Skip to main content
NCBI home page
International Journal of Experimental Pathology logoLink to International Journal of Experimental Pathology
. 2008 Aug;89(4):223–231. doi: 10.1111/j.1365-2613.2008.00576.x

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

Tse-Min Chen *, Yi-Maun Subeq ‡, Ru-Ping Lee ‡, Tzyy-Wen Chiou †,1, Bang-Gee Hsu §,¶,1
PMCID: PMC2525782  PMID: 18422601

Abstract

Thioacetamide (TAA) has been used extensively in the development of animal models of acute liver injury. Frequently, TAA is administered intraperitoneally to induce liver damage under anaesthesia. However, it is rarely administered by intravenous injection in conscious rats. The experiments in this study were designed to induce acute liver damage by single intravenous injection of TAA (0, 70 and 280 mg/kg) in unrestrained rats. Biochemical parameters and cytokines measured during the 60-h period following TAA administration, included white blood cells (WBC), haemoglobulin (Hb), platelet, aspartate transferase (GOT), alanine transferase (GPT), total bilirubin (TBIL), direct bilirubin (DBI), albumin, ammonia (NH3), r-glutamyl transpeptidase (r-GT), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Rats were sacrificed by decapitation 60 h after TAA administration and livers were removed immediately for pathology and immunohistochemical (IHC) examination. Another group of rats were sacrificed by decapitation 1, 6 and 24 h after TAA administration and livers were removed immediately for time course change of pathology and IHC examination. TAA significantly increased blood WBC, GOT, GPT, TBIL, DBIL, NH3, r-GT, TNF-α and IL-6 levels but decreased the blood Hb, platelet and albumin level. The levels of histopathological damage in the liver after intravenous TAA administration were also increased with a dose-dependent trend and more increased at 60 h after TAA administration. The levels of inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) detected by IHC in the liver after intravenous TAA administration were also increased with a dose-dependent trend and more increased at 1 h after TAA administration. Single intravenous TAA administration without anaesthesia is a restorable animal model which may be used to investigate acute liver damage.

Keywords: acute liver damage, animal model, thioacetamide

Acute liver failure is a major challenge for hepatologists. Acute liver failure can rapidly lead to multiorgan failure and death (Bernal & Wendon 1999). Common causes of acute liver failure include acute viral hepatitis, and drug- or toxin-induced liver injury (Gill & Sterling 2001). Despite advances in intensive care and the development of new treatment modalities, acute liver failure remains a condition associated with high mortality rates. Liver transplantation remains the only effective treatment (Bernal & Wendon 1999; Gill & Sterling 2001).

Thioacetamide (TAA) has been used for several years to induce a model of acute liver injury in rats (Shapiro et al. 2006). Thioacetamide is a potent centrilobular hepatotoxicant, which undergoes a two-step bioactivation mediated by microsomal CYP2E1 to thioacetamide sulphoxide (TASO), and further to a reactive metabolite thioacetamide-S, S-dioxide (TASO2) (Chilakapati et al. 2005). It can release inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB), leading to centrilobular necrosis (Diez-Fernandez et al. 1997; Lu et al. 1999; Bruck et al. 2002; Rahman & Hodgson 2003; Shapiro et al. 2006). In a previously described rat model of acute liver injury, TAA is administered intraperitoneally to induce fulminant liver failure and causes a high mortality rate (Belanger & Butterworth 2005; Shapiro et al. 2006). The aim of this study was to use single intravenous TAA to induce restorable acute liver damage in rats without anaesthesia, and to investigate the time course of its effects on blood biochemistry, inflammatory cytokines (tumour necrosis factor-α; interleukin-6), liver histopathology, and iNOS and NF-κB immunohistochemistry (IHC) in liver.

Materials and methods

Sixty-six male Wistar–Kyoto rats weighing 260–300 g were purchased from the National Animal Center. Rats were housed in our animal center under a controlled environment at a temperature of 22 ± 1 °C with a 12 h light/dark cycle. Food and water were provided ad libitum. The Animal Care and Use Committee approved experimental protocol.

Preparation of animals

Animals were anaesthetized with ether inhalation for about 10 min. During the period of anaesthesia, a femoral artery was catheterized for the blood sample. A femoral vein was catheterized for intravenous administration of drugs or fluid. The operation was completed within 15 min, and the section wound was as small as possible (less than 0.5 cm2). After the operation, the animal was placed in a metabolic cage (Shingshieying Instruments, Hualien, Taiwan). The rat awakened soon after the operation and waited overnight later for intravenous TAA administration in conscious state. We have developed a simple technique to maintain the rats in a conscious state without restrain and anaesthesia as described previously (Lee et al. 2002; Hsu et al. 2006).

Experimental design

Thirty animals were randomly divided into three groups. In the vehicle group (n = 10), intravenous drip 1 ml of normal saline were given. In the TAA-70 group (n = 10), rats received 70 mg/kg thioacetamide (TAA, Sigma Chemical, St Louis, MO, USA) in 1 ml normal saline. In the TAA-280 group (n = 10), 280 mg/kg thioacetamide in 1 ml normal saline were given. Rats were sacrificed by decapitation at 60 h after TAA injection, and the liver was removed immediately for histological and immunohistochemical (IHC) examination.

Time course of liver damage

Another 36 animals were randomly divided into three groups. In the vehicle group (n = 12), intravenous drip 1 ml of normal saline were given. In the TAA-70 group (n = 12), rats received 70 mg/kg thioacetamide (TAA, Sigma Chemical) in 1 ml normal saline. In the TAA-280 group (n = 12), 280 mg/kg thioacetamide in 1 ml normal saline were given. Rats (each group n = 4) were sacrificed by decapitation at 1, 6 and 24 h after TAA injection, and the liver was removed immediately for histological and immunohistochemical (IHC) examination.

Blood sample analyses

Blood samples (0.5 ml) for measurements of white blood cells (WBC), haemoglobulin (Hb), platelet, aspartate transferase (GOT), alanine transferase (GPT), total bilirubin (TBIL), direct bilirubin (DBIL), albumin, ammonia (NH3), r-glutamyl transpeptidase (r-GT), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were taken before TAA administration, and taken at 1, 3, 6, 9, 12, 18, 24, 48 and 60 h after TAA administration. Approximately 0.1 ml blood samples for the determination of WBC, Hb and platelet (Sysmex K-1000, Sysmex American, Mundelein, IL, USA) and the remaining 0.4 ml were centrifuged immediately at 3000 rpm for 10 min. The serum was decanted and separated in two parts; one part of serum was stored at 4 °C for biochemical examinations within 1 h after collection. Serum levels of GOT, GPT, TBIL, DBIL, albumin, NH3 and r-GT were measured with an autoanalyzer (Vitros 750; Johnson & Johnson, Rochester, NY, USA) for evaluating various biochemical data. Another part was stored at −80 °C for later analysis of TNF-α and IL-6 concentration (Hsu et al. 2006).

TNF-α and IL-6 measured by ELISA

TNF-α and IL-6 concentrations in blood samples were measured separately by antibody enzyme-linked immunosorbent assay (ELISA) with the commercial antibody pair, the recombinant standard and the biotin–streptavidin–peroxidase detection system (Endogen, Rockford, IL, USA) as described previously (Chen et al. 2007). Blood samples were collected in serum-separated tubes. All reagents, samples and working standards were brought to room temperature and prepared according to the manufacturer's directions. Quantification of the reactions was determined by the optical density using an automated ELISA reader (Sunrise, Tecan Co., Grödingen, Austria) at 450/540 nm wavelengths.

Histological examination

Liver was removed immediately after sacrifice. These tissue specimens were fixed overnight in 4% buffered formaldehyde, processed by standard methods and stained for haematoxylin and eosin (H & E). One observer in a blind fashion performed the analysis of tissues. Liver injury score in the sections was evaluated as follows: 0, minimal or no evidence of injury; 1, mild injury consisting of cytoplasmic vacuolation and focal nuclear pyknosis; 2, moderate to severe injury with extensive nuclear pyknosis, cytoplasmic hypereosinophilia and loss of intercellular borders and 3, severe necrosis with disintegration of hepatic cords, haemorrhage and neutrophil infiltration. All evaluations were made on 5 fields per section and 5 sections per liver (Hsu et al. 2006).

Immunohistochemical examination

For immunohistochemistry, serial sections (4 μm) were deparaffinized, rehydrated and incubated with the different mouse monoclonal antibodies at 4 °C overnight according to the manufacturer's directions. Antigen retrieval was used for inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B/P65 (NF-KB p65). Dilutions were 1 in 50 for iNOS, and 1 in 100 for NF-kB/p65 (Neomarkers, Lab Vision Corporation, Fremont, CA, USA). Cover tissue with biotinylated goat antimouse polyvalent secondary antibody, incubated at room temperature for 10 min. After washing, the slides were incubated in peroxidase conjugated streptavidin–biotin complex (Dako, Copenhagen, Denmark) for 10 min. Semi-quantification of positive cells by immunohistochemistry was performed on paraffin-embedded tissue sections and was counted 10 high-power field (×200) per section, and data were expressed as percentage of positive area examined (Jo et al. 2006). All scoring was performed in a blinded manner on coded slides.

Data analysis

Data were expressed as means ± SEM. The significance of differences in the measured values between groups was analysed using a two-way analysis of variance (anova) for repeated measurements followed by a Fisher's t test. A P-value less than 0.05 was considered statistically significant.

Results

Effects of TAA on white blood cells (WBC), haemoglobulin (Hb) and platelets

WBC levels were first decreased and then increased in the TAA-280 group (Figure 1a). There were no significant changes of WBC levels after TAA administration in the vehicle and the TAA-70 groups. Compared with the TAA-70 group, WBC levels were first decreased at 1, 3, 6 and 9 h and then increased at 48 and 60 h in the TAA-280 group (*P< 0.05; Figure 1a). Haemoglobulin decreased gradually in all groups (Figure 1b). Compared with the vehicle group, the TAA-70 group had decreased Hb levels at 1, 3, 24, 48 and 60 h (#P< 0.05; Figure 1b). The values of Hb levels in the TAA-280 group were lower than those in the TAA-70 group at 9, 12, 18, 24, 48 and 60 h (*P< 0.05; Figure 1b). The TAA-70 group had lower platelet counts than the vehicle group at 9, 12, 18, 48 and 60 h (#P< 0.05; Figure 1c). Compared with the TAA-70 group, the TAA-280 group had lower platelet counts at 9, 18, 48 and 60 h (*P< 0.05; Figure 1c).

Figure 1.

Figure 1

Open in a new tab

Change in (a) white blood cell count (WBC), (b) haemoglobulin (Hb) and (c) platelet count after intravenous thioacetamide-induced acute liver damage in rats. *P< 0.05 for the TAA-280 group compared with the TAA-70 group. #P< 0.05 for the TAA-70 group compared with the vehicle group.

Effects of TAA on aspartate transferase (GOT) and alanine transferase (GPT)

Blood levels of GOT (Figure 2a) and GPT (Figure 2b) increased to a peak at 24 h after 70 mg/kg TAA intravenous injection (TAA-70 group) and at 48 h after 280 mg/kg TAA intravenous injection (TAA-280 group). Compared with the vehicle group, the TAA-70 group had higher blood values of GOT and GPT at 18 and 24 h (#P< 0.05). In the TAA-280 group, GOT and GPT levels were higher than those in the other groups at 24, 48 and 60 h (*P< 0.05).

Figure 2.

Figure 2

Open in a new tab

Change in (a) serum aspartate transferase (GOT) and (b) alanine transferase (GPT) levels after intravenous thioacetamide-induced acute liver damage in rats. *P< 0.05 for the TAA-280 group compared with the TAA-70 group. #P< 0.05 for the TAA-70 group compared with the vehicle group.

Effects of TAA on total bilirubin (TBIL) and direct bilirubin (DBIL)

In the TAA-280 group, TBIL and DBIL increased to a peak at 48 h after TAA injection (Figure 3a,b). Compared with the vehicle group, the TAA-70 group had higher blood values of TBIL at 3, 18 and 24 h (#P< 0.05; Figure 3a). In the TAA-280 group, TBIL levels were higher than in the TAA-70 group at 9, 12, 18, 24, 48 and 60 h (*P< 0.05; Figure 3a). There were no significant changes of DBIL levels in the vehicle and the TAA-70 groups. DBIL levels were higher in the TAA-280 group than in the TAA-70 group at 12, 18, 24, 48 and 60 h (*P< 0.05; Figure 3b).

Figure 3.

Figure 3

Open in a new tab

Change in (a) serum total bilirubin (TBIL) and (b) direct bilirubin (DBIL) levels after intravenous thioacetamide-induced acute liver damage in rats. *P< 0.05 for the TAA-280 group compared with the TAA-70 group. #P< 0.05 for the TAA-70 group compared with the vehicle group.

Effects of TAA on albumin, ammonia (NH3) and r-glutamyl transpeptidase (r-GT)

The blood level of albumin decreased after TAA administration. Compared with the vehicle group, the TAA-70 group had lower albumin levels at 48 and 60 h (#P< 0.05; Figure 4a). The values of albumin in the TAA-280 group were lower than those in the TAA-70 group at 48 and 60 h (*P< 0.05; Figure 4a). The blood level of NH3 reached a peak at 24 h after administration of 70 mg/kg and 280 mg/kg TAA (Figure 4b). Compared with the vehicle group, the TAA-70 group had higher NH3 levels at 12, 18, 24, 48 and 60 h (#P< 0.05; Figure 4b). The values of blood NH3 in the TAA-280 group were higher than those in the TAA-70 group at 12, 18, 24, 48 and 60 h (*P< 0.05; Figure 4b). Serum r-GT reached a peak at 48 h after intravenous TAA injection (Figure 4c). The TAA-70 group had higher r-GT values than the vehicle group at 3, 6, 9, 12, 18, 24, 48 and 60 h (#P< 0.05; Figure 4c). Compared with the TAA-70 group, the TAA-280 group had higher values of r-GT at 3, 6, 9, 12, 18, 24, 48 and 60 h (*P< 0.05; Figure 4c).

Figure 4.

Figure 4

Open in a new tab

Change in (a) serum albumin, (b) ammonia (NH3) and (c) r-glutamyl transpeptidase (r-GT) levels after intravenous thioacetamide-induced acute liver damage in rats. *P< 0.05 for the TAA-280 group compared with the TAA-70 group. #P< 0.05 for the TAA-70 group compared with the vehicle group.

Effects of TAA on serum levels of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6)

TAA administration greatly increased serum TNF-α, which reached to peak at 6 h in the TAA-70 group (Figure 5a). Compared with the vehicle group, the TAA-70 group had higher serum values of TNF-α at 1, 3, 6, 9, 12, 18, 24, 48 and 60 h (#P< 0.05; Figure 5a). TAA administration greatly increased the serum TNF-α level at 1 h which reached a peak at 18 h in the TAA-280 group (Figure 5a). In the TAA-280 group, the TNF-α level was higher than in the TAA-70 group at 1, 3, 9, 12, 18, 24, 48 and 60 h (*P< 0.05; Figure 5a). Compared with the vehicle group, the TAA-70 group had higher serum values of IL-6 at 1, 3, 6, 9, 12, 18, 24, 48 and 60 h (#P< 0.05; Figure 5b). Compared with the TAA-70 group, the TAA-280 group had higher values of IL-6 at 1, 3, 18 and 24 h (*P < 0.05; Figure 5b).

Figure 5.

Figure 5

Open in a new tab

Change in (a) serum tumour necrosis factor-α (TNF-α) and (b) interleukin-10 (IL-10) levels after intravenous thioacetamide-induced acute liver damage in rats. *P< 0.05 for the TAA-280 group compared with the TAA-70 group. #P< 0.05 for the TAA-70 group compared with the vehicle group.

Histological findings

Histopathological analysis of the H & E-stained tissue liver tissue sections revealed periportal necrosis and severe leucocytes infiltration in the TAA-280 group (Figure 6k,o). Mild leucocytes infiltration in the TAA-70 group was also noted (Figure 6i,n). The severe liver damage at H & E pathology stained was found at 60 h after TAA administration in TAA-280 group. The liver injury score significantly increased after intravenous 70 mg/kg TAA compared with the vehicle group at 24 and 60 h after TAA administration (#P< 0.05; Figure 6i and 6p) and was significantly greater in the intravenous 280 mg/kg TAA group compared with the TAA-70 group at 6, 24 and 60 h after TAA administration (*P< 0.05; Figure 6h,i,p). Immunohistochemical study of iNOS (Figure 7) and NF-κB (Figure 8) revealed a dose-dependent increase in the liver. The percentage of iNOS and NF-κB positive cells in the liver was significantly higher in the intravenous 70 mg/kg TAA group compared with the vehicle group at 1, 6, 24 and 60 h [#P< 0.05; Figure 7d,h,i,p (iNOS) and Figure 8d,h,i,p (NF-κB)] and in the intravenous 280 mg/kg TAA group compared with the TAA-70 group at 1, 6, 24 and 60 h [*P< 0.05; Figure 7d,h,i,p (iNOS) and Figure 8d,h,i,p (NF-κB)].

Figure 6.

Figure 6

Open in a new tab

Histopathological changes in the liver after intravenous thioacetamide administration. Liver tissue sections at 1, 6, 24 and 60 h from the vehicle group (a, e, i and m), the TAA-70 group (b, f, j and n) and the TAA-280 group (c, g, k and o) stained with haematoxylin and eosin (magnification ×200). Liver injury score (d, h, l and p) after intravenous thioacetamide-induced acute liver damage at 1, 6, 24 and 60 h in rats. *P< 0.05 for the TAA-280 group compared with the TAA-70 group. #P< 0.05 for the TAA-70 group compared with the vehicle group.

Figure 7.

Figure 7

Open in a new tab

Immunohistochemisty of iNOS in the liver. Histological sections at 1, 6, 24 and 60 h from the vehicle group (a, e, i and m), the TAA-70 group (b, f, j and n) and the TAA-280 group (c, g, k and o) (magnification ×200). Inducible nitric oxide synthase (iNOS) positive liver score (d, h, l and p) after intravenous thioacetamide-induced acute liver damage at 1, 6, 24 and 60 h in rats. *P< 0.05 for the TAA-280 group compared with the TAA-70 group. #P< 0.05 for the TAA-70 group compared with the vehicle group.

Figure 8.

Figure 8

Open in a new tab

Immunohistochemisty of NF-κB in the liver. Histological sections at 1, 6, 24 and 60 h from the vehicle group (a, e, i and m), the TAA-70 group (b, f, j and n), and the TAA-280 group (c, g, k and o) (magnification ×200). NF-κB positive liver score (d, h, l and p) after intravenous thioacetamide-induced acute liver damage at 1, 6, 24 and 60 h in rats. *P< 0.05 for the TAA-280 group compared with the TAA-70 group. #P< 0.05 for the TAA-70 group compared with the vehicle group.

Discussion

The availability of adequate experimental models of acute liver damage is essential for development and testing of therapeutic approaches for patients with acute liver damage. In this study, a single intravenous injection of TAA was shown to have dose-dependent effects on liver biochemical, pathological and proinflammatory cytokines (TNF-α and IL-6) changes and to provide a restorable model of acute liver damage in rats without anaesthesia. Intravenous TAA administration dose dependently increased blood GOT, GPT, TBIL, DBIL, NH3 and r-GT levels and decreased Hb, platelet and albumin levels. These results indicate that hepatocellular injury and liver dysfunction occurred as a result of TAA administration. In addition, TAA administration increased blood WBC and levels of inflammatory cytokines, such as TNF-α and IL-6. Dose-dependent increases in iNOS and NF-κB in IHC changes in liver were also found. These changes indicate that the mechanism of TAA-induced liver damage in our study may have been produced by NF-κB and iNOS activation and that increases in levels of TNF-α and IL-6 inflammatory cytokines caused liver damage.

Surgical hepatectomy and pharmacological hepatotoxins are widely used in animal models to induce acute liver damage (Rahman & Hodgson 2000; Belanger & Butterworth 2005). The disadvantages of surgical models include the infection which occurs and the reliance on surgical expertise (Rahman & Hodgson 2000). While models generated with hepatotoxins are free of such constraints they also have various disadvantages. For example, galactosamine is costly, results in a highly variable time to death and non-uniform fatality, and the lack of an equivalent clinical syndrome in humans has restricted its use (Belanger & Butterworth 2005). Acetaminophen-based models have proven the most difficult to develop because of the need to closely monitor plasma acetaminophen concentration and refractory anaemia (Belanger & Butterworth 2005). Carbon tetrachloride-induced acute liver damage is poorly reproduced and is potentially hazardous to laboratory personnel (Rahman & Hodgson 2000). Concanavalin A- and lipopolysaccharide-induced acute liver damage do not reflect the clinical pattern of human disease (Rahman & Hodgson 2000). The clinical features, biochemical and histological alterations in TAA-induced liver damage have been extensively studied and are highly similar to human acute liver damage (Rahman & Hodgson 2000; Belanger & Butterworth 2005). Three consecutive intraperitoneal injections of 400 mg/kg TAA every 24 h in rats induce hepatic encephalopathy, hypoglycaemia, hypotension, renal failure, a high mortality rate and careful supportive care must be administered (Belanger & Butterworth 2005). Intraperitoneal TAA administration in rats may unintentionally result in injection into abdominal organs, which could have misleading effects on results (Rahman & Hodgson 2000; Belanger & Butterworth 2005; Shapiro et al. 2006). Furthermore, blood samples that are taken under anaesthesia may affect data on biochemistry or cytokines (Hsu et al. 2005; Peng et al. 2006). The single intravenous administration of TAA in our model did not induce hepatic encephalopathy, hypoglycemia, hypotension or renal failure and none of the rats died during the first 60 h. In addition, no changes in kidney histopathology were found (data not shown). The liver biochemical markers peaked at 48 h and were significantly decreased from peak values 60 h after TAA administration. These findings demonstrate that single intravenous TAA administration results in a stable, restorable model of acute liver damage, and is not a model of fulminant liver failure. It therefore has excellent potential to serve as a model to study acute liver damage.

Recent data have implicated TNF-α and IL-6 as molecular mediators of the immune response in acute and chronic liver damage (Lacour et al. 2005). These molecular mediators have been shown to be the factors that facilitate the priming events in liver regeneration (Akerman et al. 1992; Streetz et al. 2000). Knockout mice lacking TNF-α or IL-6 have diminished ability to restore liver mass, and increased mortality after liver damage (Cressman et al. 1996; Yamada et al. 1998). TNF-α has a pivotal role in liver pathophysiology because it holds the capacity to induce both hepatocyte cell death and hepatocyte proliferation via both NF-κB-dependent gene expression (Wullaert et al. 2007). However, IL-6 binds to hepatocytes by interacting with an 80-kDa membrane glycoprotein (gp80) that complexes with gp130 and promotes association with Janus kinases and is one of the key regulators of the initial steps of liver regeneration (Luedde & Trautwein 2006). In this study, we showed that a single intravenous dose of TAA could induce an increase in serum TNF-α and IL-6 and produce a suitable model for studying the mechanism of acute liver damage and regeneration.

The increased production of iNOS and activation of NF-κB have been implicated in the pathogenesis of acute liver damage following TAA administration (Diez-Fernandez et al. 1997; Lu et al. 1999; Bruck et al. 2002; Rahman & Hodgson 2003; Shapiro et al. 2006). Previous studies revealed that inhibition of NF-κB activity can improve TAA-induced acute liver damage in rats (Bruck et al. 2002, 2004; Shapiro et al. 2006). Administration of the iNOS inhibitor aminoguanidine also reduces the severity of damage in the liver and improves mortality after TAA intraperitoneal administration (Rahman & Hodgson 2003). In our model of acute liver failure, a single intravenous TAA administration had a dose-dependent effect and increased iNOS and NF-κB levels in the liver at 1, 6, 24 and 60 h. The more increased iNOS and NF-κB levels in the liver occurred at 1 h after TAA administration in TAA-280 group. Molecular methods such as reverse transcriptase-polymerase chain reaction to determine gene expression, electrophoretic mobility shift assay for NF-κB, and Western blot for iNOS after single intravenous TAA administration may be informative.

In conclusion, this study demonstrated that single intravenous TAA administration provides a restorable model of acute liver damage, which allows blood data to be monitored over time course without anaesthesia. Moreover, this model appears to be suitable for use in studying the mechanisms responsible for acute liver damage and in developing and testing new therapeutic approaches.

Acknowledgments

This work was supported in part by grants from the National Science Council (NSC 96-2314-B-303-004-MY2). The authors are grateful to Mr. Shu Jang Kou of Mike Biological Technologies for his excellent technical advice on the conscious animal experiments.

References

  1. Akerman P, Cote P, Yang SQ, et al. Antibodies to tumor necrosis factor-alpha inhibit liver regeneration after partial hepatectomy. Am. J. Physiol. 1992;263:G579–G585. doi: 10.1152/ajpgi.1992.263.4.G579. [DOI] [PubMed] [Google Scholar]
  2. Belanger M, Butterworth RF. Acute liver failure: a critical appraisal of available animal models. Metab. Brain Dis. 2005;20:409–423. doi: 10.1007/s11011-005-7927-z. [DOI] [PubMed] [Google Scholar]
  3. Bernal W, Wendon J. Acute liver failure; clinical features and management. Eur. J. Gastroenterol. Hepatol. 1999;11:977–984. doi: 10.1097/00042737-199909000-00005. [DOI] [PubMed] [Google Scholar]
  4. Bruck R, Aeed H, Schey R, et al. Pyrrolidine dithiocarbamate protects against thioacetamide-induced fulminant hepatic failure in rats. J. Hepatol. 2002;36:370–377. doi: 10.1016/s0168-8278(01)00290-2. [DOI] [PubMed] [Google Scholar]
  5. Bruck R, Aeed H, Avni Y, et al. Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats. J. Hepatol. 2004;40:86–93. doi: 10.1016/s0168-8278(03)00504-x. [DOI] [PubMed] [Google Scholar]
  6. Chen CH, Lee RP, Wu WT, Liao KW, Hsu N, Hsu BG. Fluvastatin attenuate endotoxin shock induced organ damage in conscious rats. Resuscitation. 2007;74:166–174. doi: 10.1016/j.resuscitation.2006.12.002. [DOI] [PubMed] [Google Scholar]
  7. Chilakapati J, Shankar K, Korrapati MC, Hill RA, Mehendale HM. Saturation toxicokinetics of thioacetamide: role in initiation of liver injury. Drug Metab. Dispos. 2005;33:1877–1885. doi: 10.1124/dmd.105.005520. [DOI] [PubMed] [Google Scholar]
  8. Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379–1383. doi: 10.1126/science.274.5291.1379. [DOI] [PubMed] [Google Scholar]
  9. Diez-Fernandez C, Sanz N, Bosca L, Hortelano S, Cascales M. Involvement of nitric oxide synthesis in hepatic perturbations induced in rats by a necrogenic dose of thioacetamide. Br. J. Clin. Pharmacol. 1997;121:820–826. doi: 10.1038/sj.bjp.0701191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gill RQ, Sterling RK. Acute liver failure. J. Clin. Gastroenterol. 2001;33:191–198. doi: 10.1097/00004836-200109000-00005. [DOI] [PubMed] [Google Scholar]
  11. Hsu BG, Yang FL, Lee RP, Peng TC, Chen HI. Posttreatment with low dose propofol on inflammation responses to lipopolysaccharide-induced shock in conscious rats. Clin. Exp. Pharmacol. Physiol. 2005;32:24–29. doi: 10.1111/j.1440-1681.2005.04155.x. [DOI] [PubMed] [Google Scholar]
  12. Hsu BG, Lee RP, Yang FL, Harn HJ, Chen HI. Post-treatment with N-acetylcysteine ameliorates the endotoxin shock-induced organ damage in conscious rats. Life Sci. 2006;79:2010–2016. doi: 10.1016/j.lfs.2006.06.040. [DOI] [PubMed] [Google Scholar]
  13. Jo SK, Ko GJ, Boo CS, Cho WY, Kim HK. Heat preconditioning attenuates renal injury in ischemic ARF in rats: role of heat-shock protein 70 on NF-kappa B-mediated inflammation and on tubular cell injury. J. Am. Soc. Nephrol. 2006;17:3082–3892. doi: 10.1681/ASN.2005101077. [DOI] [PubMed] [Google Scholar]
  14. Lacour S, Gautier JC, Pallardy M, Roberts R. Cytokines as potential biomarkers of liver toxicity. Cancer Biomark. 2005;1:29–39. doi: 10.3233/cbm-2005-1105. [DOI] [PubMed] [Google Scholar]
  15. Lee RP, Wang D, Lin NT, Chen HI. Physiological and chemical indicators for early and late stages of sepsis in conscious rats. J. Biomed. Sci. 2002;9:613–621. doi: 10.1159/000067290. [DOI] [PubMed] [Google Scholar]
  16. Lu SC, Huang ZZ, Yang H, Tsukamoto H. Effect of thioacetamide on the hepatic expression of gammaglutamylcysteine synthetase subunits in the rat. Toxicol. Appl. Pharmacol. 1999;159:161–168. doi: 10.1006/taap.1999.8729. [DOI] [PubMed] [Google Scholar]
  17. Luedde T, Trautwein C. Intracellular survival pathways in the liver. Liver Int. 2006;26:1163–1174. doi: 10.1111/j.1478-3231.2006.01366.x. [DOI] [PubMed] [Google Scholar]
  18. Peng TC, Liao KW, Lai HL, Chang FM, Harn HJ, Lee RP. The physiological changes of cumulative hemorrhagic shock in conscious rats. J. Biomed. Sci. 2006;13:385–394. doi: 10.1007/s11373-005-9065-3. [DOI] [PubMed] [Google Scholar]
  19. Rahman TM, Hodgson HJ. Aminal models of acute hepatic failure. Int. J. Exp. Path. 2000;81:145–157. doi: 10.1046/j.1365-2613.2000.00144.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rahman TM, Hodgson HJ. The effects of early and late administration of inhibitors of inducible nitric oxide synthase in a thioacetamide-induced model of acute hepatic failure in the rat. J. Hepatol. 2003;38:583–590. doi: 10.1016/s0168-8278(03)00050-3. [DOI] [PubMed] [Google Scholar]
  21. Shapiro H, Ashkenazi M, Weizman N, Shahmurov M, Aeed H, Bruck R. Curcumin ameliorates acute thioacetamide-induced hepatotoxicity. J. Gastroenterol. Hepatol. 2006;21:358–366. doi: 10.1111/j.1440-1746.2005.03984.x. [DOI] [PubMed] [Google Scholar]
  22. Streetz KL, Luedde T, Manns MP, Trautwein C. Interleukin 6 and liver regeneration. Gut. 2000;47:309–312. doi: 10.1136/gut.47.2.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wullaert A, van Loo G, Heyninck K, Beyaert R. Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond. Endocr. Rev. 2007;28:365–386. doi: 10.1210/er.2006-0031. [DOI] [PubMed] [Google Scholar]
  24. Yamada Y, Webber EM, Kirillova I, Peschon JJ, Fausto N. Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. Hepatology. 1998;28:959–970. doi: 10.1002/hep.510280410. [DOI] [PubMed] [Google Scholar]

Articles from International Journal of Experimental Pathology are provided here courtesy of Wiley

RESOURCES