Impact Factor
  • ISSN 1674-8301
  • CN 32-1810/R
Volume 33 Issue 4
Jul.  2019
Turn off MathJax
Article Contents
Rampes Sanketh, Ma Daqing. Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies[J]. The Journal of Biomedical Research, 2019, 33(4): 221-234. doi: 10.7555/JBR.32.20180087
Citation: Rampes Sanketh, Ma Daqing. Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies[J]. The Journal of Biomedical Research, 2019, 33(4): 221-234. doi: 10.7555/JBR.32.20180087

Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies

doi: 10.7555/JBR.32.20180087
More Information
  • Corresponding author: Daqing Ma, Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, UK. Tel: (0044) 020 3315 8495, E-mail: d.ma@imperial.ac.uk
  • Received: 2018-09-12
  • Revised: 2018-10-10
  • Accepted: 2018-10-17
  • Published: 2019-12-01
  • Issue Date: 2019-07-01
  • Hepatic ischemia-reperfusion injury is a major cause of liver transplant failure, and is of increasing significance due to increased use of expanded criteria livers for transplantation. This review summarizes the mechanisms and protective strategies for hepatic ischemia-reperfusion injury in the context of liver transplantation. Pharmacological therapies, the use of pre-and post-conditioning and machine perfusion are discussed as protective strategies. The use of machine perfusion offers significant potential in the reconditioning of liver grafts and the prevention of hepatic ischemia-reperfusion injury, and is an exciting and active area of research, which needs more study clinically.


  • loading
  • [1]
    Ikeda T, Yanaga K, Kishikawa K, et al. Ischemic injury in liver transplantation: difference in injury sites between warm and cold ischemia in rats[J]. Hepatology, 1992, 16(2): 454–461. doi: 10.1002/hep.1840160226
    Jaeschke H. Reperfusion injury after warm ischemia or cold storage of the liver: role of apoptotic cell death[J]. Transplant Proc, 2002, 34(7): 2656–2658. doi: 10.1016/S0041-1345(02)03464-4
    Huet PM, Nagaoka MR, Desbiens G, et al. Sinusoidal endothelial cell and hepatocyte death following cold ischemia-warm reperfusion of the rat liver[J]. Hepatology, 2004, 39(4): 1110–1119. doi: 10.1002/hep.20157
    Kupiec-Weglinski JW, Busuttil RW. Ischemia and reperfusion injury in liver transplantation[J]. Transplant Proc, 2005, 37(4): 1653–1656. doi: 10.1016/j.transproceed.2005.03.134
    Zhai Y, Busuttil RW, Kupiec-Weglinski JW. Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation[J]. Am J Transplant, 2011, 11(8): 1563–1569. doi: 10.1111/ajt.2011.11.issue-8
    Pine JK, Aldouri A, Young AL, et al. Liver transplantation following donation after cardiac death: an analysis using matched pairs[J]. Liver Transpl, 2009, 15(9): 1072–1082. doi: 10.1002/lt.v15:9
    Howard TK, Klintmalm GBG, Cofer JB, et al. The influence of preservation injury on rejection in the hepatic transplant recipient[J]. Transplantation, 1990, 49(1): 103–107. doi: 10.1097/00007890-199001000-00023
    Fellström B, Aküyrek LM, Backman U, et al. Postischemic reperfusion injury and allograft arteriosclerosis[J]. Transplant Proc, 1998, 30(8): 4278–4280. doi: 10.1016/S0041-1345(98)01412-2
    Guo WA. The search for a magic bullet to fight multiple organ failure secondary to ischemia/reperfusion injury and abdominal compartment syndrome[J]. J Surg Res, 2013, 184(2): 792–793. doi: 10.1016/j.jss.2012.06.024
    Wertheim JA, Petrowsky H, Saab S, et al. Major challenges limiting liver transplantation in the United States[J]. Am J Transplant, 2011, 11(9): 1773–1784. doi: 10.1111/j.1600-6143.2011.03587.x
    Neuberger J. Liver transplantation in the United Kingdom[J]. Liver Transpl, 2016, 22(8): 1129–1135. doi: 10.1002/lt.v22.8
    NHS Blood and Transplant. Annual activity report[EB/OL]. [2017-02-07]. www.odt.nhs.uk.
    Singal AK, Guturu P, Hmoud B, et al. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease[J]. Transplantation, 2013, 95(5): 755–760. doi: 10.1097/TP.0b013e31827afb3a
    Casillas-Ramírez A, Mosbah IB, Ramalho F, et al. Past and future approaches to ischemia-reperfusion lesion associated with liver transplantation[J]. Life Sci, 2006, 79(20): 1881–1894. doi: 10.1016/j.lfs.2006.06.024
    Fan CG, Zwacka RM, Engelhardt JF. Therapeutic approaches for ischemia/reperfusion injury in the liver[J]. J Mol Med (Berl), 1999, 77(8): 577–592. doi: 10.1007/s001099900029
    Zwacka RM, Zhou WH, Zhang YL, et al. Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-κB activation[J]. Nat Med, 1998, 4(6): 698–704. doi: 10.1038/nm0698-698
    Teoh NC, Farrell GC. Hepatic ischemia reperfusion injury: pathogenic mechanisms and basis for hepatoprotection[J]. J Gastroenterol Hepatol, 2003, 18(8): 891–902. doi: 10.1046/j.1440-1746.2003.03056.x
    Mavier P, Preaux AM, Guigui B, et al. In vitro toxicity of polymorphonuclear neutrophils to rat hepatocytes: evidence for a proteinase-mediated mechanism[J]. Hepatology, 1988, 8(2): 254–258. doi: 10.1002/hep.1840080211
    Li XK, Matin AF, Suzuki H, et al. Effect of protease inhibitor on ischemia/reperfusion injury of the rat liver[J]. Transplantation, 1993, 56(6): 1331–1336. doi: 10.1097/00007890-199312000-00008
    Nastos C, Kalimeris K, Papoutsidakis N, et al. Global consequences of liver ischemia/reperfusion injury[J]. Oxid Med Cell Longev, 2014, 2014: 906965.
    Selzner M, Selzner N, Jochum W, et al. Increased ischemic injury in old mouse liver: an ATP-dependent mechanism[J]. Liver Transpl, 2007, 13(3): 382–390. doi: 10.1002/lt.21100
    Wang D, Dou K, Song Z, et al. The Na(+)/H(+) exchange inhibitor: a new therapeutic approach for hepatic ischemia injury in rats[J]. Transplant Proc, 2003, 35(8): 3134–3135. doi: 10.1016/j.transproceed.2003.10.021
    Carini R, De Cesaris MG, Splendore R, et al. Alterations of Na+ homeostasis in hepatocyte reoxygenation injury[J]. Biochim Biophys Acta, 2000, 1500(3): 297–305. doi: 10.1016/S0925-4439(99)00114-3
    Nishimura Y, Romer LH, Lemasters JJ. Mitochondrial dysfunction and cytoskeletal disruption during chemical hypoxia to cultured rat hepatic sinusoidal endothelial cells: the pH paradox and cytoprotection by glucose, acidotic pH, and glycine[J]. Hepatology, 1998, 27(4): 1039–1049. doi: 10.1002/hep.510270420
    Vairetti M, Richelmi P, Bertè F, et al. Role of pH in protection by low sodium against hypoxic injury in isolated perfused rat livers[J]. J Hepatol, 2006, 44(5): 894–901. doi: 10.1016/j.jhep.2005.08.007
    Gores GJ, Nieminen AL, Wray BE, et al. Intracellular pH during " chemical hypoxia” in cultured rat hepatocytes. Protection by intracellular acidosis against the onset of cell death[J]. J Clin Invest, 1989, 83(2): 386–396. doi: 10.1172/JCI113896
    Jiang N, Zhang ZM, Liu L, et al. Effects of Ca2+ channel blockers on store-operated Ca2+ channel currents of Kupffer cells after hepatic ischemia/reperfusion injury in rats[J]. World J Gastroenterol, 2006, 12(29): 4694–4698. doi: 10.3748/wjg.v12.i29.4694
    Barritt GJ, Chen JL, Rychkov GY. Ca2+-permeable channels in the hepatocyte plasma membrane and their roles in hepatocyte physiology[J]. Biochim Biophys Acta, 2008, 1783(5): 651–672. doi: 10.1016/j.bbamcr.2008.01.016
    Wang HG, Pathan N, Ethell IM, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD[J]. Science, 1999, 284(5412): 339–343. doi: 10.1126/science.284.5412.339
    Anderson CD, Pierce J, Nicoud I, et al. Modulation of mitochondrial calcium management attenuates hepatic warm ischemia-reperfusion injury[J]. Liver Transpl, 2005, 11(6): 663–668. doi: 10.1002/lt.20407
    Jaeschke H, Lemasters JJ. Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury[J]. Gastroenterology, 2003, 125(4): 1246–1257. doi: 10.1016/S0016-5085(03)01209-5
    Nauta RJ, Tsimoyiannis E, Uribe M, et al. The role of calcium ions and calcium channel entry blockers in experimental ischemia-reperfusion-induced liver injury[J]. Ann Surg, 1991, 213(2): 137–142. doi: 10.1097/00000658-199102000-00008
    Hataji K, Watanabe T, Oowada S, et al. Effects of a calcium-channel blocker (CV159) on hepatic ischemia/reperfusion injury in rats: evaluation with selective NO/pO2 electrodes and an electron paramagnetic resonance spin-trapping method[J]. Biol Pharm Bull, 2010, 33(1): 77–83. doi: 10.1248/bpb.33.77
    Nicoud IB, Knox CD, Jones CM, et al. 2-APB protects against liver ischemia-reperfusion injury by reducing cellular and mitochondrial calcium uptake[J]. Am J Physiol Gastrointest Liver Physiol, 2007, 293(3): G623–G630. doi: 10.1152/ajpgi.00521.2006
    Pronobesh C, Dagagi AV, Pallab C, et al. Protective role of the calcium channel blocker amlodipine against mitochondrial injury in ischemia and reperfusion injury of rat liver[J]. Acta Pharm, 2008, 58(4): 421–428.
    Abu-Amara M, Yang SY, Tapuria N, et al. Liver ischemia/reperfusion injury: processes in inflammatory networks—a review[J]. Liver Transpl, 2010, 16(9): 1016–1032. doi: 10.1002/lt.22117
    Elmore SP, Qian T, Grissom SF, et al. The mitochondrial permeability transition initiates autophagy in rat hepatocytes[J]. FASEB J, 2001, 15(12): 2286–2287. doi: 10.1096/fj.01-0206fje
    Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy[J]. Arch Biochem Biophys, 2007, 462(2): 245–253. doi: 10.1016/j.abb.2007.03.034
    Zhao KS, Zhao GM, Wu DL, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury[J]. J Biol Chem, 2004, 279(33): 34682–34690. doi: 10.1074/jbc.M402999200
    Kim JS, Qian T, Lemasters JJ. Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes[J]. Gastroenterology, 2003, 124(2): 494–503. doi: 10.1053/gast.2003.50059
    Sastre J, Serviddio G, Pereda J, et al. Mitochondrial function in liver disease[J]. Front Biosci, 2007, 12: 1200–1209. doi: 10.2741/2138
    Videla LA. Cytoprotective and suicidal signaling in oxidative stress[J]. Biol Res, 2010, 43(3): 363–369.
    Hines IN, Hoffman JM, Scheerens H, et al. Regulation of postischemic liver injury following different durations of ischemia[J]. Am J Physiol Gastrointest Liver Physiol, 2003, 284(3): G536–G545. doi: 10.1152/ajpgi.00400.2002
    Jaeschke H. Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions[J]. Am J Physiol Gastrointest Liver Physiol, 2006, 290(6): G1083–G1088. doi: 10.1152/ajpgi.00568.2005
    Spencer NY, Zhou WH, Li Q, et al. Hepatocytes produce TNF-α following hypoxia-reoxygenation and liver ischemia-reperfusion in a NADPH oxidase- and c-Src-dependent manner[J]. Am J Physiol Gastrointest Liver Physiol, 2013, 305(1): G84–G94. doi: 10.1152/ajpgi.00430.2012
    Reiniers MJ, van Golen RF, van Gulik TM, et al. Reactive oxygen and nitrogen species in steatotic hepatocytes: a molecular perspective on the pathophysiology of ischemia-reperfusion injury in the fatty liver[J]. Antioxid Redox Signal, 2014, 21(7): 1119–1142. doi: 10.1089/ars.2013.5486
    Pardini RS. Toxicity of oxygen from naturally occurring redox-active pro-oxidants[J]. Arch Insect Biochem Physiol, 1995, 29(2): 101–118. doi: 10.1002/arch.940290203
    Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: present concepts[J]. J Gastroenterol Hepatol, 2011, 26(S1): 173–179.
    Guicciardi ME, Malhi H, Mott JL, et al. Apoptosis and necrosis in the liver[J]. Compr Physiol, 2013, 3(2): 977–1010.
    Rauen U, Polzar B, Stephan H, et al. Cold-induced apoptosis in cultured hepatocytes and liver endothelial cells: mediation by reactive oxygen species[J]. FASEB J, 1999, 13(1): 155–168. doi: 10.1096/fasebj.13.1.155
    Kawada N, Tran-Thi TA, Klein H, et al. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances: Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus[J]. Eur J Biochem, 1993, 213(2): 815–823. doi: 10.1111/ejb.1993.213.issue-2
    Kawamura E, Yamanaka N, Okamoto E, et al. Response of plasma and tissue endothelin-1 to liver ischemia and its implication in ischemia-reperfusion injury[J]. Hepatology, 1995, 21(4): 1138–1143. doi: 10.1016/0270-9139(95)90266-X
    Lefer AM, Lefer DJ. Nitric oxide. II. Nitric oxide protects in intestinal inflammation[J]. Am J Physiol, 1999, 276(3 Pt 1): G572–G575.
    Hamada T, Duarte S, Tsuchihashi S, et al. Inducible nitric oxide synthase deficiency impairs matrix metalloproteinase-9 activity and disrupts leukocyte migration in hepatic ischemia/reperfusion injury[J]. Am J Pathol, 2009, 174(6): 2265–2277. doi: 10.2353/ajpath.2009.080872
    Abu-Amara M, Yang SY, Seifalian A, et al. The nitric oxide pathway-evidence and mechanisms for protection against liver ischaemia reperfusion injury[J]. Liver Int, 2012, 32(4): 531–543. doi: 10.1111/liv.2012.32.issue-4
    Chen C, Lee WH, Zhong LW, et al. Regulatory T cells can mediate their function through the stimulation of APCs to produce immunosuppressive nitric oxide[J]. J Immunol, 2006, 176(6): 3449–3460. doi: 10.4049/jimmunol.176.6.3449
    Phillips L, Toledo AH, Lopez-Neblina F, et al. Nitric oxide mechanism of protection in ischemia and reperfusion injury[J]. J Invest Surg, 2009, 22(1): 46–55. doi: 10.1080/08941930802709470
    Lang JD Jr, Teng XJ, Chumley P, et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation[J]. J Clin Invest, 2007, 117(9): 2583–2591. doi: 10.1172/JCI31892
    Duranski MR, Greer JJM, Dejam A, et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver[J]. J Clin Invest, 2005, 115(5): 1232–1240. doi: 10.1172/JCI22493
    Li W, Meng ZH, Liu YL, et al. The hepatoprotective effect of sodium nitrite on cold ischemia-reperfusion injury[J]. J Transplant, 2012, 2012: 635179.
    Shiratori Y, Kiriyama H, Fukushi Y, et al. Modulation of ischemia-reperfusion-induced hepatic injury by Kupffer cells[J]. Dig Dis Sci, 1994, 39(6): 1265–1272. doi: 10.1007/BF02093792
    Jaeschke H, Bautista AP, Spolarics Z, et al. Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats[J]. J Leukoc Biol, 1992, 52(4): 377–382. doi: 10.1002/jlb.1992.52.issue-4
    Fondevila C, Shen XD, Tsuchihashi S, et al. The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injury[J]. Liver Transpl, 2008, 14(8): 1133–1141. doi: 10.1002/lt.v14:8
    Brock RW, Nie RG, Harris KA, et al. Kupffer cell-initiated remote hepatic injury following bilateral hindlimb ischemia is complement dependent[J]. Am J Physiol Gastrointest Liver Physiol, 2001, 280(2): G279–G284. doi: 10.1152/ajpgi.2001.280.2.G279
    Llacuna L, Marí M, Lluis JM, et al. Reactive oxygen species mediate liver injury through parenchymal nuclear factor-κB inactivation in prolonged ischemia/reperfusion[J]. Am J Pathol, 2009, 174(5): 1776–1785. doi: 10.2353/ajpath.2009.080857
    Selzner N, Selzner M, Odermatt B, et al. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-α/IL-6 in mice[J]. Gastroenterology, 2003, 124(3): 692–700. doi: 10.1053/gast.2003.50098
    Boury NM, Czuprynski CJ. Listeria monocytogenes infection increases neutrophil adhesion and damage to a murine hepatocyte cell line in vitro[J]. Immunol Lett, 1995, 46(1–2): 111–116. doi: 10.1016/0165-2478(95)00027-3
    Hanschen M, Zahler S, Krombach F, et al. Reciprocal activation between CD4+ T cells and Kupffer cells during hepatic ischemia-reperfusion[J]. Transplantation, 2008, 86(5): 710–718. doi: 10.1097/TP.0b013e3181821aa7
    Nishimura Y, Takei Y, Kawano S, et al. The F(ab’)2 fragment of an anti-ICAM-1 monoclonal antibody attenuates liver injury after orthotopic liver transplantation[J]. Transplantation, 1996, 61(1): 99–104. doi: 10.1097/00007890-199601150-00020
    Fong Y, Moldawer LL, Shires GT, et al. The biologic characteristics of cytokines and their implication in surgical injury[J]. Surg Gynecol Obstet, 1990, 170(4): 363–378.
    Leifeld L, Cheng S, Ramakers J, et al. Imbalanced intrahepatic expression of interleukin 12, interferon gamma, and interleukin 10 in fulminant hepatitis B[J]. Hepatology, 2002, 36(4 Pt 1): 1001–1008.
    Lentsch AB, Yoshidome H, Kato A, et al. Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice[J]. Hepatology, 1999, 30(6): 1448–1453. doi: 10.1002/hep.510300615
    Husted TL, Blanchard J, Schuster R, et al. Potential role for IL-23 in hepatic ischemia/reperfusion injury[J]. Inflamm Res, 2006, 55(5): 177–178. doi: 10.1007/s00011-006-0073-1
    Colletti LM, Remick DG, Burtch GD, et al. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat[J]. J Clin Invest, 1990, 85(6): 1936–1943. doi: 10.1172/JCI114656
    Colletti LM, Kunkel SL, Walz A, et al. Chemokine expression during hepatic ischemia/reperfusion-induced lung injury in the rat. The role of epithelial neutrophil activating protein[J]. J Clin Invest, 1995, 95(1): 134–141. doi: 10.1172/JCI117630
    Colletti LM, Cortis A, Lukacs N, et al. Tumor necrosis factor up-regulates intercellular adhesion molecule 1, which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat[J]. Shock, 1998, 10(3): 182–191. doi: 10.1097/00024382-199809000-00006
    Shito M, Wakabayashi G, Ueda M, et al. Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ischemia-reperfusion in the rat[J]. Transplantation, 1997, 63(1): 143–148. doi: 10.1097/00007890-199701150-00026
    Djeu JY, Matsushima K, Oppenheim JJ, et al. Functional activation of human neutrophils by recombinant monocyte-derived neutrophil chemotactic factor/IL-8[J]. J Immunol, 1990, 144(6): 2205–2210.
    Lentsch AB, Yoshidome H, Cheadle WG, et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells[J]. Hepatology, 1998, 27(2): 507–512. doi: 10.1002/hep.510270226
    Ke BB, Shen XD, Lassman CR, et al. Cytoprotective and antiapoptotic effects of IL-13 in hepatic cold ischemia/reperfusion injury are heme oxygenase-1 dependent[J]. Am J Transplant, 2003, 3(9): 1076–1082. doi: 10.1034/j.1600-6143.2003.00147.x
    Reiter RJ, Paredes SD, Manchester LC, et al. Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin[J]. Crit Rev Biochem Mol Biol, 2009, 44(4): 175–200. doi: 10.1080/10409230903044914
    López-Burillo S, Tan DX, Rodriguez-Gallego V, et al. Melatonin and its derivatives cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine and 6-methoxymelatonin reduce oxidative DNA damage induced by Fenton reagents[J]. J Pineal Res, 2003, 34(3): 178–184. doi: 10.1111/jpi.2003.34.issue-3
    Barlow-Walden LR, Reiter RJ, Abe M, et al. Melatonin stimulates brain glutathione peroxidase activity[J]. Neurochem Int, 1995, 26(5): 497–502. doi: 10.1016/0197-0186(94)00154-M
    Reiter RJ, Tan DX, Osuna C, et al. Actions of melatonin in the reduction of oxidative stress: a review[J]. J Biomed Sci, 2000, 7(6): 444–458. doi: 10.1007/BF02253360
    Okatani Y, Wakatsuki A, Reiter RJ, et al. Protective effect of melatonin against mitochondrial injury induced by ischemia and reperfusion of rat liver[J]. Eur J Pharmacol, 2003, 469(1–3): 145–152. doi: 10.1016/S0014-2999(03)01643-1
    Kireev R, Bitoun S, Cuesta S, et al. Melatonin treatment protects liver of Zucker rats after ischemia/reperfusion by diminishing oxidative stress and apoptosis[J]. Eur J Pharmacol, 2013, 701(1–3): 185–193. doi: 10.1016/j.ejphar.2012.11.038
    Vairetti M, Ferrigno A, Bertone R, et al. Exogenous melatonin enhances bile flow and ATP levels after cold storage and reperfusion in rat liver: implications for liver transplantation[J]. J Pineal Res, 2005, 38(4): 223–230. doi: 10.1111/jpi.2005.38.issue-4
    De Deken J, Rex S, Monbaliu D, et al. The efficacy of noble gases in the attenuation of ischemia reperfusion injury: a systematic review and meta-analyses[J]. Crit Care Med, 2016, 44(9): e886–e896. doi: 10.1097/CCM.0000000000001717
    Wilke HJ, Moench C, Lotz G, et al. Xenon anesthesia for liver transplant surgery: a report of four cases[J]. Transplant Proc, 2011, 43(7): 2683–2686. doi: 10.1016/j.transproceed.2011.06.029
    Thies JC, Teklote J, Clauer U, et al. The efficacy of N-acetylcysteine as a hepatoprotective agent in liver transplantation[J]. Transpl Int, 1998, 11(S1): S390–S392. doi: 10.1111/j.1432-2277.1998.tb01164.x
    Weigand MA, Plachky J, Thies JC, et al. N-acetylcysteine attenuates the increase in α-glutathione S-transferase and circulating ICAM-1 and VCAM-1 after reperfusion in humans undergoing liver transplantation[J]. Transplantation, 2001, 72(4): 694–698. doi: 10.1097/00007890-200108270-00023
    Bucuvalas JC, Ryckman FC, Krug S, et al. Effect of treatment with prostaglandin E1 and N-acetylcysteine on pediatric liver transplant recipients: a single-center study[J]. Pediatr Transplant, 2001, 5(4): 274–278. doi: 10.1034/j.1399-3046.2001.005004274.x
    Bromley PN, Cottam SJ, Hilmi I, et al. Effects of intraoperative N-acetylcysteine in orthotopic liver transplantation[J]. Br J Anaesth, 1995, 75(3): 352–354. doi: 10.1093/bja/75.3.352
    Steib A, Freys G, Collin F, et al. Does N-acetylcysteine improve hemodynamics and graft function in liver transplantation?[J]. Liver Transpl Surg, 1998, 4(2): 152–157. doi: 10.1002/(ISSN)1527-6473a
    Tsuchihashi SI, Fondevila C, Shaw GD, et al. Molecular characterization of rat leukocyte P-selectin glycoprotein ligand-1 and effect of its blockade: protection from ischemia-reperfusion injury in liver transplantation[J]. J Immunol, 2006, 176(1): 616–624. doi: 10.4049/jimmunol.176.1.616
    Dulkanchainun TS, Goss JA, Imagawa DK, et al. Reduction of hepatic ischemia/reperfusion injury by a soluble P-selectin glycoprotein ligand-1[J]. Ann Surg, 1998, 227(6): 832–840. doi: 10.1097/00000658-199806000-00006
    Amersi F, Farmer DG, Shaw GD, et al. P-selectin glycoprotein ligand-1 (rPSGL-Ig)-mediated blockade of CD62 selectin molecules protects rat steatotic liver grafts from ischemia/reperfusion injury[J]. Am J Transplant, 2002, 2(7): 600–608. doi: 10.1034/j.1600-6143.2002.20704.x
    Busuttil RW, Lipshutz GS, Kupiec-Weglinski JW, et al. rPSGL-Ig for improvement of early liver allograft function: a double-blind, placebo-controlled, single-center phase II study[J]. Am J Transplant, 2011, 11(4): 786–797. doi: 10.1111/j.1600-6143.2011.03441.x
    Valentino KL, Gutierrez M, Sanchez R, et al. First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes[J]. Int J Clin Pharmacol Ther, 2003, 41(10): 441–449. doi: 10.5414/CPP41441
    Linton SD, Aja T, Armstrong RA, et al. First-in-class pan caspase inhibitor developed for the treatment of liver disease[J]. J Med Chem, 2005, 48(22): 6779–6782. doi: 10.1021/jm050307e
    Baskin-Bey ES, Washburn K, Feng S, et al. Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury[J]. Am J Transplant, 2007, 7(1): 218–225. doi: 10.1111/ajt.2007.7.issue-1
    Song G, Ouyang GL, Bao SD. The activation of Akt/PKB signaling pathway and cell survival[J]. J Cell Mol Med, 2005, 9(1): 59–71. doi: 10.1111/jcmm.2005.9.issue-1
    Covington SM, Bauler LD, Toledo-Pereyra LH. Akt: a therapeutic target in hepatic ischemia-reperfusion injury[J]. J Invest Surg, 2017, 30(1): 47–55. doi: 10.1080/08941939.2016.1206999
    Koh PO. Melatonin prevents hepatic injury-induced decrease in Akt downstream targets phosphorylations[J]. J Pineal Res, 2011, 51(2): 214–219. doi: 10.1111/j.1600-079X.2011.00879.x
    Bertoldo MJ, Faure M, Dupont J, et al. AMPK: a master energy regulator for gonadal function[J]. Front Neurosci, 2015, 9: 235.
    Peralta C, Bartrons R, Serafin A, et al. Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat[J]. Hepatology, 2001, 34(6): 1164–1173. doi: 10.1053/jhep.2001.29197
    Ding WX, Zhang Q, Dong YB, et al. Adiponectin protects the rats liver against chronic intermittent hypoxia induced injury through AMP-activated protein kinase pathway[J]. Sci Rep, 2016, 6: 34151. doi: 10.1038/srep34151
    Zhang CZ, Liao Y, Li Q, et al. Recombinant adiponectin ameliorates liver ischemia reperfusion injury via activating the AMPK/eNOS pathway[J]. PLoS One, 2013, 8(6): e66382. doi: 10.1371/journal.pone.0066382
    Lehrke M, Lazar MA. The many faces of PPARγ[J]. Cell, 2005, 123(6): 993–999. doi: 10.1016/j.cell.2005.11.026
    Marion-Letellier R, Savoye G, Ghosh S. Fatty acids, eicosanoids and PPAR gamma[J]. Eur J Pharmacol, 2016, 785: 44–49. doi: 10.1016/j.ejphar.2015.11.004
    Zhou YL, Jia S, Wang CJ, et al. FAM3A is a target gene of peroxisome proliferator-activated receptor gamma[J]. Biochim Biophys Acta, 2013, 1830(8): 4160–4170. doi: 10.1016/j.bbagen.2013.03.029
    Yang WL, Chen J, Meng YH, et al. Novel targets for treating ischemia-reperfusion injury in the liver[J]. Int J Mol Sci, 2018, 19(5): E1302. doi: 10.3390/ijms19051302
    Xu CF, Yu CH, Li YM. Regulation of hepatic microRNA expression in response to ischemic preconditioning following ischemia/reperfusion injury in mice[J]. OMICS, 2009, 13(6): 513–520. doi: 10.1089/omi.2009.0035
    Gehrau RC, Mas VR, Dumur CI, et al. Regulation of molecular pathways in ischemia-reperfusion injury after liver transplantation[J]. Transplantation, 2013, 96(10): 926–934. doi: 10.1097/TP.0b013e3182a20398
    Mard SA, Akbari G, Dianat M, et al. Protective effects of crocin and zinc sulfate on hepatic ischemia-reperfusion injury in rats: a comparative experimental model study[J]. Biomed Pharmacother, 2017, 96: 48–55. doi: 10.1016/j.biopha.2017.09.123
    Peralta C, Hotter G, Closa D, et al. Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine[J]. Hepatology, 1997, 25(4): 934–937. doi: 10.1002/hep.510250424
    Quarrie R, Cramer BM, Lee DS, et al. Ischemic preconditioning decreases mitochondrial proton leak and reactive oxygen species production in the postischemic heart[J]. J Surg Res, 2011, 165(1): 5–14. doi: 10.1016/j.jss.2010.09.018
    Richards JA, Wigmore SJ, Devey LR. Heme oxygenase system in hepatic ischemia-reperfusion injury[J]. World J Gastroenterol, 2010, 16(48): 6068–6078. doi: 10.3748/wjg.v16.i48.6068
    Liu AD, Fang HS, Wei WW, et al. Ischemic preconditioning protects against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy[J]. Crit Care Med, 2014, 42(12): e762–e771. doi: 10.1097/CCM.0000000000000659
    Rüdiger HA, Graf R, Clavien PA. Sub-lethal oxidative stress triggers the protective effects of ischemic preconditioning in the mouse liver[J]. J Hepatol, 2003, 39(6): 972–977. doi: 10.1016/S0168-8278(03)00415-X
    Rolo AP, Teodoro JS, Peralta C, et al. Prevention of I/R injury in fatty livers by ischemic preconditioning is associated with increased mitochondrial tolerance: the key role of ATPsynthase and mitochondrial permeability transition[J]. Transpl Int, 2009, 22(11): 1081–1090. doi: 10.1111/tri.2009.22.issue-11
    Abu-Amara M, Yang SY, Quaglia A, et al. Role of endothelial nitric oxide synthase in remote ischemic preconditioning of the mouse liver[J]. Liver Transpl, 2011, 17(5): 610–619. doi: 10.1002/lt.v17.5
    Koti RS, Seifalian AM, Davidson BR. Protection of the liver by ischemic preconditioning: a review of mechanisms and clinical applications[J]. Dig Surg, 2003, 20(5): 383–396. doi: 10.1159/000072064
    Gurusamy KS, Kumar Y, Sharma D, et al. Ischaemic preconditioning for liver transplantation[J]. Cochrane Database Syst Rev, 2008, (1): CD006315.
    Nadarajah L, Yaqoob MM, McCafferty K. Ischemic conditioning in solid organ transplantation: is it worth giving your right arm for?[J]. Curr Opin Nephrol Hypertens, 2017, 26(6): 467–476. doi: 10.1097/MNH.0000000000000367
    Koneru B, Fisher A, He Y, et al. Ischemic preconditioning in deceased donor liver transplantation: a prospective randomized clinical trial of safety and efficacy[J]. Liver Transpl, 2005, 11(2): 196–202. doi: 10.1002/(ISSN)1527-6473
    Koneru B, Shareef A, Dikdan G, et al. The ischemic preconditioning paradox in deceased donor liver transplantation-evidence from a prospective randomized single blind clinical trial[J]. Am J Transplant, 2007, 7(12): 2788–2796. doi: 10.1111/ajt.2007.7.issue-12
    Theodoraki K, Karmaniolou I, Tympa A, et al. Beyond preconditioning: postconditioning as an alternative technique in the prevention of liver ischemia-reperfusion injury[J]. Oxid Med Cell Longev, 2016, 2016: 8235921.
    Sun K, Liu ZS, Sun Q. Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning[J]. World J Gastroenterol, 2004, 10(13): 1934–1938. doi: 10.3748/wjg.v10.i13.1934
    Zhang WX, Yin W, Zhang L, et al. Preconditioning and postconditioning reduce hepatic ischemia-reperfusion injury in rats[J]. Hepatobiliary Pancreat Dis Int, 2009, 8(6): 586–590.
    Yoon SY, Kim CY, Han HJ, et al. Protective effect of ischemic postconditioning against hepatic ischemic reperfusion injury in rat liver[J]. Ann Surg Treat Res, 2015, 88(5): 241–245. doi: 10.4174/astr.2015.88.5.241
    Lin HC, Lee TK, Tsai CC, et al. Ischemic postconditioning protects liver from ischemia-reperfusion injury by modulating mitochondrial permeability transition[J]. Transplantation, 2012, 93(3): 265–271. doi: 10.1097/TP.0b013e31823ef335
    Wang N, Lu JG, He XL, et al. Effects of ischemic postconditioning on reperfusion injury in rat liver grafts after orthotopic liver transplantation[J]. Hepatol Res, 2009, 39(4): 382–390. doi: 10.1111/hep.2009.39.issue-4
    Kim WH, Lee JH, Ko JS, et al. Effect of remote ischemic postconditioning on patients undergoing living donor liver transplantation[J]. Liver Transpl, 2014, 20(11): 1383–1392. doi: 10.1002/lt.23960
    Ricca L, Lemoine A, Cauchy F, et al. Ischemic postconditioning of the liver graft in adult liver transplantation[J]. Transplantation, 2015, 99(8): 1633–1643. doi: 10.1097/TP.0000000000000685
    Schlegel AA, Kalisvaart M, Muiesan P. Machine perfusion in liver transplantation: an essential treatment or just an expensive toy?[J]. Minerva Anestesiol, 2018, 84(2): 236–245.
    Liu Q, Vekemans K, Iania L, et al. Assessing warm ischemic injury of pig livers at hypothermic machine perfusion[J]. J Surg Res, 2014, 186(1): 379–389. doi: 10.1016/j.jss.2013.07.034
    Monbaliu D, Liu Q, Libbrecht L, et al. Preserving the morphology and evaluating the quality of liver grafts by hypothermic machine perfusion: a proof-of-concept study using discarded human livers[J]. Liver Transpl, 2012, 18(12): 1495–1507. doi: 10.1002/lt.v18.12
    Manekeller S, Schuppius A, Stegemann J, et al. Role of perfusion medium, oxygen and rheology for endoplasmic reticulum stress-induced cell death after hypothermic machine preservation of the liver[J]. Transpl Int, 2008, 21(2): 169–177.
    Jain S, Xu HZ, Duncan H, et al. Ex-vivo study of flow dynamics and endothelial cell structure during extended hypothermic machine perfusion preservation of livers[J]. Cryobiology, 2004, 48(3): 322–332. doi: 10.1016/j.cryobiol.2004.01.010
    Schlegel A, de Rougemont O, Graf R, et al. Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts[J]. J Hepatol, 2013, 58(2): 278–286. doi: 10.1016/j.jhep.2012.10.004
    Gallinat A, Efferz P, Paul A, et al. One or 4 h of " in-house” reconditioning by machine perfusion after cold storage improve reperfusion parameters in porcine kidneys[J]. Transpl Int, 2014, 27(11): 1214–1219. doi: 10.1111/tri.2014.27.issue-11
    Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation facilitates successful transplantation of " orphan” extended criteria donor livers[J]. Am J Transplant, 2015, 15(1): 161–169. doi: 10.1111/ajt.12958
    Dutkowski P, Schlegel A, de Oliveira M, et al. HOPE for human liver grafts obtained from donors after cardiac death[J]. J Hepatol, 2014, 60(4): 765–772. doi: 10.1016/j.jhep.2013.11.023
    Schlegel A, Muller X, Kalisvaart M, et al. Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation[J]. J Hepatol, 2019, 70(1): 50–57.
    Ravikumar R, Jassem W, Mergental H, et al. Liver transplantation after ex vivo normothermic machine preservation: a phase 1 (first-in-man) clinical trial[J]. Am J Transplant, 2016, 16(6): 1779–1787. doi: 10.1111/ajt.13708
    Xu HZ, Berendsen T, Kim K, et al. Excorporeal normothermic machine perfusion resuscitates pig DCD livers with extended warm ischemia[J]. J Surg Res, 2012, 173(2): e83–e88. doi: 10.1016/j.jss.2011.09.057
    Mergental H, Perera MTPR, Laing RW, et al. Transplantation of declined liver allografts following normothermic ex-situ evaluation[J]. Am J Transplant, 2016, 16(11): 3235–3245. doi: 10.1111/ajt.13875
    Jassem W, Xystrakis E, Ghnewa YG, et al. Normothermic machine perfusion (NMP) inhibits proinflammatory responses in the liver and promotes regeneration[J]. Hepatology, 2018. doi: 10.1002/hep.30475[Epub ahead of print
    Balfoussia D, Yerrakalva D, Hamaoui K, et al. Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant[J]. Exp Clin Transplant, 2012, 10(2): 87–100. doi: 10.6002/ect
    Watson CJE, Randle LV, Kosmoliaptsis V, et al. 26-hour storage of a declined liver before successful transplantation using ex vivo normothermic perfusion[J]. Ann Surg, 2017, 265(1): e1–e2. doi: 10.1097/SLA.0000000000001834
    Laing RW, Bhogal RH, Wallace L, et al. The use of an acellular oxygen carrier in a human liver model of normothermic machine perfusion[J]. Transplantation, 2017, 101(11): 2746–2756. doi: 10.1097/TP.0000000000001821
    op den Dries S, Karimian N, Sutton ME, et al. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers[J]. Am J Transplant, 2013, 13(5): 1327–1335. doi: 10.1111/ajt.12187
    Braat AE, Blok JJ, Putter H, et al. The eurotransplant donor risk index in liver transplantation: ET-DRI[J]. Am J Transplant, 2012, 12(10): 2789–2796. doi: 10.1111/j.1600-6143.2012.04195.x
    Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index[J]. Am J Transplant, 2006, 6(4): 783–790. doi: 10.1111/j.1600-6143.2006.01242.x
    Perera T, Mergental H, Stephenson B, et al. First human liver transplantation using a marginal allograft resuscitated by normothermic machine perfusion[J]. Liver Transpl, 2016, 22(1): 120–124. doi: 10.1002/lt.24369
    Watson CJE, Kosmoliaptsis V, Randle LV, et al. Normothermic perfusion in the assessment and preservation of declined livers before transplantation: hyperoxia and vasoplegia-important lessons from the first 12 cases[J]. Transplantation, 2017, 101(5): 1084–1098. doi: 10.1097/TP.0000000000001661
    Khorsandi SE, Quaglia A, Salehi S, et al. The microRNA expression profile in donation after cardiac death (DCD) livers and its ability to identify primary non function[J]. PLoS One, 2015, 10(5): e0127073. doi: 10.1371/journal.pone.0127073
    Bruinsma BG, Sridharan GV, Weeder PD, et al. Metabolic profiling during ex vivo machine perfusion of the human liver[J]. Sci Rep, 2016, 6: 22415. doi: 10.1038/srep22415
    Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation[J]. Nature, 2018, 557(7703): 50–56. doi: 10.1038/s41586-018-0047-9
    Durand F, Renz JF, Alkofer B, et al. Report of the Paris consensus meeting on expanded criteria donors in liver transplantation[J]. Liver Transpl, 2008, 14(12): 1694–1707. doi: 10.1002/lt.v14:12
    Spitzer AL, Lao OB, Dick AAS, et al. The biopsied donor liver: incorporating macrosteatosis into high-risk donor assessment[J]. Liver Transpl, 2010, 16(7): 874–884. doi: 10.1002/lt.v16:7
    Nativ NI, Maguire TJ, Yarmush G, et al. Liver defatting: an alternative approach to enable steatotic liver transplantation[J]. Am J Transplant, 2012, 12(12): 3176–3183. doi: 10.1111/ajt.2012.12.issue-12
    Nagrath D, Xu HZ, Tanimura Y, et al. Metabolic preconditioning of donor organs: defatting fatty livers by normothermic perfusion ex vivo[J]. Metab Eng, 2009, 11(4–5): 274–283. doi: 10.1016/j.ymben.2009.05.005
    Boteon YL, Afford SC, Mergental H. Pushing the limits: machine preservation of the liver as a tool to recondition high-risk grafts[J]. Curr Transplant Rep, 2018, 5(2): 113–120. doi: 10.1007/s40472-018-0188-7
    Goldaracena N, Echeverri J, Spetzler VN, et al. Anti-inflammatory signaling during ex vivo liver perfusion improves the preservation of pig liver grafts before transplantation[J]. Liver Transpl, 2016, 22(11): 1573–1583. doi: 10.1002/lt.v22.11
    Morales-Ruiz M, Fondevila C, Muñoz-Luque J, et al. Gene transduction of an active mutant of akt exerts cytoprotection and reduces graft injury after liver transplantation[J]. Am J Transplant, 2007, 7(4): 769–778. doi: 10.1111/ajt.2007.7.issue-4
    Van Raemdonck D, Neyrinck A, Rega F, et al. Machine perfusion in organ transplantation: a tool for ex-vivo graft conditioning with mesenchymal stem cells?[J]. Curr Opin Organ Transplant, 2013, 18(1): 24–33. doi: 10.1097/MOT.0b013e32835c494f
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (9646) PDF downloads(265) Cited by()
    Proportional views
    Relative Articles


    DownLoad:  Full-Size Img  PowerPoint