Single dose intravenous thioacetamide administration as a model of acute liver damage in rats

Chen, Tse-Min; Subeq, Yi‐Maun; Lee, Ru‐Ping; Chiou, Tzyy‐Wen; Hsu, Bang‐Gee

doi:10.1111/j.1365-2613.2008.00576.x

Cited by 66 publications

(50 citation statements)

References 26 publications

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“…The induction of the mediators in cells of portal area (mainly LMFs and biliary cells) may happen through molecules such as ROS, which have been shown to be produced in the TAA model. 34 Together with the data presented here, we suggest that upregulation of gene expression of several chemokines (mainly in LMFs and biliary cells) may be necessary to induce recruitment of inflammatory cells in a localized area beginning around the vessel walls within the portal area.…”

Section: Discussionsupporting

confidence: 82%

Induction of chemokines and cytokines before neutrophils and macrophage recruitment in different regions of rat liver after TAA administration

Amanzada¹,

Moriconi²,

Mansuroglu

et al. 2014

Laboratory Investigation

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Single-dose thioacetamide (TAA) administration induces inflammation and acute liver damage. The mechanism of inflammatory cell recruitment in the liver is still unclear. The aim of this study was to examine the sequence and recruitment of inflammatory cells in different liver regions in relation to CXC-and CC-chemokine and cytokine expression during acute liver injury. Single-dose TAA was administered to rats intraperitoneally, and animals were killed at different time points thereafter. Serum and liver tissue were taken and frozen immediately. Tissue was used for immunostaining cryostat sections, RNA, and protein extraction. RT-PCR and western blotting were performed for RNA and protein analysis, respectively. An early increase (3 h) in CXCL8/IL-8 levels was measured followed by a marked release in MCP1/CCL2 (24 h) serum levels after TAA administration compared with controls. Similarly, an early increase in specific RNA of hepatic chemokines CXCL1/KC and CXCL8/IL-8 was found at 3 h, followed by an upregulation of CXCL5/LIX (6 h), CXCL2/MIP-2 (12 h), and MCP1/CCL2 gene expression at 24-48 h. Further, an induction of pro-inflammatory cytokines IFN-g and IL-1b followed by IL-6 and TNF-a was observed with a maximum at 12 h. The magnitude of increase in gene expression of TNF-a and MCP1/CCL2 was the highest among all cytokines and chemokines, respectively. By means of immunohistochemistry, an early (12-24 h) increase in the number of only neutrophil granulocytes (NGs) attached to and around portal vessel walls was observed, followed by increased numbers of mononuclear phagocytes (24-48 h) along the sinusoids. Treatment of the human monocytic cell line U-937 with TNF-a increased the gene expression of CXCL1/KC, CXCL8/IL-8, and MCP1/ CCL2. Conversely, adding of infliximab (IFX) to the culture medium inhibited this upregulation significantly. In conclusion, single-dose TAA administration induces a sequence of events with a defined upregulation of gene expression of inflammatory chemokines and cytokines and a transient accumulation of NGs within the portal area and macrophages along the sinusoids throughout the liver. Periportal inflammation seems to precede hepatocellular damage.

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Section: Discussionsupporting

confidence: 82%

Induction of chemokines and cytokines before neutrophils and macrophage recruitment in different regions of rat liver after TAA administration

Amanzada¹,

Moriconi²,

Mansuroglu

et al. 2014

Laboratory Investigation

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“…OS participates as a critical factor in the mechanism of HE production, especially in hyperammonemic conditions (Kosenko et al, 1997;Norenberg, 2003). Results from the present study revealed marked increase in serum ammonia levels of TAA-treated rats after 6 weeks, compared to normal control that was consistent with other investigations (Chen et al, 2008;Farjam et al, 2012;Huang et al, 2012). Ammonia also reduced intracellular levels of glutathione (GSH) (Murthy et al, 2001).…”

Section: Resultssupporting

confidence: 92%

“…This leads to oxidative stress (Lena and Subramanian, 2004;Norenberg et al, 2004b), which eventually results in increased levels of lipid peroxidation products (MDA) and decreased levels of antioxidants (GSH and SOD) in TAA-treated rats. Consequently, CLF following TAA administration is well established by the elevated activities of liver transaminases (ALT and AST) in the present study, indicating cellular leakage and loss of functional integrity of hepatic membrane (Chen et al, 2008;AlAttar, 2012;Anbarasu et al, 2012;Farjam et al, 2012). The extensive liver injury induced by TAA through its free radical generation mechanism, which in turn has the ability to cause hepatic damage resulting in increased leakage of cellular enzymes.…”

Section: Resultssupporting

confidence: 50%

Antioxidant and Hypo-Ammonemic Activities of Alpha-Lactalbumin and Vitamin C in Thioacetamide-Induced Liver and Brain Damage in Rats

Mansour¹,

Nada²,

Elmahmoudy³

et al. 2015

J App Pharm Sci

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Hepatic encephalopathy (HE) is a syndrome resulting from acute or chronic liver failure. The main hypothesis suggests a state of hyperammonemia which is responsible for both direct and indirect alterations in cerebral metabolism with increased production of reactive oxygen and nitrogen species. The effect of milk-derived alphalactalbumin (α-LAC) and vitamin C (vit. C) was evaluated in thioacetamide (TAA)-induced HEmodel in the current study. Animals were treated with TAA (100 mg/kg, i.p.) or saline thrice weekly for six weeks to induce HE then treatment groups received orally α-LAC (100 or150 mg/kg) and /or vit. C (500 mg/kg)daily for two weeks. Twenty-four hours after last treatment sera, liver and brain samples were collected to assess serum ammonia level, activities of alanine transaminase (ALT), and aspartate transaminase (AST), brain and liver oxidative stress parameters as well as histopathological investigations.TAA rats experienced increases in serum activities of ALT and AST as well as serum levels of ammonia. Furthermore, TAA induced hepatic and brain oxidative damage as indicated by increase in lipid peroxidation (LP), decrease in reduced glutathione (GSH) and decrease in superoxide dismutase (SOD) activity as well as increased nitric oxide (NO) levels. TAA caused distortion of hepatic and brain architecture as shown by histopathological examination. Treatment with α-LAC either alone or combined with vit. C resulted in improved liver functions by decline in serum AST and ALT activities and reduction in serum ammonia level. Alpha-LAC and vit. C reduced LP and NO levels while increased GSH concentration and SOD activity in hepatic and brain tissues. Finally, α-LAC-vit. C combination improved the hepatic and brain histological picture. Alpha-LAC-vit. C combination may be a promising pharmacological tool in providing a natural source of branched-chain amino acids and powerful antioxidants to combat hepatic encephalopathy-associated hyperammonemia and its consequential oxidative damage in liver and brain.

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“…The hepatotoxic ability of TAA is well described in the literature and this drug has been extensively used in rat models of ALF and HE in sequential repeated dose administration [9,[13][14][15][16] . Once in circulation, TAA is absorbed and bioactivated by hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Murine model to study brain, behavior and immunity during hepatic encephalopathy

Gomides¹

2014

WJH

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AIM:To propose an alternative model of hepatic encephalopathy (HE) in mice, resembling the human features of the disease. METHODS:Mice received two consecutive intraperitoneal injections of thioacetamide (TAA) at low dosage (300 mg/kg). Liver injury was assessed by serum transaminase levels (ALT) and liver histology (hematoxylin and eosin). Neutrophil infiltration was estimated by confocal liver intravital microscopy. Coagulopathy was evaluated using prolonged prothrombin and partial thromboplastin time. Hemodynamic parameters were measured through tail cuff. Ammonia levels were quantified in serum and brain samples. Electroencephalography (EEG) and psychomotor activity score were performed to show brain function. Brain edema was evaluated using magnetic resonance imaging. RESULTS:Mice submitted to the TAA regime developed massive liver injury, as shown by elevation of serum ALT levels and a high degree of liver necrosis. An intense hepatic neutrophil accumulation occurred in response to TAA-induced liver injury. This led to mice mortality and weight loss, which was associated with severe coagulopathy. Furthermore, TAA-treated mice presented with increased serum and cerebral levels of ammonia, in parallel with alterations in EEG spectrum and discrete brain edema, as shown by magnetic resonance imaging. In agreement with this, neuropsychomotor abnormalities ensued 36 h after TAA, fulfilling several HE features observed in humans. In this context of liver injury and neurological dysfunction, we observed lung inflammation and alterations in blood pressure and heart rate that were indicative of multiple organ dysfunction syndrome. Key words: Hepatic encephalopathy; Liver injury; Thioacetamide; Neurological dysfunction; Neuropsychomotor abnormalities; Intracranial hypertension; Cerebral herniation Core tip: The study of hepatic encephalopathy is crucial for development of new therapies but has been dampened by the absence of murine models resembling the disease in patients. We showed that sequential thioacetamide injections cause extensive liver injury in mice, leading to increased ammonia levels, electroencephalography alterations and brain edema. In line with this, mice presented with poor psychomotor activity and survival rate. Liver injury and brain function impairment by thioacetamide resulted in systemic alterations such as coagulopathy, hemodynamic instability and lung inflammation, consistent with multiple organ failure. Therefore, this alternative model may provide tools for new therapeutic insights for hepatic encephalopathy. CONCLUSION:Gomides LF, Marques PE, Faleiros BE, Pereira RV, Amaral SS, Lage TR, Resende GHS, Guidine PAM, Foureaux G, Ribeiro FM, Martins FP, Fontes MAP, Ferreira AJ, Russo RC, Teixeira MM, Moraes MF, Teixeira AL, Menezes GB. Murine model to study brain, behavior and immunity during hepatic encephalopathy. World J Hepatol 2014; 6(4): 243-250 Available from: URL:

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Single dose intravenous thioacetamide administration as a model of acute liver damage in rats

Cited by 66 publications

References 26 publications

Induction of chemokines and cytokines before neutrophils and macrophage recruitment in different regions of rat liver after TAA administration

Induction of chemokines and cytokines before neutrophils and macrophage recruitment in different regions of rat liver after TAA administration

Antioxidant and Hypo-Ammonemic Activities of Alpha-Lactalbumin and Vitamin C in Thioacetamide-Induced Liver and Brain Damage in Rats

Murine model to study brain, behavior and immunity during hepatic encephalopathy

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