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Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation.

ABSTRACT: Hepatic ischemia/reperfusion (I/R) injury is a side effect of major liver surgery that often cannot be avoided. Prolonged periods of ischemia put a metabolic strain on hepatocytes and limit the tolerable ischemia and preservation times during liver resection and transplantation, respectively. In both surgical settings, temporarily lowering the metabolic demand of the organ by reducing organ temperature effectively counteracts the negative consequences of an ischemic insult. Despite its routine use, the application of liver cooling is predicated on an incomplete understanding of the underlying protective mechanisms, which has limited a uniform and widespread implementation of liver-cooling techniques. This review therefore addresses how hypothermia-induced hypometabolism modulates hepatocyte metabolism during ischemia and thereby reduces hepatic I/R injury. The mechanisms underlying hypothermia-mediated reduction in energy expenditure during ischemia and the attenuation of mitochondrial production of reactive oxygen species during early reperfusion are described. It is further addressed how hypothermia suppresses the sterile hepatic I/R immune response and preserves the metabolic functionality of hepatocytes. Lastly, a summary of the clinical status quo of the use of liver cooling for liver resection and transplantation is provided.

SUBMITTER: Olthof PB

PROVIDER: S-EPMC4818259 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation.

Olthof Pim B PB Reiniers Megan J MJ Dirkes Marcel C MC Gulik Thomas M van TMV Golen Rowan F van RFV

Molecular medicine (Cambridge, Mass.) 20151103 1

Hepatic ischemia/reperfusion (I/R) injury is a side effect of major liver surgery that often cannot be avoided. Prolonged periods of ischemia put a metabolic strain on hepatocytes and limit the tolerable ischemia and preservation times during liver resection and transplantation, respectively. In both surgical settings, temporarily lowering the metabolic demand of the organ by reducing organ temperature effectively counteracts the negative consequences of an ischemic insult. Despite its routine u ...[more]

PMID: 26552060

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Project description:BackgroundHypothermic protection against ischemic stroke has been reported by many studies. Hypothermia is supposed to mitigate the effects of deleterious genes and proteins and promote the activity of protective genes and proteins in the ischemic brain. Metallothionein (MT)-1/2 is thought to be a crucial factor for metal homeostasis, immune function, and apoptosis. This protein was found to exert protective effects in models of brain injury as well. In the present study, we investigated the effect of hypothermia on MT expression and the underlying mechanisms.MethodsCultured bEnd.3 brain endothelial cells were exposed to oxygen glucose deprivation and reperfusion (OGD+R). Reverse transcription PCR and western blot analyses were performed to measure the expression of MT, transcription factors, and methylation regulating factors. Transcription factor binding assays were also performed. Methylation profiles of the promoter area were obtained with pyrosequencing.ResultsHypothermia protected bEnd.3 cells from OGD+R. When the cells were exposed to OGD+R, MT expression was induced. Hypothermia augmented MT levels. While OGD+R-induced MT expression was mainly associated with metal regulatory transcription factor 1 (MTF-1), MT expression promoted by hypothermia was primarily mediated by the signal transducer and activator of transcription 3 (STAT3). Significantly increased STAT3 phosphorylation at Ser727 was observed with hypothermia, and JSI-124, a STAT-3 inhibitor, suppressed MT expression. The DNA demethylating drug 5-aza-2'-deoxycytidine (5-Aza) enhanced MT expression. Some of the CpG sites in the promoter MT=> it should be "the CpG sites in the MT promoter" showed different methylation profiles and some methylation regulating factors had different expressional profiles in the presence of OGD+R and hypothermia.ConclusionsWe demonstrated that hypothermia is a potent inducer of MT gene transcription in brain endothelial cells, and enhanced MT expression might contribute to protection against ischemia. MT gene expression is induced by hypothermia mainly through the STAT3 pathway. DNA methylation may contribute to MT gene regulation under ischemic or hypothermic conditions.

Project description:Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months.MethodsThis was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson's chi-square test for binary outcomes. Effect size was measured using Cohen's d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test.ResultsEach arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months.ConclusionsEVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.

Project description:BackgroundMinimally invasive surgery (MIS) is the technique of choice in selected patients for the treatment of liver tumors. The robotic approach is considered today the natural evolution of MIS. The application of the robotic technique in liver transplantation (LT) has been recently evaluated, especially in the living donation. The aim of this paper is to review the current role of the MIS and robotic donor hepatectomy in the literature and to evaluate the possible future implication in the transplant field.MethodsWe conducted a narrative review using PubMed and Google Scholar for reports published so far, using the following keywords: minimally invasive liver surgery, laparoscopic liver surgery, robotic liver surgery, robotic living donation, laparoscopic donor hepatectomy and robotic donor hepatectomy.ResultsSeveral advantages have been claimed in favor of robotic surgery: three-dimensional (3-D) imaging with stable and high-definition view; a more rapid learning curve than the laparoscopic one; the lack of hand tremors and the freedom of movements. Compared to open surgery, the benefits showed in the studies evaluating the robotic approach in the living donation are: less postoperative pain, the shorter period before returning to normal activity despite sustaining longer operation time. Furthermore, the 3-D and magnification view makes the technique excellent in distinguishing the right plane of transection, vascular and biliary anatomy, associated with high precision of the movements and a better bleeding control (essential for donor safety) and lower rate of vascular injury.ConclusionsThe current literature does not fully support the superiority of the robotic approach versus laparoscopic or open method in living donor hepatectomy. Robotic donor hepatectomy performed by teams with high expertise and in properly selected living donors is safe and feasible. However, further data are necessary to evaluate properly the role of robotic surgery in the field of living donation.

Dataset Information

Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation.

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Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation.

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