Combination of systemic thioacetamide (TAA) injections and ethanol feeding accelerates hepatic fibrosis in C3H/He mice and is associated with intrahepatic up regulation of MMP-2, VEGF and ICAM-1

Kornek, Miroslaw; Raskopf, E.; Guetgemann, Ines; Ocker, Matthias; Gerceker, S.; Gonzalez‐Carmona, Maria A.; Rabe, Christian; Sauerbruch, Tilman; Schmitz, Volker

doi:10.1016/j.jhep.2006.03.017

Cited by 44 publications

(40 citation statements)

References 31 publications

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“…and EtOH (Figure 2A). Similar to our previous publication (15), livers of TAA-and EtOH-treated mice showed fibrotic septa with predominant porto-porto bridging ( Figure 2B and b). Additionally, hepatic regeneration nodules could be detected in several mice.…”

Section: Histological and Immunohistological Assessment Of Fibrosissupporting

confidence: 89%

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1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-Formulated, Immune-Stimulatory Vascular Endothelial Growth Factor A Small Interfering RNA (siRNA) Increases Antitumoral Efficacy in Murine Orthotopic Hepatocellular Carcinoma with Liver Fibrosis

Kornek

Lukacs‐Kornek²,

Limmer³

et al. 2008

Mol Med

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Section: Histological and Immunohistological Assessment Of Fibrosissupporting

confidence: 89%

“…injections of thioacetamide (TAA) (Sigma-Aldrich, Taufkirchen, Germany; 0.15 mg/g body weight) three times per wk for up to 24 wks in combination with alcohol feeding in sweetened drinking water (10% vol/vol) according to a published protocol (8,15,16).…”

Section: Administration Of Thioacetamide and Etohmentioning

confidence: 99%

1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-Formulated, Immune-Stimulatory Vascular Endothelial Growth Factor A Small Interfering RNA (siRNA) Increases Antitumoral Efficacy in Murine Orthotopic Hepatocellular Carcinoma with Liver Fibrosis

Kornek

Lukacs‐Kornek²,

Limmer³

et al. 2008

Mol Med

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“…Coito, unpublished observations). On the other hand, high levels of MMP-2 56 and steatosis 57 have been linked to a high susceptibility of liver fibrosis, although the link between MMP-2 and fibrosis is likely not simple and may require the simultaneous presence of other profibrosis factors. Indeed, CS1-treated OLTs at day 7, which showed increased levels of MMP-2 activity (compared with naïve livers), were characterized by minimal levels of fibronectin deposition.…”

Section: Discussionmentioning

confidence: 99%

Fibronectin-α4β1 Integrin Interactions Regulate Metalloproteinase-9 Expression in Steatotic Liver Ischemia and Reperfusion Injury

Moore

Shen

Gao

et al. 2007

The American Journal of Pathology

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Ischemia/reperfusion injury is a major cause of the highly dysfunctional rate observed in marginal steatotic orthotopic liver transplantation. In this study, we document that the interactions between fibronectin, a key extracellular matrix protein, and its integrin receptor ␣4␤1, expressed on leukocytes, specifically up-regulated the expression and activation of metalloproteinase-9 (MMP-9, gelatinase B) in a wellestablished steatotic rat liver model of ex vivo ice-cold ischemia followed by isotransplantation. The presence of the active form of MMP-9 was accompanied by massive intragraft leukocyte infiltration, high levels of proinflammatory cytokines, such as interleukin-1␤ and tumor necrosis factor-␣, and impaired liver function. Interestingly, MMP-9 activity in steatotic liver grafts was, to a certain extent, independent of the expression of its natural inhibitor, the tissue inhibitor of metalloproteinases-1. Moreover, the blockade of fibronectin-␣4␤1-integrin interactions inhibited the expression/activation of MMP-9 in steatotic orthotopic liver transplantations without significantly affecting the expression of metalloproteinase-2 (MMP-2, gelatinase A). Finally, we identified T lymphocytes and monocytes/macrophages as major sources of MMP-9 in steatotic liver grafts. Hence, these findings reveal a novel aspect of the function of fibronectin-␣4␤1 integrin interactions that holds significance for the successful use of marginal steatotic livers in transplantation. Orthotopic liver transplantation (OLT) is an effective therapeutic modality for end-stage liver disease. The critical shortage of human donor livers has provided the rationale to identify methods that would allow successful utilization of marginal steatotic donor grafts, which are characterized by higher dysfunction rate compared with nonsteatotic OLTs. 1,2Ischemia/reperfusion (I/R) insult, an antigen-independent event associated with leukocyte adhesion/migration and release of cytokines and free radicals, plays a major role in post-I/R organ injury suffered by OLTs.3,4 Leukocyte recruitment to sites of inflammatory stimulation in liver, which is a venous-driven vascular bed with slow flow rates, is poorly understood and may require distinct cascade of adhesive events compared with other organs with higher flow rates. Fibronectin (FN), a large glycoprotein with a central role in cellular adhesion and migration, is likely a key extracellular matrix (ECM) protein involved in these events. 5The role of FN in leukocyte adhesion, migration, and activation has been extensively reported.6 -8 Moreover, we have previously shown that the so-called cellular FN, which is the most potent form of FN in promoting cell spreading and migration, 9,10 is virtually absent in naïve steatotic livers, and it is expressed very early on the sinusoidal endothelium during cold ischemia, before steatotic OLT and leukocyte recruitment at the graft site. 11Leukocyte transmigration across endothelial and ECM barriers is dependent on both adhesive and focal matrix degradation mechani...

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“…Dosages for the IP route ranged from 10 mg/kg to 400 mg/kg, two to three times per week from between 5 and 20 weeks while recently most researches have used dosages of between 100 mg/kg and 200 mg/kg, three times per week for at least six weeks. Most used TAA as the only model of fibrosis and cirrhosis (12); the remainder (6) used TAA in conjunction with other models such as CCl 4 or bile duct ligation, for example. Unfortunately, neither the proportion of experimental animals which developed advanced fibrosis or cirrhosis, nor the mortality rates were reported in these studies.…”

Section: Historical Background and Current Usagementioning

confidence: 99%

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

et al. 2015

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In addition to carbon tetrachloride (CCl 4 ), thioacetamide (TAA) represents a second widely used model for the induction of experimental liver fibrosis, but can also be employed for the development of acute liver failure and liver tumours. While TAA itself is not hepatotoxic, its reactive metabolites covalently bind to proteins and lipids thereby causing oxidative stress and centrilobular necrosis. Compared with CCl 4 , TAA leads to more periportal infiltrates and more pronounced ductal proliferation. While TAA has been shown to induce liver fibrosis development in several different mouse strains, wide variations in the administration routes, doses and treatment durations have been reported. Therefore, an adoption of a universal standard operating procedure for the administration of TAA is urgently needed. For that purpose, we are presenting here two TAA models (intraperitoneal administration of 150 mg/kg of TAA three times per week for 11 weeks in rats, and TAA administration in drinking water at 300 mg/L for 2-4 months in mice) with which we have had success in reliably and reproducibly developing chronic liver injury and fibrosis.

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Combination of systemic thioacetamide (TAA) injections and ethanol feeding accelerates hepatic fibrosis in C3H/He mice and is associated with intrahepatic up regulation of MMP-2, VEGF and ICAM-1

Cited by 44 publications

References 31 publications

1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-Formulated, Immune-Stimulatory Vascular Endothelial Growth Factor A Small Interfering RNA (siRNA) Increases Antitumoral Efficacy in Murine Orthotopic Hepatocellular Carcinoma with Liver Fibrosis

1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-Formulated, Immune-Stimulatory Vascular Endothelial Growth Factor A Small Interfering RNA (siRNA) Increases Antitumoral Efficacy in Murine Orthotopic Hepatocellular Carcinoma with Liver Fibrosis

Fibronectin-α4β1 Integrin Interactions Regulate Metalloproteinase-9 Expression in Steatotic Liver Ischemia and Reperfusion Injury

Standard Operating Procedures in Experimental Liver Research: Thioacetamide model in mice and rats

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