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      Liver Graft Susceptibility during Static Cold Storage and Dynamic Machine Perfusion: DCD versus Fatty Livers

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          Abstract

          We compared static preservation (cold storage, CS, 4 °C) with dynamic preservation (machine perfusion, MP, 20 °C) followed by reperfusion using marginal livers: a model of donation after cardiac death (DCD) livers and two models of fatty livers, the methionine-choline deficient (MCD) diet model, and obese Zucker (fa/fa) rats. CS injury in DCD livers was reversed by an oxygenated washout (OW): hepatic damage, bile flow, and the ATP/ADP ratio in the OW + CS group was comparable with the ratio obtained with MP. Using fatty livers, CS preservation induced a marked release in hepatic and biliary enzymes in obese Zucker rats when compared with the MCD group. The same trend occurred for bile flow. No difference was found when comparing MP in MCD and obese Zucker rats. Fatty acid analysis demonstrated that the total saturated (SFA)/polyunsaturated fatty acid (PUFA) ratio was, respectively, 1.5 and 0.71 in obese Zucker and MCD rats. While preservation damage in DCD livers is associated with the ATP/ADP recovered with OW, injury in fatty livers is linked to fatty acid constituents: livers from obese. Zucker rats, with greater content in saturated FA, might be more prone to CS injury. On the contrary, MCD livers with elevated PUFA content might be less susceptible to hypothermia.

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          First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An International-matched Case Analysis.

          Exposure of donor liver grafts to prolonged periods of warm ischemia before procurement causes injuries including intrahepatic cholangiopathy, which may lead to graft loss. Due to unavoidable prolonged ischemic time before procurement in donation after cardiac death (DCD) donation in 1 participating center, each liver graft of this center was pretreated with the new machine perfusion "Hypothermic Oxygenated PErfusion" (HOPE) in an attempt to improve graft quality before implantation.
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            Hypoxia and hypoxia inducible factors: diverse roles in liver diseases.

            Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models. Copyright © 2011 American Association for the Study of Liver Diseases.
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              Dual hypothermic oxygenated machine perfusion in liver transplants donated after circulatory death

              Background Experimental studies have suggested that end‐ischaemic dual hypothermic oxygenated machine perfusion (DHOPE) may restore hepatocellular energy status and reduce reperfusion injury in donation after circulatory death (DCD) liver grafts. The aim of this prospective case–control study was to assess the safety and feasibility of DHOPE in DCD liver transplantation. Methods In consecutive DCD liver transplantations, liver grafts were treated with end‐ischaemic DHOPE. Outcome was compared with that in a control group of DCD liver transplantations without DHOPE, matched for donor age, donor warm ischaemia time, and recipient Model for End‐stage Liver Disease (MELD) score. All patients were followed for 1 year. Results Ten transplantations involving liver grafts treated with DHOPE were compared with 20 control procedures. There were no technical problems. All 6‐month and 1‐year graft and patient survival rates were 100 per cent in the DHOPE group. Six‐month graft survival and 1‐year graft and patient survival rates in the control group were 80, 67 and 85 per cent respectively. During DHOPE, median (i.q.r.) hepatic adenosine 5′‐triphosphate (ATP) content increased 11‐fold, from 6 (3–10) to 66 (42–87) µmol per g protein (P = 0·005). All DHOPE‐preserved livers showed excellent early function. At 1 week after transplantation peak serum alanine aminotransferase (ALT) and bilirubin levels were twofold lower in the DHOPE group than in the control group (ALT: median 966 versus 1858 units/l respectively, P = 0·006; bilirubin: median 1·0 (i.q.r. 0·7–1·4) versus 2·6 (0·9–5·1) mg/dl, P = 0·044). None of the ten DHOPE‐preserved livers required retransplantation for non‐anastomotic biliary stricture, compared with five of 20 in the control group (P = 0·140). Conclusion This clinical study of end‐ischaemic DHOPE in DCD liver transplantation suggests that the technique restores hepatic ATP, reduces reperfusion injury, and is safe and feasible. RCTs with larger numbers of patients are warranted to assess the efficacy in reducing post‐transplant biliary complications.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                31 December 2017
                January 2018
                : 19
                : 1
                : 109
                Affiliations
                [1 ]Department of Internal Medicine and Therapeutics, Unit of Cellular and Molecular Pharmacology and Toxicology, University of Pavia, 27100 Pavia, Italy; andrea.ferrigno@ 123456unipv.it (A.F.); lauragiuseppin.dipasqua01@ 123456universitadipavia.it (L.G.D.P.); clarissa.berardo01@ 123456universitadipavia.it (C.B.); veronica.siciliano01@ 123456universitadipavia.it (V.S.); plinio.richelmi@ 123456unipv.it (P.R.)
                [2 ]Department of Molecular Science, IRCCS S. Matteo, University of Pavia, 27100 Pavia, Italy; v.rizzo@ 123456smatteo.pv.it
                [3 ]Centro Grandi Strumenti, University of Pavia, 27100 Pavia, Italy; barbara.mannucci@ 123456unipv.it
                [4 ]Institute of Molecular Genetics, Italian National Research Council (CNR), 27100 Pavia, Italy; leta@ 123456igm.cnr.it
                [5 ]Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
                Author notes
                [* ]Correspondence: mariapia.vairetti@ 123456unipv.it ; Tel.: +39-0382-986398
                Author information
                https://orcid.org/0000-0003-2337-2897
                Article
                ijms-19-00109
                10.3390/ijms19010109
                5796058
                29301219
                04738290-921a-4326-bc32-ea62f0c2c311
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 November 2017
                : 26 December 2017
                Categories
                Article

                Molecular biology
                marginal livers,preservation,static cold storage,dynamic machine perfusion,dcd livers,fatty livers

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