scholarly journals Pharmacological Stimulation of Wnt/ß-catenin Signaling Pathway Attenuates the Course of Thioacetamide-Induced Acute Liver Failure

2020 ◽  
pp. 113-126 ◽  
Author(s):  
E. KOBLIHOVÁ ◽  
I. MRÁZOVÁ ◽  
Z. VAŇOURKOVÁ ◽  
H. MAXOVÁ ◽  
S. KIKERLOVÁ ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Signaling Pathway ◽  
New Approach ◽  
Lewis Rats ◽  
Hepatocyte Regeneration ◽  
Pharmacological Stimulation ◽  
Late Treatment ◽  
Final Survival ◽  
Stimulation Of

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.

scholarly journals HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Runkuan Yang ◽  
Xiaoping Zou ◽  
Jyrki Tenhunen ◽  
Tor Inge Tønnessen
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Multiple Organ Failure ◽  
Organ Failure ◽  
Systemic Inflammation ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Multiple Organ ◽  
Hepatocyte Regeneration ◽  
Extracellular Histones

Acute liver failure (ALF) is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF) and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bacterial translocation (BT). BT triggers/induces systemic inflammatory responses syndrome (SIRS), which can lead to MOF in ALF. Blockade of HMGB1 significantly decreases BT and improves hepatocyte regeneration in experimental acute fatal liver injury. Therefore, HMGB1 seems to be an important factor that links BT and systemic inflammation in ALF. ALF patients/animals also have high levels of circulating histones, which might be the major mediators of systemic inflammation in patients with ALF. Extracellular histones kill endothelial cells and elicit immunostimulatory effect to induce multiple organ injuries. Neutralization of histones can attenuate acute liver, lung, and brain injuries. In conclusion, HMGB1 and histones play a significant role in inducing systemic inflammation and MOF in ALF.

scholarly journals Acute Liver Failure Induced by Thioacetamide: Selection of Optimal Dosage in Wistar and Lewis Rats

2014 ◽  
pp. 491-503 ◽  
Author(s):  
E. KOBLIHOVÁ ◽  
I. MRÁZOVÁ ◽  
Z. VERNEROVÁ ◽  
M. RYSKA
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Experimental Studies ◽  
Optimal Dose ◽  
Therapeutic Window ◽  
Optimal Dosage ◽  
Lewis Rats ◽  
Human Disorder ◽  
Time Gap ◽  
Animal Size

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.

scholarly journals Kaempferol protects mice from d-GalN/LPS-induced acute liver failure by regulating the ER stress-Grp78-CHOP signaling pathway

2019 ◽  
Vol 111 ◽  
pp. 468-475 ◽  
Author(s):  
Huijuan Wang ◽  
Liyan Chen ◽  
Xiangying Zhang ◽  
Lin Xu ◽  
Bangxiang Xie ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Er Stress ◽  
Signaling Pathway

scholarly journals Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

2015 ◽  
Vol 95 (5) ◽  
pp. 504-514 ◽  
Author(s):  
Yanmin Liu ◽  
Liuluan Zhu ◽  
Shuntao Liang ◽  
Shanshan Yao ◽  
Rui Li ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Signaling Pathway ◽  
Tnf Α ◽  
Induced Apoptosis

scholarly journals Hepatocyte Transplantation Attenuates the Course of Acute Liver Failure Induced by Thioacetamide in Lewis Rats

2015 ◽  
pp. 689-700 ◽  
Author(s):  
E. KOBLIHOVÁ ◽  
O. LUKŠAN ◽  
I. MRÁZOVÁ ◽  
M. RYSKA ◽  
L. ČERVENKA
Keyword(s):  
Survival Rate ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Firefly Luciferase ◽  
Clinical Syndrome ◽  
Hepatocyte Transplantation ◽  
Plasma Albumin ◽  
Lewis Rats ◽  
New Therapeutic Approaches ◽  
Recipient Liver

Acute liver failure (ALF) is a clinical syndrome resulting from widespread damage of hepatocytes, with extremely high mortality rate. Urgent orthotopic liver transplantation was shown to be the most effective therapy for ALF but this treatment option is limited by scarcity of donor organs. Therefore, hepatocyte transplantation (Tx) has emerged as a new therapeutical measure for ALF, however, the first clinical applications proved unsatisfactory. Apparently, extensive preclinical studies are needed. Our aim was to examine if hepatocytes isolated from transgenic “firefly luciferase” Lewis rats into the recipient liver would attenuate the course of thioacetamide (TAA)-induced ALF in Lewis rats. Untreated Lewis rats after TAA administration showed a profound decrease in survival rate; no animal survived 54 h. The rats showed marked increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, in plasma level of bilirubin and ammonia (NH3), and in a significant decrease in plasma albumin. Hepatocyte Tx attenuated the course of TAA-induced ALF Lewis rats which was reflected by improved survival rate and reduced degree of liver injury showing as lowering of elevated plasma ALT, AST, NH3 and bilirubin levels and increasing plasma albumin. In addition, bioluminescence imaging analyses have shown that in the TAA damaged livers the transplanted hepatocyte were fully viable throughout the experiment. In conclusion, the results show that hepatocyte Tx into the liver can attenuate the course of TAA induced ALF in Lewis rats. This information should be considered in attempts to develop new therapeutic approaches to the treatment of ALF.

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