Acute liver failure (ALF) is a clinical condition with very high mortality rate. Its pathophysiological background is still poorly understood, which necessitates a search for optimal experimental ALF models with features resembling those of the human disorder. Taking into consideration reproducibility of induction of ALF, adequate animal size, cost of animals, the required time gap between insult and death of animals (“therapeutic window”), potential risk to investigator and other aspects, administration of thioacetamide (TAA) in rats is currently most recommended. However, the fundamental details of this ALF model have not yet been evaluated. This prompted us to investigate, first, the course of ALF as induced by intraperitoneal TAA at doses increasing from 175 to 700 mg/kg BW per day. The animals’ survival rate, plasma alanine and aspartate aminotransferase activities, and bilirubin and ammonia levels were determined over the follow-up period. Second, we examined whether Wistar and Lewis rats exhibit any differences in the course of ALF induced by different TAA doses. We found that the optimal dose for ALF induction in rats is 350 mg.kg-1 i.p., given as a single injection. Wistar rats proved more susceptible to the development of TAA-induced ALF compared with Lewis rats. Collectively, our present findings provide a sound methodological background for experimental studies aimed at evaluation of pathophysiology and development of new approaches in the therapy of ALF., E. Koblihová, I. Mrázová, Z. Vernerová, M. Ryska., and Obsahuje bibliografii
During 48 hours after application sublethal doses of hepatotoxic agent thiacetamide decrease cytochrome c oxidase activity of rat liver homogenate and isolated mitochondria to 46 % and 32 % of original values, respectively. This decrease may be prevented by simultaneous application of lipid emulsion (mixture of Lipofundin and Mygliol)
twice a day.
Acute liver failure (ALF) is known for extremely high mortality
rate, the result of widespread damage of hepatocytes. Orthotopic
liver transplantation is the only effective therapy but its
application is limited by the scarcity of donor organs. Given the
importance in the liver biology of Wnt/β-catenin signaling
pathway, we hypothesized that its stimulation could enhance
hepatocyte regeneration and attenuate the course of
thioacetamide (TAA)-induced ALF in Lewis rats. Chronic
treatment with Wnt agonist was started either immediately after
hepatotoxic insult (“early treatment”) or when signs of ALF had
developed (“late treatment”). Only 23 % of untreated Lewis rats
survived till the end of experiment. They showed marked
increases in plasma alanine aminotransferase (ALT) activity and
bilirubin and ammonia (NH3) levels; plasma albumin decreased
significantly. “Early” and “late” Wnt agonist treatment raised the
final survival rate to 69 % and 63 %, respectively, and
normalized ALT, NH3, bilirubin and albumin levels. In conclusion,
the results show that treatment with Wnt agonist attenuates the
course of TAA-induced ALF in Lewis rats, both with treatment
initiated immediately after hepatotoxic insult and in the phase
when ALF has already developed. Thus, the pharmacological
stimulation of Wnt/β-catenin signaling pathway can present
a new approach to ALF treatment.
Acute liver failure (ALF) is a clinical syndrome with high mortality rate, resulting from widespread hepatocyte damage. Its pathophysiological background is still poorly understood and preclinical studies evaluating pathophysiology and new potential therapeutic measures are needed. The model of ALF induced by administration of thioacetamide (TAA) in Lewis rats is recommended as optimal; however, the limitation of previous studies was that they were performed predominantly in male rats. In view of the growing recognition that sex as a biological variable should be taken into consideration in preclinical research, we examined its role in the development of TAA-induced ALF in Lewis rats. We found that, first, intact male Lewis rats showed lower survival rate than their female counterparts, due to augmented liver injury documented by higher plasma ammonia, and bilirubin levels and alanine aminotransferase activity. Second, in female rats castration did not alter the course of TAA-induced ALF whereas in the male gonadectomy improved the survival rate and attenuated liver injury, reducing it to levels observed in their female counterparts. In conclusion, we found that Lewis rats show a remarkable sexual dimorphism with respect to TAA-induced ALF, and male rats display dramatically poorer prognosis as compared with the females. We showed that testosterone is responsible for the deterioration of the course of TAA-induced ALF in male rats. In most general terms, our findings indicate that in the preclinical studies of the pathophysiology and treatment of ALF (at least of the TAA-induced form) the sex-linked differences should be seriously considered., Eva Koblihová, Iveta Mrázová, Zdenka Vaňourková, Hana Maxová, Miroslav Ryska, Jiří Froněk., and Obsahuje bibliografii
Thioacetamide (TAA) is widely used in the production of drugs, pesticides and dyeing auxiliaries. Moreover, it is a chemical that can cause liver damage and cancer. TAA has recently been identified to cause bone damage in animal models. However, the type of bone damage that TAA causes and its potential pathogenic mechanisms remain unclear. The toxic effects of TAA on the femurs of New Zealand white rabbits and the underlying toxicity mechanism were investigated in this study. Serum samples, the heart, liver, kidney and femurs were collected from rabbits after intraperitoneal injection of TAA for 5 months (100 and 200 mg/kg). The New Zealand white rabbits treated with TAA showed significant weight loss and femoral shortening. The activities of total bilirubin, total bile acid and gamma-glutamyl transpeptidase in the serum were increased following treatment with TAA. In addition, the cortical bone became thinner, and the trabecular thickness decreased significantly in TAA-treated rabbits, which was accompanied by significantly decreased mineral density of the cortical and trabecular bone. Moreover, there was a significant decrease in modulus of elasticity and maximum load on bone stress in TAA-treated rabbits. The western blotting results showed that the expression of phosphorylated (p)-p38 and p-ERK in femur tissues of rabbits were increased after TAA administration. Collectively, these results suggested that TAA may lead to femoral damage in rabbits by activating the p38/ERK signaling pathway.