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