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.

scholarly journals Sex-Linked Differences in the Course of Thioacetamide-Induced Acute Liver Failure in Lewis Rats

2020 ◽  
pp. 835-845
Author(s):  
E KOBLIHOVÁ ◽  
Iveta MRÁZOVÁ ◽  
Z VAŇOURKOVÁ ◽  
H MAXOVÁ ◽  
M RYSKA ◽  
...  
Keyword(s):  
Survival Rate ◽  
Liver Injury ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Female Rats ◽  
Male Rats ◽  
Preclinical Studies ◽  
Preclinical Research ◽  
Lewis Rats ◽  
General Terms

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.

Significant Improvement of Survival by Intrasplenic Hepatocyte Transplantation in Totally Hepatectomized Rats

1996 ◽  
Vol 5 (3) ◽  
pp. 369-378 ◽  
Author(s):  
Birgit A.P.M. Vogels ◽  
Martinus A.W. Maas ◽  
Anne Bosma ◽  
Robert A.F.M. Chamuleau
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Survival Time ◽  
Histological Examination ◽  
Hepatocyte Transplantation ◽  
Shunt Operation ◽  
Blood Ammonia ◽  
Liver Atrophy ◽  
Arterial Blood ◽  
Clinical Grading

The effect of intrasplenic hepatocyte transplantation (HTX) was studied in an experimental model of acute liver failure in rats with chronic liver atrophy. Rats underwent a portacaval shunt operation on Day -14 to induce liver atrophy, and underwent total hepatectomy on Day 0 as a start of acute liver failure. Intrasplenic hepatocyte or sham transplantation was performed on Day -7, -3, or -1 (n = 4 to 6 per group). During the period following hepatectomy, mean arterial blood pressure was maintained above 80 mm Hg and hypoglycaemia was prevented. Severity of hepatic encephalopathy was assessed by clinical grading and EEG spectral analysis, together with determination of blood ammonia and plasma amino acid concentrations, and “survival” time. Histological examination of the spleen and lungs was performed after sacrifice. Intrasplenic hepatocyte transplantation resulted in a significant improvement in clinical grading in all transplanted groups (p < 0.05), whereas a significant improvement in EEG left index was seen only in the group with transplantation on Day -1 (p < 0.05). In contrast to hepatocyte transplantation 1 day before total hepatectomy, rats with hepatocyte transplantation 3 and 7 days before total hepatectomy showed a significant 3- and 2-fold increase in “survival” time compared to sham transplanted controls: HTX at Day -1: 7.5 ± 0.3 h vs. 5.9 ± 0.6 h (p > 0.05), HTX at Day -3:19.7 ± 3.7 h vs. 6.5 ± 0.3 h (p < 0.05), and HTX at Day -7: 13.8 ± 3.2 h vs. 6.3 ± 0.3 h (p < 0.05). Furthermore, rats with hepatocyte transplantation on Day -3 and -7 showed significantly lower blood ammonia concentrations after total hepatectomy (p < 0.0001). Histological examination of the spleens after sacrifice showed clusters of hepatocytes in the red pulp. Hepatocytes present in the spleen for 3 and 7 days showed bile accumulation and spots of beginning necrosis. The present data show that in a hard model of complete liver failure in portacaval shunted rats, intrasplenic hepatocyte transplantation is able to prolong “survival” time significantly 2- to 3-fold. The relevance of this observation for human application is discussed.

scholarly journals Hemostatic Balance in Pediatric Acute Liver Failure: Epidemiology of Bleeding and Thrombosis, Physiology, and Current Strategies

2020 ◽  
Vol 8 ◽  
Author(s):  
Yonca Bulut ◽  
Anil Sapru ◽  
Gavin D. Roach
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Cell Activation ◽  
Protein S ◽  
Bleeding Risk ◽  
International Normalized Ratio ◽  
Clinical Syndrome ◽  
Low Grade ◽  
Endothelial Cell Activation ◽  
Pediatric Acute Liver Failure

Pediatric Acute Liver Failure (PALF) is a rapidly progressive clinical syndrome encountered in the pediatric ICU which may rapidly progress to multi-organ dysfunction, and on occasion to life threatening cerebral edema and hemorrhage. Pediatric Acute Liver Failure is defined as severe acute hepatic dysfunction accompanied by encephalopathy and liver-based coagulopathy defined as prolongation of International Normalized Ratio (INR) &gt;1.5. However, coagulopathy in PALF is complex and warrants a deeper understanding of the hemostatic balance in acute liver failure. Although an INR value of &gt;1.5 is accepted as the evidence of coagulopathy and has historically been viewed as a prognostic factor of PALF, it may not accurately reflect the bleeding risk in PALF since it only measures procoagulant factors. Paradoxically, despite the prolongation of INR, bleeding risk is lower than expected (around 5%). This is due to “rebalanced hemostasis” due to concurrent changes in procoagulant, anticoagulant and fibrinolytic systems. Since the liver is involved in both procoagulant (Factors II, V, IX, XI, and fibrinogen) and anticoagulant (Protein C, Protein S, and antithrombin) protein synthesis, PALF results in “rebalanced hemostasis” or even may shift toward a hypercoagulable state. In addition to rebalanced coagulation there is altered platelet production due to decreased thrombopoietin production by liver, increased von Willebrand factor from low grade endothelial cell activation, and hyperfibrinolysis and dysfibrinogenemia from altered synthetic liver dysfunction. All these alterations contribute to the multifactorial nature of coagulopathy in PALF. Over exuberant use of prophylactic blood products in patients with PALF may contribute to morbidities such as fluid overload, transfusion-associated lung injury, and increased thrombosis risk. It is essential to use caution when using INR values for plasma and factor administration. In this review we will summarize the complexity of coagulation in PALF, explore “rebalanced hemostasis,” and discuss the limitations of current coagulation tests. We will also review strategies to accurately diagnose the coagulopathy of PALF and targeted therapies.

scholarly journals Therapeutic Effect of Human Umbilical Cord Mesenchymal Stem Cells at Various Passages on Acute Liver Failure in Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yongting Zhang ◽  
Yuwen Li ◽  
Wenting Li ◽  
Jie Cai ◽  
Ming Yue ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Umbilical Cord ◽  
Therapeutic Potential ◽  
Human Umbilical Cord ◽  
Sd Rats ◽  
Recipient Liver ◽  
Injured Liver

Recent studies have described beneficial effects of an infusion of mesenchymal stem cells (MSCs) derived from Wharton’s jelly tissue, for the treatment of acute liver failure (ALF). However, data on the therapeutic potential of culture-expanded MSCs are lacking. We examined the therapeutic potential of passage five (P5) and ten (P10) human umbilical cord- (hUC-) MSCs via their transplantation into Sprague-Dawley (SD) rats with D-galactosamine (D-GalN) and LPS-induced acute liver failure (ALF). SD rats were randomly divided into three groups: control group, P5 hUC-MSCs group, and P10 hUC-MSCs group. After transplantation, P5 hUC-MSCs provided a significant survival benefit. The analysis of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) levels showed that transplantation with P5 hUC-MSCs was more effective than treatment with P10 hUC-MSCs. P5 hUC-MSCs also successfully downregulated the hepatic activity index (HAI) scores. Compared to P10 hUC-MSCs in vivo, P5 hUC-MSCs significantly enhanced the regeneration and inhibited the apoptosis of hepatocytes. CM-Dil-labeled hUC-MSCs were found to engraft within the recipient liver, whereas the homing of cells to the recipient liver in the P10 hUC-MSCs group was less effective compared to the P5 hUC-MSCs group. Previous studies have shown that the concentration of hepatocyte growth factor (HGF) in the injured liver was significantly increased. HGF is commonly known as the ligand of c-Met. The level of c-Met in hUC-MSCs as detected by Western blotting indicated that at a higher passage number, there is a decrease in c-Met. These data suggest that direct transplantation of P5 hUC-MSCs can more efficiently home to an injured liver. Subsequently, the P5 hUC-MSCs can rescue ALF and repopulate the livers of rats through the stimulation of endogenous liver regeneration and inhibition of hepatocellular apoptosis for compensated liver function, which is dependent on the higher level of c-Met than P10 hUC-MSCs.

O45 THE NEW POSSIBILITY OF AUTOLOGOUS HEPATOCYTE TRANSPLANTATION TO PREVENT ACUTE LIVER FAILURE AFTER MASSIVE HEPATECTOMY

2014 ◽  
Vol 60 (1) ◽  
pp. S19
Author(s):  
S. Kita ◽  
K. Yasuchika ◽  
T. Ishii ◽  
H. Katayama ◽  
T. Kawai ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Hepatocyte Transplantation ◽  
Massive Hepatectomy

Mycophenolate Mofetil and Sirolimus in Hepatocyte Transplantation in an Experimental Model of Toxic Acute Liver Failure

2014 ◽  
Vol 27 (4) ◽  
pp. 205-213 ◽  
Author(s):  
Ioannis Loukopoulos ◽  
Ioannis Sfiniadakis ◽  
Andrew Pillai ◽  
Manousos Konstantoulakis ◽  
Georgios Androulakis ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Experimental Model ◽  
Hepatocyte Transplantation

scholarly journals ACTION OF VITAMIN E ON EXPERIMENTAL SEVERE ACUTE LIVER FAILURE

2017 ◽  
Vol 54 (2) ◽  
pp. 123-129 ◽  
Author(s):  
Fabiano Moraes MIGUEL ◽  
Elizângela Gonçalves SCHEMITT ◽  
Josieli Raskopf COLARES ◽  
Renata Minuzzo HARTMANN ◽  
Maria Isabel MORGAN-MARTINS ◽  
...  
Keyword(s):  
Vitamin E ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Clinical Syndrome ◽  
Control Group ◽  
Activity Levels ◽  
Liver Functions ◽  
Life Threatening ◽  
Hepatocyte Necrosis ◽  
The One

ABSTRACT BACKGROUND Severe Acute Liver Failure (ALF) is a life-threatening clinical syndrome characterized by hepatocyte necrosis, loss of hepatic architecture, and impairment of liver functions. One of the main causes of ALF is hepatotoxicity from chemical agents, which damage hepatocytes and result in increase of reactive oxygen species. The vitamin E isoform is the one with the strongest biological antioxidant activity. OBJECTIVE To evaluate the antioxidant effect of vitamin E in this ALF model. METHODS We used 56 rats (mean weight of 300 g) divided into eight groups, four groups assessed at 24 hours and 4 assessed at 48 hours after induction: control group (CO); Vitamin E (Vit. E); Thioacetamide (TAA) and Thioacetamide + Vitamina E (TAA+Vit.E). Rats were submitted to injections of thioacetamide (400 mg/kg i.p.) at baseline and 8 hours later. Vitamin E (100 mg/kg ip) was administered 30 minutes after the second dose of thioacetamide. The 48-hour group rats received two additional doses of vitamin E (24h and 36h). At 24h or 48 hours after the administration of the first dose of TAA, rats were weighed and anesthetized and their blood sampled for evaluation of liver integrity through enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Liver tissue was sampled for assessment of lipid peroxidation (LPO) by the technique TBARS, antioxidant enzymes SOD, CAT, GPx and GST activity, levels of the NO 2 /NO 3 and histology by H&E in two times. The results were expressed as mean ± standard deviation and statistically analyzed by ANOVA followed by Student-Newman-Keuls, with P <0.05 considered as significant. RESULTS After treatment with vitamin E, we observed a reduction in liver enzymes AST (U/L) (101.32±19.45 in 24 hours and 97.85±29.65 in 48 hours) related to the TAA group (469.56± 0.69 in 24 hours and 598.23±55.45 in 48 hours) and ALT (U/L) (76.59±8.56 in 24 hours and 68.47±6.49 in 48 hours) compared to the TAA group (312.21±10.23 in 24 hours and 359.15±17.58 in 48 hours). There was a reduction of LPO (nmol/mg Prot) in the TAA+Vit.E group (0.77±0.07 in 24 hours and 0.95±0.08 in 48 hours) compared to the TAA group (1.50±0.07 in 24 hours e 1.65±0.16 in 48 hours). SOD decreased in the TAA+Vit.E group (49.48±9.47 in 24 hours and 62.45±18, 47 in 48 hours), related to the TAA group (98.46±15.48 in 24 hours and 154.13±21.46 in 48 hours), as well as GST (nmol/min/mg Prot) in the TAA+Vit.E group (350.57±36.93 in 24 hours and 453.29±13.84 in 48 hours) compared to the TAA group (561.57±64.56 in 24 hours and 673.43±38.13 in 48 hours). There was an increase in CAT (pmol/min/mg Prot) in the TAA+Vit.E group (3.40±0.44 in 24 hours and 3.0±0.35 in 48 hours) compared to the TAA group (1.65±0.21 in 24 hours and 1.86±0.42 in 48 hours). The GPx (nmol/min/mg Prot) increased in 24 hours in the TAA+Vit.E group (1.01±0.16) compared to the TAA group (0.41±0.04) and decreased in 48 hours (1.19±0.17) compared to the TAA group (1.76±0.21). There was a reduction in NO2/NO3 (mmol/L) levels in the TAA+Vit.E group (31.47±4.26 in 24 hours and 38.93±5.20 in 48 hours) compared to the TAA group (49.37±5.12 in 24 hours and 53.53±5.97 in 48 hours). The histopathological evaluation showed a decrease in liver injury (necrosis and inflammation) in both studied times. CONCLUSION These results suggest that vitamin E was able to protect the liver from lesions caused by thioacetamide.

scholarly journals Subacute liver failure of unknown origin

2018 ◽  
Vol 146 (3-4) ◽  
pp. 200-202
Author(s):  
Dragan Delic ◽  
Nikola Mitrovic ◽  
Aleksandar Urosevic ◽  
Jasmina Simonovic ◽  
Ksenija Bojovic
Keyword(s):  
Liver Cirrhosis ◽  
Hepatic Encephalopathy ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Unknown Origin ◽  
Signs And Symptoms ◽  
Clinical Syndrome ◽  
Decompensated Liver Cirrhosis ◽  
Synthetic Function ◽  
Severe Liver Dysfunction

Introduction. Acute liver failure is rare and very complex clinical syndrome, the consequences of the sudden and severe liver dysfunction. There are several causes of this condition (viruses, medications, toxins, metabolic, autoimmune and malignant diseases), but etiological agent often remains undiscovered. Case Outline. A 40-year-old male patient got ill suddenly with signs and symptoms relevant for acute hepatitis, which was confirmed with biochemical analysis. The cause of acute liver failure was not determined. Despite all therapeutic measures, clinical course of the disease was bad: severe icterus, decreased synthetic function of the liver and hepatic encephalopathy developed. In the later, subacute course of the disease, developed ascites, episodes of hepatic encephalopathy and biochemical findings of chronic hepatocellular failure. After three months treatment, in hepatic coma, there was lethal outcome. Histopathological findings confirmed the diagnosis of decompensated liver cirrhosis of unknown origin. Conclusion. The cause of acute liver failure often remains unclear; potential causes should be looked for in infections with unknown viruses or in toxins exposure. The disease is most commonly presented as subacute failure with the development of liver cirrhosis. Survival rate is low.

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.

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