Experimental Models of Acute and Chronic Liver Failure in Nude Mice to Study Hepatocyte Transplantation

2005 ◽  
Vol 14 (5) ◽  
pp. 277-290 ◽  
Author(s):  
Arnaud Gandillet ◽  
Isabelle Vidal ◽  
Eliane Alexandre ◽  
Maxime Audet ◽  
Marie-Pierre Chenard-Neu ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Partial Hepatectomy ◽  
Nude Mice ◽  
Survival Rates ◽  
Experimental Models ◽  
Chronic Liver ◽  
Hepatocyte Transplantation ◽  
Acute Injury ◽  
Published Data

Although hepatocyte transplantation is a promising therapy for acute liver failure in human, there is still a lack of animal models suffering from hepatic injury in which the benefits of hepatocyte transplantation could be evaluated solely, without the bias caused by immunosuppression. As a consequence, the aim of the study was first to develop reproducible models of partial hepatectomy and of thioacetamide (TA)- or Jo2-induced acute liver failure in nude mice. Chronic liver disease was also investigated by repeated injections of sublethal doses of thioacetamide. Survival rates, routine histologic observations, alanin aminotransferase sera content, Ki67, and caspase 3 immunodetection were investigated both after 40% partial hepatectomy and after toxic-induced damages. Liver injuries were more severe and/or precocious in nude mice than in Balb/c mice for a given treatment with a maximum of acute injury obtained 24 h after single toxic injection, and were found to be transitory and reversible within 10 days. Toxics induced apoptosis followed by necrosis, confirming recent published data. Onset of fibrosis leading to reproducible chronic cirrhosis in nude mice correlated with increasing number of Ki67-positive cells, indicating that high levels of cell proliferation occurred. Chronic cirrhosis progressively reversed to fibrosis when the treatment ceased. Preliminary results demonstrated that engrafted xenogeneic hepatocytes could be detected in the host liver by anti-MHC class I immunohistochemistry. Fractions enriched in 2n or 4n hepatocytes by cell sorting using a flow cytometer were equivalent to the unpurified fraction in terms of engraftment in control nude mice or in nude mice subjected to PH. However, in mice suffering from liver injury 24 h after Jo2 or TA treatment, the engraftment of 2n hepatocytes was about twice that of an unpurified hepatocyte population or of a population enriched in 4n hepatocytes.

Preoperative Hepatocyte Transplantation Improves the Survival of Rats with Nonalcoholic Steatohepatitis-Related Cirrhosis after Partial Hepatectomy

2014 ◽  
Vol 23 (10) ◽  
pp. 1243-1254 ◽  
Author(s):  
Yukio Nakamura ◽  
Toru Mizuguchi ◽  
Naoki Tanimizu ◽  
Norihisa Ichinohe ◽  
Hidekazu Ooe ◽  
...  
Keyword(s):  
Liver Resection ◽  
Liver Failure ◽  
Partial Hepatectomy ◽  
Nonalcoholic Steatohepatitis ◽  
Survival Rates ◽  
Rat Hepatocytes ◽  
Hepatocyte Transplantation ◽  
Ki 67 ◽  
Short And Long Term

Liver failure after liver resection for cirrhosis is a critical problem, and no effective therapy except liver transplantation is currently available. The objective of this study was to examine whether hepatocyte transplantation (HT) reduces the poststandard liver resection mortality rate of rats with nonalcoholic steatohepatitis (NASH)-related cirrhosis. Liver resection for hepatocellular carcinoma (HCC) combined with NASH-related cirrhosis has become increasingly common. We developed a rat model of acute liver failure after two-thirds partial hepatectomy (PH) for NASH-related cirrhosis. The mechanism by which HT improved the survival of the model rats was examined in short- and long-term investigations. Female DPPIV- recipient F344 rats were fed the choline-deficient l-amino acid (CDAA)-defined diet for 12 weeks. Some of the rats were transplanted with male F344 DPPIV+ rat hepatocytes 24 h before undergoing PH. The overall post-PH survival of each group was evaluated, and short- and long-term pathological and molecular biological evaluations were also performed. Overall survival was significantly longer in the HT group than the non-HT group (7-day survival rates: 46.7% and 7.7%, respectively). Compared with the recipient livers of the non-HT group, numerous Ki-67+ hepatocytes and few TUNEL+ hepatocytes were observed in the livers of the HT group. At 6 months after the HT, the DPPIV+ hepatocytes had partially replaced the recipient liver and formed hepatocyte clusters in the spleen. Preoperative HT might improve the survival of rats with NASH-related cirrhosis after PH by preventing the host hepatocytes from accelerating their growth and falling into apoptosis.

scholarly journals Mesenchymal Stem Cells Transplantation following Partial Hepatectomy: A New Concept to Promote Liver Regeneration—Systematic Review of the Literature Focused on Experimental Studies in Rodent Models

2017 ◽  
Vol 2017 ◽  
pp. 1-22 ◽  
Author(s):  
Ioannis G. Papanikolaou ◽  
Charalambos Katselis ◽  
Konstantinos Apostolou ◽  
Themistoklis Feretis ◽  
Maria Lymperi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Failure ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Chronic Liver ◽  
Review Of The Literature ◽  
Chronic Liver Injury ◽  
Stem Cells Transplantation

Mesenchymal stem cells (MSCs) are an attractive source for regenerative medicine because they are easily accessible through minimally invasive methods and have the potential to enhance liver regeneration (LG) and improve liver function, following partial hepatectomy (PH) and acute or chronic liver injury. A systematic review of the literature was conducted for articles published up to September 1st, 2016, using the MEDLINE database. The keywords that were used in various combinations were as follows: “Mesenchymal stem cells”, “transplantation”, “stem cells”, “adipose tissue derived stem cells”, “bone marrow-derived stem cells”, “partial hepatectomy”, “acute liver failure”, “chronic liver failure”, “liver fibrosis”, “liver cirrhosis”, “rats”, “mice”, and “liver regeneration”. All introduced keywords were searched for separately in MeSH Database to control relevance and terminological accuracy and validity. A total of 41 articles were identified for potential inclusion and reviewed in detail. After a strict selection process, a total of 28 articles were excluded, leaving 13 articles to form the basis of this systematic review. MSCs transplantation promoted LG and improved liver function. Furthermore, MSCs had the ability to differentiate in hepatocyte-like cells, increase survival, and protect hepatocytes by paracrine mechanisms. MSCs transplantation may provide beneficial effects in the process of LG after PH and acute or chronic liver injury. They may represent a new therapeutic option to treat posthepatectomy acute liver failure.

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.

Acute Liver Failure

2019 ◽  
pp. 264-269
Author(s):  
James Y. Findlay ◽  
Eelco F. M. Wijdicks
Keyword(s):  
Liver Disease ◽  
Liver Function ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Chronic Liver ◽  
Chronic Liver Failure ◽  
Underlying Liver Disease ◽  
Rapid Deterioration ◽  
Uncommon Condition ◽  
Acute Insult

Acute liver failure (ALF) is an uncommon condition in which an acute insult results in a rapid deterioration of liver function, encephalopathy, and coagulopathy in the absence of prior underlying liver disease. It is differentiated from rapid deterioration in the setting of underlying liver disease (acute on chronic liver failure) and from the gradual deterioration in liver function that can occur in chronic liver failure.

Liver failure

2020 ◽  
pp. 3089-3100
Author(s):  
Jane Macnaughtan ◽  
Rajiv Jalan
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Hepatic Encephalopathy ◽  
Liver Injury ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Organ Failure ◽  
Clinical Manifestations ◽  
Chronic Liver ◽  
Chronic Liver Failure

Liver failure occurs when loss of hepatic parenchymal function exceeds the capacity of hepatocytes to regenerate or repair liver injury. Acute liver failure is characterized by jaundice and prolongation of the prothrombin time in the context of recent acute liver injury, with hepatic encephalopathy occurring within 8 weeks of the first onset of liver disease. Acute-on-chronic liver failure is characterized by hepatic and/or extrahepatic organ failure in patients with cirrhosis associated with an identified or unidentified precipitating event. The commonest causes of acute liver failure are acute viral hepatitis and drugs. Acute-on-chronic liver failure is most commonly precipitated by infection, alcohol abuse, and superimposed viral infection. The main clinical manifestations are hepatic encephalopathy, coagulopathy, jaundice, renal dysfunction, and haemodynamic instability. Infection and systemic inflammation contribute to pathogenesis and critically contribute to prognosis. Specific therapy for the underlying liver disease is administered when available, but this is not possible for most causes of liver failure. Treatment is predominantly supportive, with particular emphasis on (1) correction or removal of precipitating factors; (2) if encephalopathy is present, using phosphate enemata, nonhydrolysed disaccharide laxatives, and/or rifaximin; (3) early detection and prompt treatment of complications such as hypoglycaemia, hypokalaemia, cerebral oedema, infection, and bleeding. The onset of organ failure should prompt discussion with a liver transplantation centre. The mortality of acute liver failure (without liver transplantation) is about 40%. Patients with acute liver failure who do not develop encephalopathy can be expected to recover completely. Those who recover from an episode of acute-on-chronic liver failure should be considered for liver transplantation because otherwise their subsequent mortality remains high.

scholarly journals The Effects of High-Dose Qinggan Huoxue Recipe on Acute Liver Failure Induced by D-Galactosamine in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Hong Zhu ◽  
Yang Zhang ◽  
Xiaoyu Hu ◽  
Cheng Yi ◽  
Sen Zhong ◽  
...  
Keyword(s):  
Liver Function ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Survival Curve ◽  
Survival Rates ◽  
High Mobility ◽  
Nuclear Antigen ◽  
High Dose ◽  
Improve Liver Function ◽  
Proliferating Cell

Qinggan Huoxue Recipe is a traditional Chinese medicine, which has been usually used to improve liver function in hepatitis. In order to investigate the effects of high-dose Qinggan Huoxue Recipe on acute liver failure and explore the potential mechanism, we had built acute liver failure models in rats by intraperitoneal injection of D-galactosamine (D-GalN). High-dose Qinggan Huoxue Recipe was delivered by gavage. After treatment, the blood alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB), cholinesterase (CHE), and prothrombin time (PT) were determined. The pathological score of liver tissue was recorded. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and fluorescence quantitative reverse transcription polymerase chain reaction (qRT-PCR) of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), and Caspase-3 were performed. The survival curve was also depicted. Our results demonstrated that high-dose Qinggan Huoxue Recipe could significantly improve liver function and increase survival rates in rats with acute liver failure. These effects were supposed to be mediated by suppressing inflammatory reaction and apoptosis.

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