scholarly journals Polyethylene Glycol 35 as a Perfusate Additive for Mitochondrial and Glycocalyx Protection in HOPE Liver Preservation

2020 ◽  
Vol 21 (16) ◽  
pp. 5703 ◽  
Author(s):  
Arnau Panisello Rosello ◽  
Rui Teixeira da Silva ◽  
Carlos Castro ◽  
Raquel G. Bardallo ◽  
Maria Calvo ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Water Soluble ◽  
Liver Graft ◽  
Liver Preservation ◽  
Hypothermic Preservation ◽  
Graft Preservation ◽  
Abdominal Organs ◽  
Good Target

Organ transplantation is a multifactorial process in which proper graft preservation is a mandatory step for the success of the transplantation. Hypothermic preservation of abdominal organs is mostly based on the use of several commercial solutions, including UW, Celsior, HTK and IGL-1. The presence of the oncotic agents HES (in UW) and PEG35 (in IGL-1) characterize both solution compositions, while HTK and Celsior do not contain any type of oncotic agent. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic and water-soluble polymers, which present a combination of properties of particular interest in the clinical context of ischemia-reperfusion injury (IRI): they limit edema and nitric oxide induction and modulate immunogenicity. Besides static cold storage (SCS), there are other strategies to preserve the organ, such as the use of machine perfusion (MP) in dynamic preservation strategies, which increase graft function and survival as compared to the conventional static hypothermic preservation. Here we report some considerations about using PEG35 as a component of perfusates for MP strategies (such as hypothermic oxygenated perfusion, HOPE) and its benefits for liver graft preservation. Improved liver preservation is closely related to mitochondria integrity, making this organelle a good target to increase graft viability, especially in marginal organs (e.g., steatotic livers). The final goal is to increase the pool of suitable organs, and thereby shorten patient waiting lists, a crucial problem in liver transplantation.

scholarly journals Protective Role of mTOR in Liver Ischemia/Reperfusion Injury: Involvement of Inflammation and Autophagy

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Tao Zhang ◽  
Jianrong Guo ◽  
Jian Gu ◽  
Ke Chen ◽  
Huili Li ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mammalian Target Of Rapamycin ◽  
Graft Function ◽  
Protective Role ◽  
Liver Graft ◽  
Current Evidence ◽  
Liver Ischemia ◽  
Pathological Conditions

Liver ischemia/reperfusion (IR) injury is a common phenomenon after liver resection and transplantation, which often results in liver graft dysfunction such as delayed graft function and primary nonfunction. The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved serine/threonine protein kinase, which coordinates cell growth and metabolism through sensing environmental inputs under physiological or pathological conditions, involved in the pathophysiological process of IR injury. In this review, we mainly present current evidence of the beneficial role of mTOR in modulating inflammation and autophagy under liver IR to provide some evidence for the potential therapies for liver IR injury.

scholarly journals The impact of desflurane and sevoflurane on the intraoperative and early postoperative period in liver transplantation

2021 ◽  
Vol 13 (4) ◽  
pp. 328-338
Author(s):  
S. V. Zhuravel ◽  
N. K. Kuznetsova ◽  
V. E. Aleksandrova ◽  
I. I. Goncharova
Keyword(s):  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Postoperative Period ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Early Postoperative Period ◽  
Liver Graft ◽  
Inhalation Anesthetics ◽  
The Impact

Background. A pressing issue is the choice of an anesthetic agent for liver transplantation. The mechanism of the organprotective properties of desflurane and sevoflurane is not fully understood. It is important to understand the effects of desflurane and sevoflurane on the severity of ischemia-reperfusion injury of the liver graftAim. To study the effect of desflurane and sevoflurane on the intraoperative and early postoperative period in liver transplantation.Material and methods. The study included 47 patients with liver cirrhosis of various etiologies who underwent cadaveric liver transplantation between February and December 2020. The groups compared in the study included 24 patients who received desflurane and 23 patients who received sevoflurane.Results. There were no statistically significant differences in the effect of desflurane and sevoflurane on hemodynamic parameters, on the need for vasopressor drugs. Episodes of bradycardia and cardiac arrhythmias were significantly more frequent when using sevoflurane. Patients were extubated significantly faster after surgery in the desflurane group. In the early postoperative period, desflurane and sevoflurane did not adversely affect significantly the liver graft function and the degree of its ischemia-reperfusion injury. The groups appeared comparable in rates of using the renal replacement therapy, the incidence of the graft dysfunction development in the postoperative period, and the surgery outcomes.Conclusions. The use of modern inhalation anesthetics desflurane and sevoflurane to maintain anesthesia during liver transplantation does not adversely affect the course of the intraoperative and early postoperative period.

scholarly journals Protective Effect of Intravenous High Molecular Weight Polyethylene Glycol on Fatty Liver Preservation

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Mohamed Bejaoui ◽  
Eirini Pantazi ◽  
Emma Folch-Puy ◽  
Arnau Panisello ◽  
María Calvo ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Liver Injury ◽  
High Molecular Weight ◽  
Intravenous Administration ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Water Soluble ◽  
Isolated Perfused Rat Liver ◽  
Cold Ischemia ◽  
Liver Preservation

Ischemia reperfusion injury (IRI) leads to significant tissue damage in liver surgery. Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have proved their effectiveness against IRI. The objective of our study was to investigate the potential protective effects of intravenous administration of a high molecular weight PEG of 35 kDa (PEG 35) in steatotic livers subjected to cold ischemia reperfusion. In this study, we used isolated perfused rat liver model to assess the effects of PEG 35 intravenous administration after prolonged cold ischemia (24 h, 4°C) and after reperfusion (2 h, 37°C). Liver injury was measured by transaminases levels and mitochondrial damage was determined by confocal microscopy assessing mitochondrial polarization (after cold storage) and by measuring glutamate dehydrogenase activity (after reperfusion). Also, cell signaling pathways involved in the physiopathology of IRI were assessed by western blot technique. Our results show that intravenous administration of PEG 35 at 10 mg/kg ameliorated liver injury and protected the mitochondria. Moreover, PEG 35 administration induced a significant phosphorylation of prosurvival protein kinase B (Akt) and activation of cytoprotective factors e-NOS and AMPK. In conclusion, intravenous PEG 35 efficiently protects steatotic livers exposed to cold IRI.

scholarly journals Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Hui Liu ◽  
Chang Chun Ling ◽  
Wai Ho Oscar Yeung ◽  
Li Pang ◽  
Jiang Liu ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Tumor Recurrence ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Liver Graft ◽  
Mouse Tumor ◽  
Hepatic Ischemia ◽  
Tlr4 Signaling

AbstractTumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.

Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-κB

2000 ◽  
Vol 279 (3) ◽  
pp. L528-L536 ◽  
Author(s):  
Scott D. Ross ◽  
Irving L. Kron ◽  
James J. Gangemi ◽  
Kimberly S. Shockey ◽  
Mark Stoler ◽  
...  
Keyword(s):  
Lung Function ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Nuclear Factor Κb ◽  
Pyrrolidine Dithiocarbamate ◽  
Nuclear Factor ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial

A central role for nuclear factor-κB (NF-κB) in the induction of lung inflammatory injury is emerging. We hypothesized that NF-κB is a critical early regulator of the inflammatory response in lung ischemia-reperfusion injury, and inhibition of NF-κB activation reduces this injury and improves pulmonary graft function. With use of a porcine transplantation model, left lungs were harvested and stored in cold Euro-Collins preservation solution for 6 h before transplantation. Activation of NF-κB occurred 30 min and 1 h after transplant and declined to near baseline levels after 4 h. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-κB, given to the lung graft during organ preservation (40 mmol/l) effectively inhibited NF-κB activation and significantly improved lung function. Compared with control lungs 4 h after transplant, PDTC-treated lungs displayed significantly higher oxygenation, lower Pco2, reduced mean pulmonary arterial pressure, and reduced edema and cellular infiltration. These results demonstrate that NF-κB is rapidly activated and is associated with poor pulmonary graft function in transplant reperfusion injury, and targeting of NF-κB may be a promising therapy to reduce this injury and improve lung function.

Liver X Receptors Activation Attenuates Ischemia Reperfusion Injury of Liver Graft in Rats

2017 ◽  
Vol 32 (4) ◽  
pp. 298-303 ◽  
Author(s):  
Ming-xiang Cheng ◽  
Ping Huang ◽  
Qiang He ◽  
Yong Chen ◽  
Jin-zheng Li
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Liver Graft ◽  
Liver X Receptors ◽  
X Receptors

scholarly journals Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

2020 ◽  
Author(s):  
Caitriona M. McEvoy ◽  
Sergi Clotet-Freixas ◽  
Tomas Tokar ◽  
Chiara Pastrello ◽  
Shelby Reid ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Kidney Injury ◽  
Tca Cycle ◽  
Proteomics Analysis ◽  
Beneficial Effects ◽  
Kidney Perfusion

AbstractNormothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid ß-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

scholarly journals Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

2020 ◽  
Vol 21 (9) ◽  
pp. 3132 ◽  
Author(s):  
Julia Hofmann ◽  
Giorgi Otarashvili ◽  
Andras Meszaros ◽  
Susanne Ebner ◽  
Annemarie Weissenbacher ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Ros Production ◽  
Machine Perfusion ◽  
Redox Stress ◽  
Molecular Events ◽  
Regulate Cell Death

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

Inhibition of TLR2 promotes graft function in a murine model of renal transplant ischemia‐reperfusion injury

2011 ◽  
Vol 26 (2) ◽  
pp. 799-807 ◽  
Author(s):  
Conrad A. Farrar ◽  
Brian Keogh ◽  
William McCormack ◽  
Aisling O'Shaughnessy ◽  
Andrew Parker ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Reperfusion Injury ◽  
Murine Model ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Function
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