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New Frontiers in Organ Preservation and Hepatoprotection

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 47260

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Special Issue Editor

Prof. Dr. René Hany Tolba

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Guest Editor

Rheinisch-Westfalische Technische Hochschule Aachen, Institute for Laboratory Animal Science and Experimental Surgery, Aachen, Germany
Interests: ischemia reperfusion; liver transplantation; organ preservation; laboratory animal science

Special Issue Information

Dear Colleagues,

Hepatic ischemia reperfusion injury (IRI) represents a significant risk of inferior outcomes following major liver resections and orthotopic liver transplantation (OLT). IRI has been recognized to be associated with severe complications, such as post-reperfusion syndrome, allograft and remnant liver dysfunction or even allograft rejection. Over the last few decades, several methods have been developed aiming to reduce liver IRI in different clinical and experimental settings. Although accumulating evidence shows the potential positive effects of various protective strategies, multiple challenges remain to be solved.

This Special Issue will cover a selection of original articles and state-of-the-art comprehensive review articles on recent research topics in the field of basic and translational hepatobiliary research and liver transplantation. This includes a broad spectrum of pharmacological treatments using synthetic or biological agents and/or surgical approaches (e.g., local/remote ischemic conditioning), ex vivo allograft therapies using dynamic or static organ preservation, and approaches aiming for the modulation of liver regeneration and mechanisms of injury. Clinical trials and studies will also be considered if they deliver mechanistic insights using molecular biological methods. Nevertheless, contributions are not strictly limited to the fields that are mentioned in the keywords.

Prof. Dr. René Hany Tolba
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Liver transplantation
Partial hepatectomy
Organ preservation
Ischemia reperfusion injury
Machine perfusion
Cold storage
Subcellular mechanisms
Liver regeneration
Allograft rejection
Pharmacological and surgical strategies of hepatoprotection

Published Papers (14 papers)

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Editorial

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4 pages, 4634 KiB

Open AccessEditorial

New Frontiers in Organ Preservation and Hepatoprotection

by Zoltan Czigany and René Hany Tolba

Int. J. Mol. Sci. 2022, 23(8), 4379; https://doi.org/10.3390/ijms23084379 - 15 Apr 2022

Cited by 1 | Viewed by 1579

Abstract

This editorial aims to summarize the 13 scientific articles published in the Special Issue entitled “New Frontiers in Organ Preservation and Hepatoprotection” [...] Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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Research

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11 pages, 2710 KiB

Open AccessArticle

Metabotropic Glutamate Receptor Blockade Reduces Preservation Damage in Livers from Donors after Cardiac Death

by Laura Giuseppina Di Pasqua, Clarissa Berardo, Marta Cagna, Roberta Verta, Debora Collotta, Ferdinando Nicoletti, Andrea Ferrigno, Massimo Collino and Mariapia Vairetti

Int. J. Mol. Sci. 2021, 22(5), 2234; https://doi.org/10.3390/ijms22052234 - 24 Feb 2021

Cited by 3 | Viewed by 1707

Abstract

We previously demonstrated that the blockade of mGluR5 by 2-methyl-6(phenylethynyl)pyridine (MPEP) reduces both cold and warm ischemia/reperfusion injury. Here we evaluated whether MPEP reduces the hepatic preservation injury in rat livers from cardiac-death-donors (DCDs). Livers from DCD rats were isolated after an in situ warm ischemia (30 min) and preserved for 22 h at 4 °C with UW solution. Next, 10 mg/Kg MPEP or vehicle were administered 30 min before the portal clamping and added to the UW solution (3 µM). LDH released during washout was quantified. Liver samples were collected for iNOS, eNOS, NO, TNF-α, ICAM-1, caspase-3 and caspase-9 protein expression and nuclear factor-erythroid-2-related factor-2 (Nrf2) gene analysis. Lower LDH levels were detected in control grafts versus DCD groups. An increase in eNOS and NO content occurred after MPEP treatment; iNOS and TNF-α content was unchanged. ICAM-1 expression was reduced in the MPEP-treated livers as well as the levels of caspase-3 and caspase-9. Nrf2, oxidative stress-sensitive gene, was recovered to control value by MPEP. These results suggest that MPEP can be used to reclaim DCD livers subjected to an additional period of cold ischemia during hypothermic storage. MPEP protects against apoptosis and increased eNOS, whose overexpression has been previously demonstrated to be protective in hepatic ischemia/reperfusion damage. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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12 pages, 4422 KiB

Open AccessArticle

Steatotic Livers Are More Susceptible to Ischemia Reperfusion Damage after Transplantation and Show Increased γδ T Cell Infiltration

by Elke Eggenhofer, Anja Groell, Henrik Junger, Amoon Kasi, Alexander Kroemer, Edward K. Geissler, Hans J. Schlitt and Marcus N. Scherer

Int. J. Mol. Sci. 2021, 22(4), 2036; https://doi.org/10.3390/ijms22042036 - 18 Feb 2021

Cited by 9 | Viewed by 2098

Abstract

Liver transplantation (LTx) is often the only possible therapy for many end-stage liver diseases, but successful long-term transplant outcomes are limited by multiple factors, including ischemia reperfusion injury (IRI). This situation is aggravated by a shortage of transplantable organs, thus encouraging the use of inferior quality organs. Here, we have investigated early hepatic IRI in a retrospective, exploratory, monocentric case-control study considering organ marginality. We analyzed standard LTx biopsies from 46 patients taken at the end of cold organ preparation and two hours after reperfusion, and we showed that early IRI was present after two hours in 63% of cases. Looking at our data in general, in accordance with Eurotransplant criteria, a marginal transplant was allocated at our institution in about 54% of cases. We found that patients with a marginal-organ LTx showing evidence of IRI had a significantly worse one-year survival rate (51% vs. 75%). As we saw in our study cohort, the marginality of these livers was almost entirely due to steatosis. In contrast, survival rates in patients receiving a non-marginal transplant were not influenced by the presence or absence of IRI. Poorer outcomes in marginal organs prompted us to examine pre- and post-reperfusion biopsies, and it was revealed that transplants with IRI demonstrated significantly greater T cell infiltration. Molecular analyses showed that higher mRNA expression levels of CXCL-1, CD3 and TCRγ locus genes were found in IRI livers. We therefore conclude that the marginality of an organ, namely steatosis, exacerbates early IRI by enhancing effector immune cell infiltration. Preemptive strategies targeting immune pathways could increase the safety of using marginal organs for LTx. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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10 pages, 1570 KiB

Open AccessArticle

Custodiol-N Is Superior to Custodiol^® Solution in Experimental Rat Uterus Preservation

by Viktorija Zitkute, Mindaugas Kvietkauskas, Vygante Maskoliunaite, Bettina Leber, Diana Ramasauskaite, Kestutis Strupas, Philipp Stiegler and Peter Schemmer

Int. J. Mol. Sci. 2020, 21(21), 8015; https://doi.org/10.3390/ijms21218015 - 28 Oct 2020

Cited by 6 | Viewed by 1831

Abstract

Uterus transplantation (UTx) is the first and only available treatment for women with absolute uterine factor infertility. However, clinical application is limited by the lack of organs, ischemia/reperfusion injury, as well as immunosuppression after UTx. Several different preservation solutions are used in experimental and clinical UTx, including Custodiol^® solution. Recently, the novel Custodiol-N solution was developed with superior results in organ preservation. However, the solution was not tested yet in UTx. Therefore, the aims of this study were to evaluate the effect of Custodiol-N in uterus prolonged cold preservation time (8 and 24 h), compared to Custodiol^® solution. Uterus tissue samples were obtained from adult Sprague Dawley rats (n = 10/group). Cold ischemic injury was estimated by histology, including immunohistochemistry, and biochemical tissue analyses. After 8 h of cold ischemia, higher percentage of tissue edema, necrosis signs and myeloperoxidase expression, as well as lower superoxide dismutase activity were found in Custodiol^® compared to Custodiol-N (p < 0.05). These differences were more pronounced after 24 h of cold preservation time (p < 0.05). This study demonstrated that Custodiol-N protects uterus grafts from cold ischemic injury better than standard Custodiol^® most likely via inhibition of oxidative stress and tissue edema. It seems that iron chelators in the composition of Custodiol-N play an important protective role against cold ischemia. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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17 pages, 3084 KiB

Open AccessArticle

Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation

by Zoltan Czigany, Eve Christiana Craigie, Georg Lurje, Shaowei Song, Kei Yonezawa, Yuzo Yamamoto, Thomas Minor and René Hany Tolba

Int. J. Mol. Sci. 2020, 21(18), 6747; https://doi.org/10.3390/ijms21186747 - 14 Sep 2020

Cited by 7 | Viewed by 2781

Abstract

Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A_2a receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs (n = 10; 20–25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group (n = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A_2a receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; p < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; p < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; p = 0.04). The ex vivo administration of adenosine A_2a receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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17 pages, 5465 KiB

Open AccessArticle

Sulforaphane Elicits Protective Effects in Intestinal Ischemia Reperfusion Injury

by Zhiquan Chen, Annika Mohr, Barbara Heitplatz, Uwe Hansen, Andreas Pascher, Jens G. Brockmann and Felix Becker

Int. J. Mol. Sci. 2020, 21(15), 5189; https://doi.org/10.3390/ijms21155189 - 22 Jul 2020

Cited by 9 | Viewed by 2580

Abstract

Intestinal ischemia reperfusion injury (IRI) is an inherent, unavoidable event of intestinal transplantation, contributing to allograft failure and rejection. The inflammatory state elicited by intestinal IRI is characterized by heightened leukocyte recruitment to the gut, which is amplified by a cross-talk with platelets at the endothelial border. Sulforaphane (SFN), a naturally occurring isothiocyanate, exhibits anti-inflammatory characteristics and has been shown to reduce platelet activation and block leukocyte adhesion. Thus, the aim of this study was to investigate protective effects and mechanism of action of SFN in a murine model of intestinal IRI. Intestinal IRI was induced by superior mesenteric artery occlusion for 30 min, followed by reperfusion for 2 h, 8 h or 24 h. To investigate cellular interactions, leukocytes were in vivo stained with rhodamine and platelets were harvested from donor animals and ex vivo stained. Mice (C57BL/6J) were divided into three groups: (1) control, (2) SFN treatment 24 h prior to reperfusion and (3) SFN treatment 24 h prior to platelet donation. Leukocyte and platelet recruitment was analyzed via intravital microscopy. Tissue was analyzed for morphological alterations in intestinal mucosa, barrier permeability, and leukocyte infiltration. Leukocyte rolling and adhesion was significantly reduced 2 h and 8 h after reperfusion. Mice receiving SFN treated platelets exhibited significantly decreased leukocyte and platelet recruitment. SFN showed protection for intestinal tissue with less damage observed in histopathological and ultrastructural evaluation. In summary, the data presented provide evidence for SFN as a potential therapeutic strategy against intestinal IRI. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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18 pages, 5814 KiB

Open AccessArticle

Reg3α and Reg3β Expressions Followed by JAK2/STAT3 Activation Play a Pivotal Role in the Acceleration of Liver Hypertrophy in a Rat ALPPS Model

by Naohiko Otsuka, Masato Yoshioka, Yuki Abe, Yasuhiko Nakagawa, Hiroshi Uchinami and Yuzo Yamamoto

Int. J. Mol. Sci. 2020, 21(11), 4077; https://doi.org/10.3390/ijms21114077 - 7 Jun 2020

Cited by 9 | Viewed by 2920

Abstract

To explore the underlying mechanism of rapid liver hypertrophy by liver partition in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), liver partition at different sites was investigated. Increased inflammatory cytokines owing to the liver partition have been reportedly responsible. If this were true, rapid liver hypertrophy should be achieved regardless of where the liver was split. A male Sprague-Dawley rat model was created, in which a liver split was placed inside the portal vein ligated lobe (PiLL), in addition to the ALPPS and portal vein ligation (PVL) models. Liver regeneration rate, inflammatory cytokine levels, activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and expressions of regenerating islet-derived (Reg)3α and Reg3β were investigated. The liver regeneration rate was significantly higher in the ALPPS group than in the PiLL group, whereas inflammatory cytokine levels were nearly equal. Additional volume increase in ALPPS group over PVL and PiLL groups was JAK2/STAT3-dependent. Reg3α and Reg3β expressions were observed only in the ALPPS group. An increase in inflammatory cytokines was not enough to describe the mechanism of rapid liver hypertrophy in ALPPS. Expressions of Reg3α and Reg3β could play an important role in conjunction with an activation of the JAK2/STAT3 pathway. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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Review

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17 pages, 4063 KiB

Open AccessReview

Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation

by Tamara Horváth, Dávid Kurszán Jász, Bálint Baráth, Marietta Zita Poles, Mihály Boros and Petra Hartmann

Int. J. Mol. Sci. 2021, 22(6), 2816; https://doi.org/10.3390/ijms22062816 - 10 Mar 2021

Cited by 11 | Viewed by 3955

Abstract

Allograft ischemia during liver transplantation (LT) adversely affects the function of mitochondria, resulting in impairment of oxidative phosphorylation and compromised post-transplant recovery of the affected organ. Several preservation methods have been developed to improve donor organ quality; however, their effects on mitochondrial functions have not yet been compared. This study aimed to summarize the available data on mitochondrial effects of graft preservation methods in preclinical models of LT. Furthermore, a network meta-analysis was conducted to determine if any of these treatments provide a superior benefit, suggesting that they might be used on humans. A systematic search was conducted using electronic databases (EMBASE, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science) for controlled animal studies using preservation methods for LT. The ATP content of the graft was the primary outcome, as this is an indicator overall mitochondrial function. Secondary outcomes were the respiratory activity of mitochondrial complexes, cytochrome c and aspartate aminotransferase (ALT) release. Both a random-effects model and the SYRCLE risk of bias analysis for animal studies were used. After a comprehensive search of the databases, 25 studies were enrolled in the analysis. Treatments that had the most significant protective effect on ATP content included hypothermic and subnormothermic machine perfusion (HMP and SNMP) (MD = −1.0, 95% CI: (−2.3, 0.3) and MD = −1.1, 95% CI: (−3.2, 1.02)), while the effects of warm ischemia (WI) without cold storage (WI) and normothermic machine perfusion (NMP) were less pronounced (MD = −1.8, 95% CI: (−2.9, −0.7) and MD = −2.1 MD; CI: (−4.6; 0.4)). The subgroup of static cold storage (SCS) with shorter preservation time (< 12 h) yielded better results than SCS ≥ 12 h, NMP and WI, in terms of ATP preservation and the respiratory capacity of complexes. HMP and SNMP stand out in terms of mitochondrial protection when compared to other treatments for LT in animals. The shorter storage time at lower temperatures, together with the dynamic preservation, provided superior protection for the grafts in terms of mitochondrial function. Additional clinical studies on human patients including marginal donors and longer ischemia times are needed to confirm any superiority of preservation methods with respect to mitochondrial function. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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19 pages, 909 KiB

Open AccessReview

Strategies for Liver Transplantation Tolerance

by Filip Cvetkovski, J. Mark Hexham and Erik Berglund

Int. J. Mol. Sci. 2021, 22(5), 2253; https://doi.org/10.3390/ijms22052253 - 24 Feb 2021

Cited by 14 | Viewed by 3350

Abstract

Liver transplant (LT) recipients require life-long immunosuppression (IS) therapy to preserve allograft function. The risks of chronic IS include an increased frequency of malignancy, infection, renal impairment, and other systemic toxicities. Despite advances in IS, long-term LT outcomes have not been improved over the past three decades. Standard-of-care (SoC) therapy can, in rare cases, lead to development of operational tolerance that permits safe withdrawal of maintenance IS. However, successful IS withdrawal cannot be reliably predicted and, in current prospective studies, is attempted several years after the transplant procedure, after considerable exposure to the cumulative burden of maintenance therapy. A recent pilot clinical trial in liver tolerance induction demonstrated that peri-transplant immunomodulation, using a regulatory T-cell (Treg) approach, can reduce donor-specific alloreactivity and allow early IS withdrawal. Herein we review protocols for active tolerance induction in liver transplantation, with a focus on identifying tolerogenic cell populations, as well as barriers to tolerance. In addition, we propose the use of novel IS agents to promote immunomodulatory mechanisms favoring tolerance. With numerous IS withdrawal trials underway, improved monitoring and use of novel immunomodulatory strategies will help provide the necessary knowledge to establish an active liver tolerance induction protocol for widespread use. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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24 pages, 1669 KiB

Open AccessReview

Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury—An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies

by Norbert Nemeth, Katalin Peto, Zsuzsanna Magyar, Zoltan Klarik, Gabor Varga, Mihai Oltean, Anna Mantas, Zoltan Czigany and Rene H. Tolba

Int. J. Mol. Sci. 2021, 22(4), 1864; https://doi.org/10.3390/ijms22041864 - 13 Feb 2021

Cited by 23 | Viewed by 4230

Abstract

Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular–pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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21 pages, 1278 KiB

Open AccessReview

Liver Regeneration after Hepatectomy and Partial Liver Transplantation

by Shintaro Yagi, Masaaki Hirata, Yosuke Miyachi and Shinji Uemoto

Int. J. Mol. Sci. 2020, 21(21), 8414; https://doi.org/10.3390/ijms21218414 - 9 Nov 2020

Cited by 72 | Viewed by 9381

Abstract

The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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17 pages, 259 KiB

Open AccessReview

The Role of Metabolomics in Current Concepts of Organ Preservation

by Mindaugas Kvietkauskas, Viktorija Zitkute, Bettina Leber, Kestutis Strupas, Philipp Stiegler and Peter Schemmer

Int. J. Mol. Sci. 2020, 21(18), 6607; https://doi.org/10.3390/ijms21186607 - 10 Sep 2020

Cited by 17 | Viewed by 2148

Abstract

In solid organ transplantation (Tx), both survival rates and quality of life have improved dramatically over the last few decades. Each year, the number of people on the wait list continues to increase, widening the gap between organ supply and demand. Therefore, the use of extended criteria donor grafts is growing, despite higher susceptibility to ischemia-reperfusion injury (IRI) and consecutive inferior Tx outcomes. Thus, tools to characterize organ quality prior to Tx are crucial components for Tx success. Innovative techniques of metabolic profiling revealed key pathways and mechanisms involved in IRI occurring during organ preservation. Although large-scale trials are needed, metabolomics appears to be a promising tool to characterize potential biomarkers, for the assessment of graft quality before Tx and evaluate graft-related outcomes. In this comprehensive review, we summarize the currently available literature on the use of metabolomics in solid organ Tx, with a special focus on metabolic profiling during graft preservation to assess organ quality prior to Tx. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

16 pages, 584 KiB

Open AccessReview

HTK-N: Modified Histidine-Tryptophan-Ketoglutarate Solution—A Promising New Tool in Solid Organ Preservation

by Annika Mohr, Jens G. Brockmann and Felix Becker

Int. J. Mol. Sci. 2020, 21(18), 6468; https://doi.org/10.3390/ijms21186468 - 4 Sep 2020

Cited by 18 | Viewed by 3452

Abstract

To ameliorate ischemia-induced graft injury, optimal organ preservation remains a critical hallmark event in solid organ transplantation. Although numerous preservation solutions are in use, they still have functional limitations. Here, we present a concise review of a modified Histidine-Tryptophan-Ketoglutarate (HTK) solution, named HTK-N. Its composition differs from standard HTK solution, carrying larger antioxidative capacity and providing inherent toxicity as well as improved tolerance to cold aiming to attenuate cold storage injury in organ transplantation. The amino acids glycine, alanine and arginine were supplemented, N-acetyl-histidine partially replaced histidine, and aspartate and lactobionate substituted chloride. Several in vitro studies confirmed the superiority of HTK-N in comparison to HTK, being tested in vivo in animal models for liver, kidney, pancreas, small bowel, heart and lung transplantation to adjust ingredients for required conditions, as well as to determine its innocuousness, applicability and potential advantages. HTK-N solution has proven to be advantageous especially in the preservation of liver and heart grafts in vivo and in vitro. Thus, ongoing clinical trials and further studies in large animal models and consequently in humans are inevitable to show its ability minimizing ischemia-induced graft injury in the sequel of organ transplantation. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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29 pages, 1197 KiB

Open AccessReview

Necroptosis in Hepatosteatotic Ischaemia-Reperfusion Injury

by Raji Baidya, Darrell H. G. Crawford, Jérémie Gautheron, Haolu Wang and Kim R. Bridle

Int. J. Mol. Sci. 2020, 21(16), 5931; https://doi.org/10.3390/ijms21165931 - 18 Aug 2020

Cited by 20 | Viewed by 4327

Abstract

While liver transplantation remains the sole treatment option for patients with end-stage liver disease, there are numerous limitations to liver transplantation including the scarcity of donor livers and a rise in livers that are unsuitable to transplant such as those with excess steatosis. Fatty livers are susceptible to ischaemia-reperfusion (IR) injury during transplantation and IR injury results in primary graft non-function, graft failure and mortality. Recent studies have described new cell death pathways which differ from the traditional apoptotic pathway. Necroptosis, a regulated form of cell death, has been associated with hepatic IR injury. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be instrumental in the execution of necroptosis. The study of hepatic necroptosis and potential therapeutic approaches to attenuate IR injury will be a key factor in improving our knowledge regarding liver transplantation with fatty donor livers. In this review, we focus on the effect of hepatic steatosis during liver transplantation as well as molecular mechanisms of necroptosis and its involvement during liver IR injury. We also discuss the immune responses triggered during necroptosis and examine the utility of necroptosis inhibitors as potential therapeutic approaches to alleviate IR injury. Full article

(This article belongs to the Special Issue New Frontiers in Organ Preservation and Hepatoprotection)

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