Biochim Biophys Acta. 1997; 1362(2-3):135–44.
- Meyer C, Meindl-Beinker NM, Dooley S. TGF-beta signaling in alcohol induced hepatic injury. Front Biosci (Landmark Ed). 2010; 15:740–9.
- Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol. 2011; 301(5):G825–34.
- Kume H, Okazaki K, Sasaki H. Hepatoprotective effects of whey protein on D-galactosamine-induced hepatitis and liver fibrosis in rats. Biosci Biotechnol Biochem. 2006; 70(5):1281–5.
- Jonker AM, Dijkhuis FW, Hardonk MJ, Moerkerk P, Ten Kate J, et al. Immunohistochemical study of hepatic fibrosis induced in rats by multiple galactosamine injections. Hepatology. 1994; 19(3):775–81.
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