Abstract
The liver has the amazing capacity to repair itself after injury; however, the same processes that are involved in liver regeneration after acute injury can cause serious consequences during chronic liver injury. In an effort to repair damage, activated hepatic stellate cells trigger a cascade of events that lead to deposition and accumulation of extracellular matrix components causing the progressive replacement of the liver parenchyma by scar tissue, thus resulting in fibrosis. Although fibrosis occurs as a result of many chronic liver diseases, the molecular mechanisms involved depend on the underlying etiology. Since studying liver fibrosis in human subjects is complicated by many factors, mouse models of liver fibrosis that mimic the human conditions fill this void. This review summarizes the general mouse models of liver fibrosis and mouse models that mimic specific human disease conditions that result in liver fibrosis. Additionally, recent progress that has been made in understanding the molecular mechanisms involved in the fibrogenic processes of each of the human disease conditions is highlighted.
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Introduction
The repeated insult that occurs during the progression of many chronic liver diseases continuously activates the wound healing response; it is this chronic activation of the wound healing response that causes liver fibrosis [1, 2]. The activation of hepatic stellate cells (HSCs), which are the main collagen-producing cell in the liver, is a pivotal event during liver fibrogenesis. Provoked by chronic liver injury, activated HSCs display a myofibroblast phenotype and exhibit fibrogenic potential [1–3]. Activated HSCs set in motion a cascade of molecular, cellular, and tissue events that lead to the deposition and accumulation of extracellular matrix (ECM) components, especially collagen, to limit hepatic damage observed in chronic liver diseases [3–6]. However, the accumulation of collagen and other ECM components that occurs in chronic hepatic injury results in the progressive replacement of the liver parenchyma by scar tissue, thus resulting in fibrosis [1].
While liver fibrosis is the outcome of many different chronic liver diseases including chronic hepatitis C virus (HCV) infection, alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), and autoimmune liver diseases, the pathogenesis of liver fibrosis depends on the underlying etiology [1, 2]. Therefore, liver fibrogenesis must be studied in the context of each of the chronic liver diseases that result in fibrosis. Mouse models of liver fibrosis that mimic human liver fibrosis have contributed to this need and have greatly enhanced the study of liver fibrosis [7, 8].
Rodent models can address specific questions that are difficult to address in human studies. Due to the lack of an early diagnosis of liver fibrosis in human subjects and the invasive nature of liver biopsies, which is the standard for liver fibrosis assessment, multiple sampling at different stages of liver fibrogenesis in humans is challenging. However, mouse models provide researchers with the opportunity to conduct studies using multiple samples and at different stages of liver fibrogenesis [8]. The use of mice has the advantage that the whole organ and organism is intact, which is one of the limitations of in vitro studies with human tissues or cell lines [8]. Finally, genetic studies using knockout mice or the ability to knockdown specific genes can be used to determine the role of these genes in the progression of liver fibrosis [8].
Although the use of mouse models in the study of liver fibrosis is a powerful tool, these models are not without their disadvantages. Most notably, there is a lack of an appropriate mouse model for liver fibrosis caused by alcohol abuse and chronic HCV infection [8]. Also, there are species differences between humans and mice in the immune response, gene regulation, and metabolic, pharmacological, and tissue responses [8].
Despite these limitations, liver fibrosis research using both human subjects and mouse models has seen countless advancements in recent years. The purpose of this review article is to discuss some of the most recent advances in the study of liver fibrosis and to specifically parallel the advancements in mouse models of liver fibrosis to their human liver fibrosis counterparts.
General Mouse Models of Liver Fibrosis
Repetitive Toxic Insults
Carbon Tetrachloride
Carbon tetrachloride (CCl4) is a hepatic toxin that is commonly used to induce toxic liver injury in mice. CCl4 is converted to a free radical by reductive dehalogenation catalyzed by cytochrome p450 2E1 (CYP2E1) in hepatocytes, which induces lipid peroxidation and membrane damage that causes centralobular necrosis [9–11]. CCl4 is a fast acting toxin with morphological changes appearing at 15 min [12]. Acute administration (single dose) of CCl4 results in centralobular necrosis and reversible injury that triggers a wound healing response [13, 14•]. In addition to hepatocyte necrosis, acute administration of CCl4 triggers apoptosis of large cholangiocytes, which is followed by the activation of proliferation and compensatory de novo expression of secretin receptor in small cholangiocytes [15, 16]. Liver fibrosis develops progressively during repetitive administration of CCl4 [17–19]. Fibrosis appears initially in pericentral areas, which then progresses to bridging fibrosis, cirrhosis, and eventually hepatocellular carcinoma [17–20]. CCl4 has been administered to mice via different routes including intraperitoneal [18], subcutaneous [19], and oral gavage [19]. Each route has distinct advantages and disadvantages that have been reviewed elsewhere [8, 19, 21]. In addition to the progression of fibrosis and cirrhosis, the CCl4 model has been used to study the mechanisms regulating the reversibility/resolution of fibrosis [22, 23•].
Thioacetamide
Thioacetamide (TAA) is an organosulfur compound that has metabolic intermediates that are toxic to the liver. One intermediate, thioacetamide-S-oxidase, is a reactive oxygen species (ROS) that covalently bind to hepatic macromolecules resulting in necrosis of hepatocytes [21]. CPY2E1 has been shown to mediate TAA-induce hepatoxicity in mice [24, 25]. Chronic treatment of mice with TAA induces liver damage, fibrosis, and eventually cirrhosis, which is associated with elevated oxidative stress and activation of hepatic stellate cells [26–28•]. TAA can be administered by intraperitoneal injections or in the drinking water. The disadvantage of TAA is that it takes a relatively long time to induce liver fibrosis and there is the potential for the development of hepatocellular carcinoma [28–30•].
Dimethyl or Diethylnitrosamine
Dimethyl or diethylnitrosamine (DMN and DEN) are highly toxic to the liver and are hydroxylated by CYP2E1 to form bioactive diazonium ions that react with nucleic acids to form alkylation products [31, 32]. DMN and DEN models are characterized by centrilobular and periportal liver damage with the subsequent development of liver fibrosis and cirrhosis [33–35•]. These models provide a unique opportunity to study the pathogenesis of liver fibrosis to hepatocellular carcinoma [33–35•].
Bile Duct Ligation (BDL)
Model of Secondary Biliary Fibrosis
Ligation of the common bile duct (BDL) stimulates the proliferation of biliary epithelial cells (BEC) (i.e., cholangiocytes) that line the bile ducts along with cholestasis, portal inflammation, and subsequently portal fibrosis [36]. Although the model is characterized by extensive ductular proliferation, portal myofibroblasts have been proposed to be an important contributor to the progression of biliary fibrosis [37, 38•]. Rats are more suitable for the model due to a lack of a gall bladder. However, despite higher surgical complications and mortality the model is commonly used in mice [8].
Abcb4−/−
The ATP-binding cassette subfamily B member 4 (ABCB4) is a gene that encodes the multidrug resistance 3 (MDR3) protein (MDR2 in mice), which is a canalicular translocator for phosphatidylcholine [39]. A mutation in the ABCB4 gene can cause progressive familial intrahepatic cholestasis (PFIC3) and primary biliary cirrhosis (PBC). Due to the lack of protection against bile acids [40–42], these individuals experience increased damage of the biliary epithelium, ductular proliferation, and potential progressive portal fibrosis [43]. ABCB4 knockout mice (Abcb4−/−) have been used to study the pathophysiology of PFIC3 and PBC, and their potential therapies. Abcb−/− mouse models have also been used to study cholestasis of pregnancy and drug-induced cholestasis [44].
Recent studies using Abcb−/− mice have provided insight into the pathophysiology behind chronic cholestatic liver disease and have explored new therapeutic options for the treatment of these diseases. Alterations in lipid metabolism and in the expression of canalicular transporters that regulate bile composition contribute to the progression of cholestatic liver disease in Abcb−/− mice [45••, 46]. Recently, a derivative of ursodeoxycholic acid (UDCA), norUDCA, has been found to decrease hepatobiliary injury in BDL mice, raising the possibility that norUDCA could be used as a therapeutic in the treatment of cholestatic liver disease [47•].
d-galactosamine (d-GalN)
d-galactosamine (d-GalN) is a hepatotoxin, which causes acute hepatic injury and has been a good model for monitoring the progression of chronic biliary diseases. d-GalN causes UDP glucose and UDP galactose deficiency, loss of intracellular calcium homeostasis, inhibition of energy metabolism of hepatocytes, and injuries of the mitochondrial enzymes affecting lipoprotein interactions [48–50]. To understand the inflammation-induced pathway in hepatocytes, d-GalN/Lipopolysaccharide treatment was performed to show that hepatic injury is facilitated by TNF-α. For therapeutic purposes, S-adenosyl-l-methionine (SAMe) was found to have protective effects in vivo and in vitro on liver cell damage caused by d-GalN [51], including enhanced bile secretion, improved liver function tests, and amelioration of symptoms of d-GalN-induced hepatotoxic mice [52, 53]. Glucuronidation was found to be an important step in the pathogenesis of ethinylestradiol (EE)-induced cholestasis. When administered with d-GalN, there was an improvement in cholestasis because d-GalN decreases the UDP-GA availability required by EE 17 β-glucuronide, thus showing that these molecules are involved in cholestasis [54]. Hepatoxins, such as d-GalN, can cause inhibition of mature hepatocytes. When this occurs, a regenerative process occurs where hepatic stem/progenitor cells become activated eventually forming hepatocytes or BEC [55–60]. Using the d-GalN injury model, the Thy 1+ cells would differentiate into hepatocytes and cholangiocytes on day 2 and 3 of hepatic injury to aid in the recovery process [61].
Methione and Choline Deficient (MCD) and Choline-Deficient l-Amino Acid Defined Diet (CDAA)
The methionine and choline deficient diet (MCD) is a common dietary mouse model that is used for studying the pathophysiology of NASH [21]. The diet contains about 40 % of high sucrose and 10 % of high fat. This diet lacks methionine and choline, which are required in mitochondrial β-oxidation and synthesis of low-density lipoprotein (LDL) [62]. It can cause more ROS, mitochondrial DNA damage, and apoptosis compared to other NASH models [63]. Wistar rats are more susceptible to this diet, but Long-Evans and Sprague–Dawley rats are also used in presenting steatosis [64]. The disadvantage regarding this model is that the metabolic profile has differences compared to human NASH [65–67].
Recent studies using the MCD diet model have elucidated factors involved in the progression or reduction of NASH. Mesenchymal epithelial transition factor (c-met) receptor signaling has been shown to activate anti-apoptotic pathways in hepatocytes (74). Caspases, most recently Caspase 3, have been shown to be involved in the proapoptotic and proinflammatory processes in NASH (75). Finally, a therapeutic study was done regarding Sitaglipin in MCD fed mice. Sitagliptin showed attenuation of hepatic steatosis, inflammation, and fibrosis insinuating future therapy application [68•]. However, the next step would be to check long-term side effect profiles of Sitagliptin in NASH mouse models.
Choline-deficient l-amino-acid-defined (CDAA) is a well-known dietary model that induces pathogenesis related to NASH. During continuous consumption of a CDAA diet, animal models have shown induction of steatosis, lobular inflammation, and fibrosis [69, 70]. In one study, CDAA fed Wistar rats continued to have fibrosis even after reverting back to a choline sufficient diet, but the steatosis and lobular inflammation improved. The persistent fibrosis was likely due to the hypoxic damage and oxidative stress the CDAA diet caused (79). Choline is an essential nutrient that is involved in VLDL production via phosphatidylcholine. Without choline, hepatic lipidosis can occur causing a decrease in lipid and cholesterol excretion [71–73].
Choline deficiency can also cause oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress. Consequently, the animal model is more susceptible to hypoxic damage resulting in significant hepatocellular death [71, 74, 75]. Lack of choline can also cause induction of a proinflammatory cascade that eventually activates HSC causing fibrosis [76, 77].
Mouse Models that Mimic Specific Human Diseases
Autoimmune Fibrosis
Primary Biliary Cirrhosis (PBC)
PBC is a chronic cholestatic liver disease that predominantly affects middle age women [78]. Intrahepatic small bile ducts are progressively destroyed by an immune-mediated attack and the disease may slowly progress until liver cirrhosis. PBC is considered an autoimmune disease. Antimitochondrial antibodies (AMAs) directed against the E2 component of the pyruvate dehydrogenase complex (PDC-E2) are present in the sera of about 95 % of the patients, and are detectable years before the appearance of clinical symptoms [78–80].
Animal models of PBC aim to specifically recapitulate the complex pathophysiological characteristics of the human disease. Despite remarkable advances in the last decade, to date none of the proposed models can perfectly resemble the complexity of the human disease.
Murine models of PBC can be divided into spontaneous models, if biliary alterations appear in genetically modified animals without additional interventions, and induced models, in which biliary damage appears after breakdown of tolerance to PDC.
Koarada et al. described the NOD.c3c4 congenic mouse as the first spontaneous model for autoimmune biliary diseases [81, 82]. NOD.c3c4 mice develop lymphocytic peribiliary infiltrates, autoantibodies, and progressive cholestasis [81]. The full-blown disease is present in 50 % of the females and in 25 % of male within 1 year of age [83]. Moreover, 55 % of the NOD.c3c4 mice develop antibodies against the PDC-E2 complex before the biliary lesions are completely formed. The microscopic alterations in the liver include the infiltration of CD3+, CD4+, and CD8+ T cells with sporadic formation of granulomas [83]. Despite the fact that NOD.c3c4 mice recapitulate several features of the human disease, the appearance of alterations that are not found in PBC patients is reported too. Biliary cysts in the intrahepatic bile ducts develop in the majority of the animals, and seem related to a B cells response [84]. Moreover, unlike PBC, common bile duct dilatation is also present in NOD.c3c4 mice [83].
An alternative model for PBC is the dominant-negative TGF-β receptor II (dnTGF-βRII) mouse [85]. CD4+ and CD8+ T cells of dnTGF-βRII mice over-express a mutated form of the TGF-βRII that is incapable of signal transduction. As a result, the immune homeostasis is altered and clusters of immune cells infiltrate the liver parenchyma [86]. Gershwin and coworkers showed that dnTGF-βRII mice develop several features of human PBC, including spontaneous production of antimitocondrial antibodies to PDC-E2, CD4+, and CD8+ T cells infiltration within the portal tract of 6- to 7-month-old mice, and increased levels of IFN-γ, TNF-α, IL-6, and IL-12p40 [85, 87]. However, the general dysregulation of self-tolerance in dnTGF-βRII mice should not be overlooked. In fact, starting from 3 to 4 months of age, dnTGF-βRII mice develop a wasting syndrome associated with diarrhea due to marked to severe inflammatory bowel disease, with infiltration of lymphocytes, macrophages, and plasma cells in the gut [86]. Mild inflammatory infiltrates appear also in the lungs, stomach, duodenum, pancreas, and kidney [86]. The development of cholangitis in dnTGF-βRII mice does not seem to be related to abnormalities of the biliary tree. Indeed, bile duct inflammation occurs also if splenocytes of dnTGF-βRII mice are transferred into recombinase-deficient (Rag1−/−) mice, which lack a diversified B and T cell receptor repertoire [88]. In addition, CD8+ T cells seem to be the primary effectors of the inflammation [88].
The importance of immune regulation in the pathogenesis of PBC has been further emphasized in a subsequent murine model, the IL-2Rα−/− mouse. Wakabayashi et al. reported the development of autoimmune cholangitis and AMAs in IL-2Rα−/− mice [89]. However, severe anemia, lymphoproliferative disorders, and inflammatory bowel disease are prevalent in these mice, especially after 2 months of age [90]. Similar to dnTGF-βRII mice, CD8+ T cells have been involved in the pathogenesis of the biliary injury, while CD4+ T cells are responsible for the colitis [91].
The AE2−/− mouse is considered an additional mouse model of PBC [92]. The anion exchanger (AE) 2 is a Cl−/HCO3 − exchanger expressed in different cells, where it regulates the intracellular pH [93]. In cholangiocytes, AE2 is located at the apical membrane and is the main transporter responsible for bicarbonate secretion in bile [94]. At 15 months of age, most of AE2−/− mice develop AMAs against the PDC-E2 inner lipoyl domain, increased alkaline phosphatase levels in plasma and different degrees of portal inflammation. However, the liver damage is not progressive, a slight fibrosis is reported only in mice with florid portal infiltrates, and there are no gender differences [92]. Together with the liver phenotype, AE2−/− mice develop alterations in the immune system. Enlarged spleen, reduced CD4+/CD8+ ratio, and altered cytokine production have been described in AE2−/− mice, possibly as a consequence of defective pH regulation in immune cells [92, 95]. Interestingly, natural regulatory T cells (Tregs) are also reduced in this mouse model. This finding is in accordance with what has been described in PBC patients [96] and in dnTGF-βRII and IL-2Rα−/− models [85, 89], underlying an important pathogenic role of loss of tolerance in PBC.
The induced mouse models of PBC rely on the breakdown of tolerance to PDC, the mitochondrial autoantigen against which AMA are directed. Jones et al. reported that immunization of SJL/L mice with intraperitoneal injections of bovine PDC-E2 emulsified in complete Freund’s adjuvant containing 10 mg/ml of Mycobacterium tuberculosis is able to induce AMA formation and non-suppurative destructive cholangitis [97, 98]. Some authors have, however, questioned the specificity of the immune response in SJL/L mice [99, 100]. Recently, an additional model for PBC has been successfully induced by the immunization of mice with 2-octynoic acid (2OA) coupled to bovine serum albumin [101]. Immunized mice manifest typical autoantibody formation and cholangitis but fail to develop fibrosis. 2OA is a chemically synthetized compound which is widely present in cosmetic products. This model offers, therefore, an intriguing conceptual support to an environmental origin of PBC [101]. To this extent, previous work showed that xenobiotic modification of PDC-E2 is able to generate new antigens that react with the autoantibodies present in PBC sera [102].
In conclusion, considerable advances in the understanding of PBC pathophysiology have been made in recent years through the study of animal models [103]. Since UDCA still represent the only recommended medical treatment for PBC, murine models offer also the possibility to evaluate potential new drugs. Different compounds have indeed shown promising effects in attenuating the biliary damage in a number of PBC models, suggesting new therapeutic approaches that deserve further studies [104•, 105].
Primary Sclerosing Cholangitis (PSC)
Primary sclerosing cholangitis (PSC), first described in the mid-1850s is characterized grossly by chronic cholestasis accompanied by inflammation of the biliary epithelium resulting in multifocal biliary strictures. PSC is asymptomatic in 50 % of the diagnosed patients [106].
Diagnosis of PSC is made through liver enzyme assessment where the most commonly dysregulated candidate is alkaline phosphatase. Total bilirubin remains normal in most of the cases, whereas the level of amino transferases is elevated in a very small number of patients [107]. One of the major risk factors contributing to the development of PSC is inflammatory bowel disease [108]. A multitude of factors have been deemed responsible for the development and progression of this disease. Considering the heterogeneity of PSC and all the variable factors contributing to this disease, a single animal model mimicking human PSC is hard to develop. Hence, there are a few different models that are used to study the mechanisms involved PSC pathogenesis.
MDR2−/−
Liver cirrhosis resulting from chronic cholangiopathies such as PSC is marked by a massive increase in liver fibrosis. The MDR2−/− mice develop severe biliary fibrosis, and thus have been used has a model of liver fibrogenesis in PSC [109].
Decreased phosphatidylcholine in the bile of MDR2−/− mice might potentiate the toxicity of other bile acids. It is a multistep process where there is leakage of bile (from disrupted tight junctions and basement membranes of bile ducts) into portal tracts causing inflammation and fibrosis [110]. Fibrosis in MDR2−/− mice is caused by a time-dependent alteration in expression of pro- and anti-fibrotic genes [109, 110]. The inflammatory response in MDR2−/− mice varies according to the age of the animal, although there is over-expression of at least some factors such as TNF-α, IL-1β, Il-6, TGF-β1, and IFN-γ when compared to MDR2+/+ control mice. The MDR2−/− animals can thus serve as a good model to intervene for developing treatment strategies to tackle the fibrotic response in PSC. norUDCA or UDCA treatment has already proved to ameliorate fibrosis in PSC models, though controversies exist in regard to their applicability in human subjects [111].
CFTR Mutation
Mouse models with mutations in the exon 10 of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene have been shown to develop focal cholangitis and biliary cirrhosis [112]. Specifically, loss of function of the CFTR gene in BEC results in decreased bile flow and alkalinization in subjects with CF. In a study to evaluate the role of CFTR gene in development of cholangitis, mice with disrupted CFTR gene (cftr −/−) were fed Dextran sodium sulfate (DSS) to induce colitis. DSS caused biliary damage and portal inflammation as displayed by enhanced ductular reaction and high reactivity of cholangiocytes (isolated from the cftr −/− mice) toward LPS treatment [113]. After DSS treatment, intestinal permeability to microbial products as well as endotoxins is increased which reach the liver via portal circulation resulting in inflammation and fibrosis [114, 115]. Taken together, these results suggest that the CFTR mutation is not the only cause for biliary cirrhosis and portal hypertension. This is statistically supported by patient data where it is found that among patients with CF disorder, about 40 % display abnormal hepatic imaging and biochemistry and among which only 5–10 % develop focal biliary cirrhosis and portal hypertension [116]. This is an indication that CFTR dysfunction predisposes to liver diseases.
3,5-Diethoxycarbonyl-1,4-Dihydrocholine (DDC)
To study the pathological alterations occurring in the earlier phases of PBC and PSC, a slowly progressing model is essential. Fickert and colleagues have demonstrated that continuous feeding of 3,5-diethoxycarbonyl-1,4-dihydrocholidine (DDC) induced chronic cholangiopathy that progressed slowly over a period of time. Mice fed with this xenobiotic agent for a week showed ductal proliferation, which progressed slowly over time, and by 4 weeks post treatment the bile ducts contained pigment plugs. The intraductal plugs showed autofluorescence generated from biliary protoporphyrin secretion [117]. Infiltration of neutrophils around both large and small bile ducts, an increase in serum transaminases and an induction of reactive phenotype of the BEC was also observed in the DDC fed mice. Recently, morphological studies confirmed hepatocellular necrosis and phagocytosis of these necrotic cells by Kupffer cells and showed compensatory hepatocyte proliferation in response to DDC-induced injury. This study also revealed that bile canalicular abnormalities occur prior to ductular reactions and periductal fibrosis in this novel xenobiotic-induced model of primary sclerosing cholangitis [118••]. This was the first study showing these characteristics associated with progression of PSC.
Autoimmune Hepatitis (AIH)
Autoimmune hepatitis (AIH) is a form of chronic hepatitis. It is characterized by histological findings (most commonly interface hepatitis), elevated serum aminotransferases, hypergammaglobulinemia, and seropositivity for ANA, anti-LKM-1, and SMA, after the exclusion of other causes of chronic hepatitis [119]. It is important to exclude other causes of chronic hepatitis by checking viral serologies, obtaining a good history for substance abuse including alcohol, and ruling out biliary sources of chronic hepatitis. Disease severity can range from asymptomatic hepatitis [120] to severe, fulminant hepatic failure [121]. Although the cause of AIH remains unknown, the working model of pathogenesis is recognition of self-antigen or autoantibody/antigen complexes by CD4+ T cells [122] resulting in loss of tolerance and progressive necroinflammation and fibrosis in a host with genetic pre-disposition [123]. HLA genes have increasingly been implicated in the genetic link of AIH [123].
Cytokines, specifically TGF-β, have been shown in murine models to play a large role in immune tolerance. TGF-β is secreted by phagocytes that are exposed to apoptotic T cells. This contributes to immune tolerance by inducing CD4 + Foxp3 + regulatory T cells via CD3-specific antibody [124]. Additionally, TGF-β is found to have increased expression in hepatic inflammation. This overexpression is thought to play a role in the suppression of an autoimmune response. Impairment of this signaling pathway has been shown to increase susceptibility of AIH based on histological findings in murine models [125]. This pathway has, therefore, been used to produce animal models of AIH. TGF-β1−/− mice spontaneously develop necroinflammatory hepatitis recapitulating human aspects of AIH [126, 127].
Conclusion
Liver fibrosis is the consequence of many chronic liver diseases and regardless of the etiology is the result of a highly coordinated process. Murine models of liver fibrosis recapitulating fibrogenesis in human liver disease conditions are valuable tools for studying the fibrogenic process of specific diseases. Although recent advances have been made in understanding the molecular mechanisms involved in fibrogenesis and in discovering novel tools that can aid in the diagnosis and treatment of liver fibrosis, additional studies are still needed. Specifically, the efficacy of these diagnostics and therapeutics in human patients still needs to be explored.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115(2):209–218. doi:10.1172/JCI24282
Friedman SL (2003) Liver fibrosis—from bench to bedside. J Hepatol 38(Suppl 1):S38–S53
Friedman SL (2000) Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275(4):2247–2250
Forbes SJ, Parola M (2011) Liver fibrogenic cells. Best Pract Res Clin Gastroenterol 25(2):207–217. doi:10.1016/j.bpg.2011.02.006
Friedman SL (2008) Mechanisms of hepatic fibrogenesis. Gastroenterology 134(6):1655–1669. doi:10.1053/j.gastro.2008.03.003
Lee UE, Friedman SL (2011) Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol 25(2):195–206. doi:10.1016/j.bpg.2011.02.005
Kawada N (2011) Evolution of hepatic fibrosis research. Hepatol Res 41(3):199–208. doi:10.1111/j.1872-034X.2011.00776.x
Starkel P, Leclercq IA (2011) Animal models for the study of hepatic fibrosis. Best Pract Res Clin Gastroenterol 25(2):319–333. doi:10.1016/j.bpg.2011.02.004
Farkas D, Tannenbaum SR (2005) In vitro methods to study chemically-induced hepatotoxicity: a literature review. Curr Drug Metab 6(2):111–125
Johnston DE, Kroening C (1998) Mechanism of early carbon tetrachloride toxicity in cultured rat hepatocytes. Pharmacol Toxicol 83(6):231–239
James R, Desmond P, Kupfer A, Schenker S, Branch RA (1981) The differential localization of various drug metabolizing systems within the rat liver lobule as determined by the hepatotoxins allyl alcohol, carbon tetrachloride and bromobenzene. J Pharmacol Exp Ther 217(1):127–132
Perrissoud D, Auderset G, Reymond O, Maignan MF (1981) The effect of carbon tetrachloride on isolated rat hepatocytes. Virchows Arch B Cell Pathol Incl Mol Pathol 35(2):83–91
Bruckner JV, MacKenzie WF, Muralidhara S, Luthra R, Kyle GM, Acosta D (1986) Oral toxicity of carbon tetrachloride: acute, subacute, and subchronic studies in rats. Fundam Appl Toxicol 6(1):16–34
• Oumi N, Taniguchi KA, Kanai AM, Yasunaga M, Nakanishi T, Sato K (2012) A crucial role of bone morphogenetic protein signaling in the wound healing response in acute liver injury induced by carbon tetrachloride. Int J Hepatol 2012:476820. doi:10.1155/2012/476820. The results of this study show that in mice with a conditional knockout of Bmp1a, the wound-healing response triggered by CCl4-induced liver injury is retarded. Notably, aggravated histological features, reduced expression of albumin and Tdo2 gene expression, and decreased proliferation was observed; suggesting that BMP signaling plays a crucial role in ameliorating acute liver injury
LeSage GD, Glaser SS, Marucci L, Benedetti A, Phinizy JL, Rodgers R et al (1999) Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver. Am J Physiol 276(5 Pt 1):G1289–G1301
LeSage GD, Benedetti A, Glaser S, Marucci L, Tretjak Z, Caligiuri A et al (1999) Acute carbon tetrachloride feeding selectively damages large, but not small, cholangiocytes from normal rat liver. Hepatology 29(2):307–319. doi:10.1002/hep.510290242
Bosma A, Brouwer A, Seifert WF, Knook DL (1988) Synergism between ethanol and carbon tetrachloride in the generation of liver fibrosis. J Pathol 156(1):15–21. doi:10.1002/path.1711560106
Constandinou C, Henderson N, Iredale JP (2005) Modeling liver fibrosis in rodents. Methods Mol Med 117:237–250. doi:10.1385/1-59259-940-0:237
Domenicali M, Caraceni P, Giannone F, Baldassarre M, Lucchetti G, Quarta C et al (2009) A novel model of CCl4-induced cirrhosis with ascites in the mouse. J Hepatol 51(6):991–999. doi:10.1016/j.jhep.2009.09.008
Frezza EE, Gerunda GE, Farinati F, DeMaria N, Galligioni A, Plebani F et al (1994) CCL4-induced liver cirrhosis and hepatocellular carcinoma in rats: relationship to plasma zinc, copper and estradiol levels. Hepatogastroenterology 41(4):367–369
Liu Y, Meyer C, Xu C, Weng H, Hellerbrand C, ten Dijke P et al (2013) Animal models of chronic liver diseases. Am J Physiol Gastrointest Liver Physiol 304(5):G449–G468. doi:10.1152/ajpgi.00199.2012
Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S et al (1998) Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 102(3):538–549. doi:10.1172/JCI1018
• Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC et al (2012) Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143(4):1073–1083 e22. doi:10.1053/j.gastro.2012.06.036. The results of this study show that deactivation of HSCs leads to the termination of fibrogenesis but these reverted HSCs are highly responsive to recurring fibrogenic stimulation
Kang JS, Wanibuchi H, Morimura K, Wongpoomchai R, Chusiri Y, Gonzalez FJ et al (2008) Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity. Toxicol Appl Pharmacol 228(3):295–300. doi:10.1016/j.taap.2007.11.010
Chilakapati J, Korrapati MC, Shankar K, Hill RA, Warbritton A, Latendresse JR et al (2007) Role of CYP2E1 and saturation kinetics in the bioactivation of thioacetamide: effects of diet restriction and phenobarbital. Toxicol Appl Pharmacol 219(1):72–84. doi:10.1016/j.taap.2006.11.036
Porter WR, Gudzinowicz MJ, Neal RA (1979) Thioacetamide-induced hepatic necrosis. II. Pharmacokinetics of thioacetamide and thioacetamide-S-oxide in the rat. J Pharmacol Exp Ther 208(3):386–391
Bruck R, Hershkoviz R, Lider O, Shirin H, Aeed H, Halpern Z (1997) The use of synthetic analogues of Arg-Gly-Asp (RGD) and soluble receptor of tumor necrosis factor to prevent acute and chronic experimental liver injury. Yale J Biol Med 70(4):391–402
• Ohyama T, Sato K, Kishimoto K, Yamazaki Y, Horiguchi N, Ichikawa T et al (2012) Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence. Br J Pharmacol 165(4b):1173–1187. doi:10.1111/j.1476-5381.2011.01599.x. This study explored the anti-fibrotic and antioxidative effect of azelnidipine, which is widely used in clinical practice as a calcium channel blocker. The results of the study showed that azelnidipine inhibited TGF-β1- and AngII-induced HSC activation in vitro and attenuated CCl4- and TAA-induced liver fibrosis; suggesting that azelnidipine may be used as an anti-fibrotic therapeutic
Newell P, Villanueva A, Friedman SL, Koike K, Llovet JM (2008) Experimental models of hepatocellular carcinoma. J Hepatol 48(5):858–879. doi:10.1016/j.jhep.2008.01.008
• Sakurai T, Kudo M, Umemura A, He G, Elsharkawy AM, Seki E et al (2013) p38alpha inhibits liver fibrogenesis and consequent hepatocarcinogenesis by curtailing accumulation of reactive oxygen species. Cancer Res 73(1):215–224. doi:10.1158/0008-5472.CAN-12-1602. In this study, the TAA mouse model was used to examine the role of the stress-activated protein kinase, p38α, in ROS metabolism, liver fibrogenesis, and hepatocarcinogenesis. The results of this study showed thatp38α and its target HSP25/HSP27 reduce ROS accumulation in liver parenchymal cells; suggesting a crucial role for these proteins in the protection against liver fibrosis and hepatocarcinoma
Kroeger-Koepke MB, Koepke SR, McClusky GA, Magee PN, Michejda CJ (1981) alpha-Hydroxylation pathway in the in vitro metabolism of carcinogenic nitrosamines: N-nitrosodimethylamine and N-nitroso-N-methylaniline. Proc Natl Acad Sci USA 78(10):6489–6493
Poirier LA (1975) Hepatocarcinogenesis by diethylnitrosamine in rats fed high dietary levels of lipotropes. J Natl Cancer Inst 54(1):137–140
Yoshida T, Ogata H, Kamio M, Joo A, Shiraishi H, Tokunaga Y et al (2004) SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis. J Exp Med 199(12):1701–1707. doi:10.1084/jem.20031675
Zheng JF, Liang LJ (2008) Intra-portal transplantation of bone marrow stromal cells ameliorates liver fibrosis in mice. Hepatobiliary Pancreat Dis Int 7(3):264–270
• Fuchs BC, Hoshida Y, Fujii T, Wei L, Yamada S, Lauwers GY et al (2014). Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology 59(4):1577–1590. doi:10.1002/hep.26898. The results of this study showed that in the DEN rat model, CCl4 mouse model, and BDL rat model, the EGFR inhibitor, erlotinib, decreased liver injury, fibrosis, and hepatocyte proliferation. These results suggest that erlotinib, which is already FDA approved, may be a novel treatment option for high-risk cirrhosis patients for reducing fibrosis and preventing HCC
Iredale JP, Benyon RC, Arthur MJ, Ferris WF, Alcolado R, Winwood PJ et al (1996) Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology 24(1):176–184. doi:10.1002/hep.510240129
Fickert P, Fuchsbichler A, Moustafa T, Wagner M, Zollner G, Halilbasic E et al (2009) Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol 175(6):2392–2405. doi:10.2353/ajpath.2009.090114
• Kim KH, Chen CC, Monzon RI, Lau LF (2013) Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol 33(10):2078–2090. doi:10.1128/MCB.00049-13. The results of this study showed that CCN1, which is not required for normal liver development or regeneration, is upregulated in response to CCL4- or BDL-induced liver injury and functions to both prevent liver fibrosis and promote liver fibrosis regression. These findings identify the CCN1-signaling pathway as a possible target for the development of new therapeutic options for the treatment of liver fibrosis
Jacquemin E, De Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M et al (2001) The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 120(6):1448–1458
Ruetz S, Gros P (1994) Phosphatidylcholine translocase: a physiological role for the mdr2 gene. Cell 77(7):1071–1081. doi:10.1016/0092-8674(94)90446-4
Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L et al (1993) Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75(3):451–462
van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P et al (1996) MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 87(3):507–517. doi:10.1016/S0092-8674(00)81370-7
Oude Elferink RP (2007) Paulusma CC. Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Arch 453(5):601–610. doi:10.1007/s00424-006-0062-9
Trauner M, Fickert P, Wagner M (2007) MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis 27(1):77–98. doi:10.1055/s-2006-960172
•• Cai SY, Mennone A, Soroka CJ, Boyer JL (2014) Altered expression and function of canalicular transporters during early development of cholestatic liver injury in Abcb4-deficient mice. Am J Physiol Gastrointest Liver Physiol 306(8):G670–G676. doi:10.1152/ajpgi.00334.2013. The results of this study showed that the canalicular transporters that determine the formation of bile, including: Bsep, Mrp2, ABCg5, Ost-α, and Ntcp, are altered early in the development of cholestasis in Abcd4 −/− mice, suggesting that the disregulation of these transporters may play a role in the pathogenesis of cholestasis
Fickert P, Magnes C, Guelly C, Thueringer A, Frank S et al (2012) Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 142(1):140–151. doi:10.1053/j.gastro.2011.09.051
• Fickert P, Pollheimer MJ, Silbert D, Moustafa T, Halilbasic E, Krones E et al (2013) Differential effects of norUDCA and UDCA in obstructive cholestasis in mice. J Hepatol 58(6):1201–1208. doi:10.1016/j.jhep.2013.01.026. The results of this study showed that the UDCA derivative, norUDCA, which is significantly less toxic than UDCA, ameliorated liver injury in Abcb4 −/− BDL mice; suggesting that there are important differences in the metabolism and therapeutic implications of UDCA and norUDCA
Keppler D, Frohlich J, Reutter W, Wieland O, Decker K (1969) Changes in uridine nucleotides during liver perfusion with D-galactosamine. FEBS Lett 4(4):278–280
Mangeney-Andreani M, Sire O, Montagne-Clavel J, Nordmann R, Nordmann J (1982) Inhibitory effect of d-galactosamine administration on fatty acid oxidation in rat hepatocytes. FEBS Lett 145(2):267–270
Sire O, Mangeney M, Montagne J, Nordmann R, Nordmann J (1983) Carnitine palmitoyltransferase I. Inhibition by d-galactosamine and role of phospholipids. Eur J Biochem 136(2):371–375
Stramentinoli G, Gualano M, Ideo G (1978) Protective role of S-adenosyl-l-methionine on liver injury induced by d-galactosamine in rats. Biochem Pharmacol 27(10):1431–1433
Almasio P, Bortolini M, Pagliaro L, Coltorti M (1990) Role of S-adenosyl-l-methionine in the treatment of intrahepatic cholestasis. Drugs 40(Suppl 3):111–123
Osman E, Owen JS, Burroughs AK (1993) Review article: S-Adenosyl-l-Methionine—a new therapeutic agent in liver disease? Aliment Pharmacol Ther 7(1):21–28. doi:10.1111/j.1365-2036.1993.tb00065.x
Crocenzi FA, Pellegrino JM, Catania VA, Luquita MG, Roma MG, Mottino AD et al (2006) Galactosamine prevents ethinylestradiol-induced cholestasis. Drug Metab Dispos 34(6):993–997. doi:10.1124/dmd.106.009308
Fausto N, Campbell JS (2003) The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 120(1):117–130
Forbes S, Vig P, Poulsom R, Thomas H, Alison M (2002) Hepatic stem cells. J Pathol 197(4):510–518. doi:10.1002/path.1163
Knight B, Matthews VB, Olynyk JK, Yeoh GC (2005) Jekyll and Hyde: evolving perspectives on the function and potential of the adult liver progenitor (oval) cell. BioEssays 27(11):1192–1202. doi:10.1002/bies.20311
Roskams TA, Libbrecht L, Desmet VJ (2003) Progenitor cells in diseased human liver. Semin Liver Dis 23(4):385–396. doi:10.1055/s-2004-815564
Sell S (2001) The role of progenitor cells in repair of liver injury and in liver transplantation. Wound Repair Regen 9(6):467–482
Walkup MH, Gerber DA (2006) Hepatic stem cells: in search of. Stem Cells 24(8):1833–1840. doi:10.1634/stemcells.2006-0063
Kon J, Ichinohe N, Ooe H, Chen Q, Sasaki K, Mitaka T (2009) Thy1-positive cells have bipotential ability to differentiate into hepatocytes and biliary epithelial cells in galactosamine-induced rat liver regeneration. Am J Pathol 175(6):2362–2371
Anstee QM, Goldin RD (2006) Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 87(1):1–16. doi:10.1111/j.0959-9673.2006.00465.x
Gao D, Wei C, Chen L, Huang J, Yang S, Diehl AM (2004) Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease. Am J Physiol Gastrointest Liver Physiol 287(5):G1070–G1077. doi:10.1152/ajpgi.00228.2004
Kirsch R, Clarkson V, Shephard EG, Marais DA, Jaffer MA, Woodburne VE et al (2003) Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies. J Gastroenterol Hepatol 18(11):1272–1282
Larter CZ, Yeh MM, Williams J, Bell-Anderson KS, Farrell GC (2008) MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes. J Hepatol 49(3):407–416. doi:10.1016/j.jhep.2008.03.026
Leclercq IA, Lebrun VA, Starkel P, Horsmans YJ (2007) Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARgamma agonist pioglitazone. Lab Invest 87(1):56–65. doi:10.1038/labinvest.3700489
Rinella ME, Green RM (2004) The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol 40(1):47–51
• Jung YA, Choi YK, Jung GS, Seo HY, Kim HS, Jang BK et al (2014) Sitagliptin attenuates methionine/choline-deficient diet-induced steatohepatitis. Diabetes Res Clin Pract 105(1):47–57. doi:10.1016/j.diabres.2014.04.028. The results of this study show that sitagliptin, a drug commonly prescribed to type II diabetes patients to lower blood sugar, attenuates hepatic steatosis, inflammation, and fibrosis, suggesting that sitagliptin may be a promising option for the treatment of liver fibrosis
da Costa KA, Garner SC, Chang J, Zeisel SH (1995) Effects of prolonged (1 year) choline deficiency and subsequent re-feeding of choline on 1,2-sn-diradylglycerol, fatty acids and protein kinase C in rat liver. Carcinogenesis 16(2):327–334
Ghoshal AK, Rushmore TH, Farber E (1987) Initiation of carcinogenesis by a dietary deficiency of choline in the absence of added carcinogens. Cancer Lett 36(3):289–296
Corbin KD, Zeisel SH (2012) Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Curr Opin Gastroenterol 28(2):159–165. doi:10.1097/MOG.0b013e32834e7b4b
de Wit NJW, Afman LA, Mensink M, Müller M (2012) Phenotyping the effect of diet on non-alcoholic fatty liver disease. J Hepatol 57(6):1370–1373. doi:10.1016/j.jhep.2012.07.003
Walkey CJ, Yu L, Agellon LB, Vance DE (1998) Biochemical and evolutionary significance of phospholipid methylation. J Biol Chem 273(42):27043–27046
Berthiaume F, Barbe L, Mokuno Y, MacDonald AD, Jindal R, Yarmush ML (2009) Steatosis reversibly increases hepatocyte sensitivity to hypoxia-reoxygenation injury. J Surg Res 152(1):54–60. doi:10.1016/j.jss.2007.12.784
Hensley K, Kotake Y, Sang H, Pye QN, Wallis GL, Kolker LM et al (2000) Dietary choline restriction causes complex I dysfunction and increased H(2)O(2) generation in liver mitochondria. Carcinogenesis 21(5):983–989
Koca SS, Bahcecioglu IH, Poyrazoglu OK, Ozercan IH, Sahin K, Ustundag B (2008) The treatment with antibody of TNF-alpha reduces the inflammation, necrosis and fibrosis in the non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet. Inflammation 31(2):91–98. doi:10.1007/s10753-007-9053-z
Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A et al (2006) Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55(3):415–424. doi:10.1136/gut.2005.071118
Kaplan MM, Gershwin ME (2005) Primary biliary cirrhosis. N Engl J Med 353(12):1261–1273. doi:10.1056/NEJMra043898
Gershwin ME, Mackay IR (2008) The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 47(2):737–745. doi:10.1002/hep.22042
Hirschfield GM, Gershwin ME (2013) The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 8:303–330. doi:10.1146/annurev-pathol-020712-164014
Koarada S, Wu Y, Fertig N, Sass DA, Nalesnik M, Todd JA et al (2004) Genetic control of autoimmunity: protection from diabetes, but spontaneous autoimmune biliary disease in a nonobese diabetic congenic strain. J Immunol 173(4):2315–2323
Mason AL (2006) An autoimmune biliary disease mouse model for primary biliary cirrhosis: something for everyone. Hepatology 44(4):1047–1050. doi:10.1002/hep.21390
Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R et al (2006) NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 203(5):1209–1219. doi:10.1084/jem.20051911
Moritoki Y, Tsuda M, Tsuneyama K, Zhang W, Yoshida K, Lian ZX et al (2011) B cells promote hepatic inflammation, biliary cyst formation, and salivary gland inflammation in the NOD.c3c4 model of autoimmune cholangitis. Cell Immunol 268(1):16–23. doi:10.1016/j.cellimm.2011.01.005
Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS et al (2006) Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 177(3):1655–1660
Gorelik L, Flavell RA (2000) Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12(2):171–181
Ueno Y, Ambrosini YM, Moritoki Y, Ridgway WM, Gershwin ME (2010) Murine models of autoimmune cholangitis. Curr Opin Gastroenterol 26(3):274–279. doi:10.1097/MOG.0b013e32833755aa
Yang GX, Lian ZX, Chuang YH, Moritoki Y, Lan RY, Wakabayashi K et al (2008) Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice. Hepatology 47(6):1974–1982. doi:10.1002/hep.22226
Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH et al (2006) IL-2 receptor alpha(−/−) mice and the development of primary biliary cirrhosis. Hepatology 44(5):1240–1249. doi:10.1002/hep.21385
Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW (1995) Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3(4):521–530
Hsu W, Zhang W, Tsuneyama K, Moritoki Y, Ridgway WM, Ansari AA et al (2009) Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Ralpha(−/−) mice. Hepatology 49(1):133–140. doi:10.1002/hep.22591
Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I et al (2008) Ae2a, b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology 134(5):1482–1493. doi:10.1053/j.gastro.2008.02.020
Romero MF, Fulton CM, Boron WF (2004) The SLC4 family of HCO 3—transporters. Pflugers Arch 447(5):495–509. doi:10.1007/s00424-003-1180-2
Martinez-Anso E, Castillo JE, Diez J, Medina JF, Prieto J (1994) Immunohistochemical detection of chloride/bicarbonate anion exchangers in human liver. Hepatology 19(6):1400–1406
Fickert P, Trauner M (2009) When lightning strikes twice: the plot thickens for a dual role of the anion exchanger 2 (AE2/SLC4A2) in the pathogenesis and treatment of primary biliary cirrhosis. J Hepatol 50(3):633–635. doi:10.1016/j.jhep.2008.12.006
Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y et al (2006) Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 43(4):729–737. doi:10.1002/hep.21123
Jones DE, Palmer JM, Kirby JA, De Cruz DJ, McCaughan GW, Sedgwick JD et al (2000) Experimental autoimmune cholangitis: a mouse model of immune-mediated cholangiopathy. Liver 20(5):351–356
Jones DE, Palmer JM, Yeaman SJ, Kirby JA, Bassendine MF (1999) Breakdown of tolerance to pyruvate dehydrogenase complex in experimental autoimmune cholangitis: a mouse model of primary biliary cirrhosis. Hepatology 30(1):65–70. doi:10.1002/hep.510300123
Sasaki M, Long SA, Van De Water J, He XS, Shultz L, Coppel RL (2002) The SJL/J mouse is not a model for PBC. Hepatology 35(5):1284–1286. doi:10.1053/jhep.2002.32540
Jones DE, Palmer JM, Burt AD, Kirby JA (2008) The specificity of liver inflammation in mouse models of primary biliary cirrhosis. Hepatology 48(4):1353–1354; author reply 4–5. doi:10.1002/hep.22522
Wakabayashi K, Lian ZX, Leung PS, Moritoki Y, Tsuneyama K, Kurth MJ et al (2008) Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology 48(2):531–540. doi:10.1002/hep.22390
Amano K, Leung PS, Rieger R, Quan C, Wang X, Marik J et al (2005) Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol 174(9):5874–5883
Concepcion AR, Medina JF (2012) Approaches to the pathogenesis of primary biliary cirrhosis through animal models. Clin Res Hepatol Gastroenterol 36(1):21–28. doi:10.1016/j.clinre.2011.07.007
• Dhirapong A, Yang GX, Nadler S, Zhang W, Tsuneyama K, Leung P et al (2013) Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology 57(2):708–715. doi:10.1002/hep.26067. The results of this study showed that CTLA-4-Ig treatment completely inhibits the development of cholangitis in a mouse model of PBC (2OA-BSA). Additionally, treatment with CTLA-4-Ig after the development of cholangitis reduced T-cell infiltrates and cholangiocyte damage; therefore, CTLA-4-Ig may prove to be a new treatment option for PBC patients
Moritoki Y, Lian ZX, Lindor K, Tuscano J, Tsuneyama K, Zhang W et al (2009) B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice. Hepatology 50(6):1893–1903. doi:10.1002/hep.23238
Porayko MK, Wiesner RH, LaRusso NF, Ludwig J, MacCarty RL, Steiner BL et al (1990) Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease. Gastroenterology 98(6):1594–1602
Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B et al (2010) Diagnosis and management of primary sclerosing cholangitis. Hepatology 51(2):660–678. doi:10.1002/hep.23294
Olsson R, Danielsson A, Jarnerot G, Lindstrom E, Loof L, Rolny P et al (1991) Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 100(5 Pt 1):1319–1323
Popov Y, Patsenker E, Fickert P, Trauner M, Schuppan D (2005) Mdr2 (Abcb4)−/− mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol 43(6):1045–1054. doi:10.1016/j.jhep.2005.06.025
Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H et al (2004) Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127(1):261–274
Fickert P, Wagner M, Marschall HU, Fuchsbichler A, Zollner G, Tsybrovskyy O et al (2006) 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 130(2):465–481. doi:10.1053/j.gastro.2005.10.018
Pollheimer MJ, Halilbasic E, Fickert P, Trauner M (2011) Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 25(6):727–739. doi:10.1016/j.bpg.2011.10.009
Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C et al (2011) Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-kappaB-mediated inflammatory response in mice. Gastroenterology 141(4):1498–508, 508 e1–5. doi:10.1053/j.gastro.2011.06.052
Blanco PG, Zaman MM, Junaidi O, Sheth S, Yantiss RK, Nasser IA et al (2004) Induction of colitis in cftr−/− mice results in bile duct injury. Am J Physiol Gastrointest Liver Physiol 287(2):G491–G496. doi:10.1152/ajpgi.00452.2003
Neilly PJ, Gardiner KR, Kirk SJ, Jennings G, Anderson NH, Elia M et al (1995) Endotoxaemia and cytokine production in experimental colitis. Br J Surg 82(11):1479–1482
Martin CR, Zaman MM, Ketwaroo GA, Bhutta AQ, Coronel E, Popov Y et al (2012) CFTR dysfunction predisposes to fibrotic liver disease in a murine model. Am J Physiol Gastrointest Liver Physiol 303(4):G474–G481. doi:10.1152/ajpgi.00055.2012
Fickert P, Stoger U, Fuchsbichler A, Moustafa T, Marschall HU, Weiglein AH et al (2007) A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. Am J Pathol 171(2):525–536. doi:10.1152/ajpgi.00055.2012
•• Miyao M, Ozeki M, Abiru H, Manabe S, Kotani H, Tsuruyama T et al (2013) Bile canalicular abnormalities in the early phase of a mouse model of sclerosing cholangitis. Dig Liver Dis 45(3):216–225. 10.1016/j.dld.2012.09.007. The results of this study validate DDC, the mouse model that is used for the early phases of PSC, by showing that bile canalicular abnormalities occur during the early phase of sclerosis
Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D et al (2010) Diagnosis and management of autoimmune hepatitis. Hepatology 51(6):2193–2213. doi:10.1002/hep.23584
Kogan J, Safadi R, Ashur Y, Shouval D, Ilan Y (2002) Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: a study of 68 patients. J Clin Gastroenterol 35(1):75–81
Kessler W, Cummings O, Eckert G, Chalasani N, Lumeng L, Kwo P (2004) Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis. Clin Gastroenterol Hepatol 2:625–631
Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G (2002) Pathogenesis of autoimmune hepatitis. Clin Liver Dis 6(3):727–737
Krawitt EL (2006) Autoimmune hepatitis. N Engl J Med 354(1):54–66. doi:10.1056/NEJMra050408
Perruche S, Zhang P, Liu Y, Saas P, Bluestone JA, Chen W (2008) CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med 14(5):528–535. doi:10.1038/nm1749
Schramm C, Protschka M, Kohler HH, Podlech J, Reddehase MJ, Schirmacher P et al (2003) Impairment of TGF-beta signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice. Am J Physiol Gastrointest Liver Physiol 284(3):G525–G535. doi:10.1152/ajpgi.00286.2002
Gorham JD, Lin JT, Sung JL, Rudner LA, French MA (2001) Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependent hepatitis. J Immunol 166(10):6413–6422
Czaja AJ (2010) Animal models of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol 4(4):429–443. doi:10.1586/egh.10.42
Acknowledgments
This material is the result of work supported with resources and the use of facilities at the Central Texas Veterans Health Care System, Temple, Texas. The views presented are those of the authors and do not necessarily represent the views of the Department of Veteran Affairs. This work was supported by the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White Hospital, a VA research Career Scientist Award, a VA Merit Award to Dr. Alpini, the NIH grants DK062975, DK58411 and DK07698 to Drs. Alpini and Glaser and a VA Merit Award to Dr. Glaser.
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Martínez, A.K., Maroni, L., Marzioni, M. et al. Mouse Models of Liver Fibrosis Mimic Human Liver Fibrosis of Different Etiologies. Curr Pathobiol Rep 2, 143–153 (2014). https://doi.org/10.1007/s40139-014-0050-2
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DOI: https://doi.org/10.1007/s40139-014-0050-2