Abstract
Hepatic ischemia/reperfusion (I/R) injury is a serious complication that compromises liver function because of extensive hepatocellular loss, which impacts diverse clinical settings such as liver surgery and liver transplantation. The mechanisms responsible for hepatic I/R injury are not well understood despite the identification of several intercellular and molecular mechanisms involved in the hepatocellular cell death, with a predominant role for reactive oxygen species (ROS) generation. Oxygen is a vital element to sustain life but its partial reduction generates toxic ROS that participate in liver I/R damage. Mitochondria are one of the main sources of ROS production in the cell, and current data point that mitochondrial dysfunction mediates hepatic I/R damage. In liver transplantation or in hepatic resections ischemia followed by reperfusion is accompanied by an increase in ROS generation leading to liver injury. The contribution of hepatic lipid composition, particularly lipid composition of mitochondrial membranes determine the increased ROS generation during hepatic I/R due to compromised mitochondrial antioxidant defenses. Accumulating evidence from clinical and experimental observations indicates that steatotic grafts in liver transplantation increase reperfusion injury and liver transplant failure. In this chapter we will review recent data on the interplay between mitochondria, ROS generation, and antioxidant defense in liver damage after I/R, and provide evidence that mitochondrial cholesterol accumulation stands as an important player in liver I/R damage, thus emerging as a novel target for intervention.
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Ajamieh H, Farrell G, Wong HJ, Yu J, Chu E, Chen J, Teoh N (2012) Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. J Gastroenterol Hepatol 27(8):1353–1361
Bailly-Maitre B, Fondevila C, Kaldas F, Droin N, Luciano F, Ricci JE, Croxton R et al (2006) Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. Proc Natl Acad Sci U S A 103:2809–2814
Batinić-Haberle I, Cuzzocrea S, Rebouças JS, Ferrer-Sueta G, Mazzon E, Di Paola R, Radi R, Spasojević I, Benov L, Salvemini D (2009) Pure MnTBAP selectively scavenges peroxynitrite over superoxide: comparison of pure and commercial MnTBAP samples to MnTE-2-PyP in two models of oxidative stress injury, an SOD-specific Escherichia coli model and carrageenan-induced pleurisy. Free Radic Biol Med 46:192–201
Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants and aging. Cell 120:483–495
Belghiti J, Durand F (2000) Living donor liver transplantation: present and future. Br J Surg 87(11):1441–1443
Bilzer M, Gerbes AL (2000) Preservation injury of the liver: mechanisms and novel therapeutic strategies. J Hepatol 32:508–515
Borrelli A, Schiattarella A, Fasano S, Occhiello A, Pica A, Sehr P, Tommasino M, Nuesch JP, Rommelaere J (2006) Tumor suppressive activity of a variant isoform of manganese superoxide dismutase released by a human liposarcoma cell line. Int J Cancer 119:932–943
Bosch M, Marí M, Herms A, Fernández A, Fajardo A, Kassan A, Giralt A, Colell A, Balgoma D, Barbero E, González-Moreno E, Matias N, Tebar F, Balsinde J, Camps M, Enrich C, Gross SP, García-Ruiz C, Pérez-Navarro E, Fernández-Checa JC, Pol A (2011) Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr Biol 21(8):681–686
Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716
Cadenas E, Boveris A, Ragan CI, Stoppani AOM (1977) Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria. Arch Biochem Biophys 180:248–257
Caron KM, Soo SC, Wetsel WC, Stocco DM, Clark BJ, Parker KL (1997) Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci U S A 94(21):11540–11545
Casillas-Ramírez A, Mosbah IB, Ramalho F, Roselló-Catafau J, Peralta C (2006) Past and future approaches to ischemia-reperfusion lesion associated with liver transplantation. Life Sci 79(20):1881–1894
Colell A, García-Ruiz C, Lluis JM, Coll O, Mari M, Fernández-Checa JC (2003) Cholesterol impairs the adenine nucleotide translocator-mediated mitochondrial permeability transition through altered membrane fluidity. J Biol Chem 278(36):33928–33935
Datta G, Fuller BJ, Davidson BR (2013) Molecular mechanisms of liver ischemia reperfusion injury: Insights from transgenic knockout models. World J Gastroenterol 21:1683–1698
Dikalov S (2011) Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med 51(7):1289–1301
Dröge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S, Gmünder H (1994) Functions of glutathione and glutathione disulfide in immunology and immunopathology. FASEB J 8(14):1131–1138. Review
El-Brady AM, Moritz W, Contaldo C, Tian Y, Graf R, Clavien PA (2007) Prevention of reperfusion injury and microcirculatory failure in macrosteatosis mouse liver by omega-3 fatty acids. Hepatology 45:855–863
Facundo HT, de Paula JG, Kowaltowski AJ (2007) Mitochondrial ATP-sensitive K+ channels are redox-sensitive pathways that control reactive oxygen species production. Free Radic Biol Med 42(7):1039–1048
Fernández A, Colell A, Caballero F, Matías N, García-Ruiz C, Fernández-Checa JC (2009) Mitochondrial S-adenosyl-L-methionine transport is insensitive to alcohol-mediated changes in membrane dynamics. Alcohol Clin Exp Res 33:1169–1180
Fishbein TM, Fiel MI, Emre S, Cubukcu O, Guy SR, Schwartz ME et al (1997) Use of livers with microvesicular fat safely expands the donor pool. Transplantation 64:248–251
Fusai G, Glantzounis GK, Hafez T, Yang W, Quaglia A, Sheth H et al (2005) N-acetylcysteine ameliorates the late phase of liver ischemia/reperfusion injury in the rabbit with hepatic steatosis. Clin Sci 109:465–473
Gerschman R, Gilbert DL, Nye SW, Dwyer P, Fenn W (1954) Oxygen poisoning and x-irradiation: a mechanism in common. Science 119(3097):623–626
Gonzalez-Flecha B, Cutrin JC, Boveris A (1993) Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion. J Clin Invest 91:456–464
Guillaume M, Rodriguez-Vilarrupla A, Gracia-Sancho J, Rosado E, Mancini A, Bosch J, Garcia-Pagán JC (2013) Recombinant human manganese superoxide dismutase reduces liver fibrosis and portal pressure in CCl4-cirrhotic rats. J Hepatol 58:240–246
Gracia-Sancho J, Russo L, García-Calderó H, García-Pagán JC, García-Cardeña G, Bosch J (2011) Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver. Gut 60(4):517–524
Gujral JS, Farhood A, Bajt ML, Jaeschke H (2003) Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice. Hepatology 38(2):355–363
Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1(6):401–408
Hakamada K, Sasaki M, Takahashi K, Umehara Y, Konn M (1997) Sinusoidal flow block after warm ischemia in rats with diet induced fatty liver. J Surg Res 70:12–20
Hasegawa T, Malle E, Farhood A, Jaeschke H (2005) Generation of hypochlorite-modified proteins by neutrophils during ischemia-reperfusion injury in rat liver: attenuation by ischemic preconditioning. Am J Physiol Gastrointest Liver Physiol 289(4):G760–G767
Hide D, Ortega-Ribera M, Fernández-Iglesias A, Fondevila C, Salvadó MJ, Arola L, García-Pagán JC, Mancini A, Bosch J, Gracia-Sancho J (2014) A novel form of the human manganese superoxide dismutase protects rat and human livers undergoing ischaemia and reperfusion injury. Clin Sci (Lond) 127(8):527–537
Hirst J, King MS, Pryde KR (2008) The production of reactive oxygen species by complex I. Biochem Soc Trans 36:976–980
Hong F, Radaeva S, Pan HN, Tian Z, Veech R, Gao B (2004) Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease. Hepatology 40(4):933–941
Jaeschke H (2003) Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol 284:G15–G26
Jaeschke H, Lemasters JJ (2003) Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology 125:1246–1257
Jaeschke H, Bautista AP, Spolarics Z, Spitzer JJ (1991) Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia. Free Radic Res Commun 15(5):277–284
Jang JH, Moritz W, Graf R, Clavien PA (2008) Preconditioning with death ligands FasL and TNF-alpha protects the cirrhotic mouse liver against ischaemic injury. Gut 57(4):492–499
Jassem W, Fuggle SV, Rela M, Koo DD, Heaton ND (2002) The role of mitochondria in ischemia/reperfusion injury. Transplantation 73(4):493–499
Jastroch M, Divakaruni AJ, Mookerjee S, Treberg JR, Brand MD (2010) Mitochondrial proton and electron leaks. Essays Biochem 47:53–67
Jungermann K, Kietzmann T (2000) Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology 31:225–260
Kang JW, Lee SM (2014) Impaired expression of caveolin-1 contributes to hepatic ischemia reperfusion injury. Biochem Biophys Res Commun 450:1351–1357
Kim GW, Kondo T, Noshita N, Chan PH (2002) Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice: implications for the production and role of superoxide radicals. Stroke 33:809–815
Kim JS, Nitta T, Mohuczy D, O'Malley KA, Moldawer LL, Dunn WA Jr, Behrns KE (2008) Impaired autophagy: a mechanism of mitochondrial dysfunction in anoxic rat hepatocytes. Hepatology 47(5):1725–1736
Kim JS, Wang JH, Biel TG, Flores-Toro JA, Vijayvargiya R, Zendejas I, Behrns KE (2013) Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers. Toxicol Appl Pharmacol 273(3):600–610
Koti RS, Yang W, Glantzounis G, Quaglia A, Davidson BR, Seifalian AM (2005) Effect of ischaemic preconditioning on hepatic oxygenation, microcirculation and function in a rat model of moderate hepatic steatosis. Clin Sci (Lond) 108(1):55–63
Kuboki S, Okaya T, Schuster R, Blanchard J, Denenberg A, Wong HR, Lentsch AB (2007) Hepatocyte NF-kappaB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia. Am J Physiol Gastrointest Liver Physiol 292(1):G201–G207
Kussmaul L, Hirst J (2006) The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci U S A 103:7607–7612
Lai IR, Chang KJ, Tsai HW, Chen CF (2008) Pharmacological preconditioning with simvastatin protects liver from ischemia-reperfusion injury by heme oxygenase-1 induction. Transplantation 85:732–738
Lambert AJ, Brand MD (2004) Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. Biochem J 382:511–517
Lemasters JJ (2001) Hypoxic, ischemic, and reperfusion injury to liver. In: Arias IM (ed) The liver: biology and pathobiology, 4th edn. Lippincott Williams & Wilkins, Philadelphia, pp 257–279
Llacuna L, Fernandez A, von Montfort C, Matias N, Martinez L, Caballero F, Rimola A, Elena M, Morales A, Fernandez-Checa JC, Garcia-Ruiz C (2011) Targeting cholesterol at different levels of the mevalonate pathway protects fatty livers against ischemia-reperfusion injury. J Hepatol 54:1002–1010
Llacuna L, Mari M, LLuis JM, Garcia-Ruiz C, Fernandez-Checa A, Morales A (2009) Reactive oxygen species mediate liver injury through parenchymal nuclear factor-B inactivation in prolonged ischemia/reperfusion. Am J Pathol 174:1776–1785
Llacuna L, Marí M, Garcia-Ruiz C, Fernandez-Checa JC, Morales A (2006) Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology 44(3):561–572
Lou H, Kaplowitz N (2007) Glutathione depletion down-regulates tumor necrosis factor alpha-induced NF-kappaB activity via IkappaB kinase-dependent and-independent mechanisms. J Biol Chem 282(40):29470–29481
Ma X, Jin M, Cai Y, Xia H, Long K, Liu J, Yu Q, Yuan J (2011) Mitochondrial electron transport chain complex III is required for antimycin A to inhibit autophagy. Chem Biol 18:1474–1481
Mancini A, Borrelli A, Schiattarella A, Fasano S, Occhiello A, Pica A, Sehr P, Tommasino M, Nuesch JP, Rommelaere J (2006) Tumor suppressive activity of a variant isoform of manganese superoxide dismutase released by a human liposarcoma cell line. Int J Cancer 119:932–943
Mancini A, Borrelli A, Schiattarella A, Aloj L, Aurilio M, Morelli F, Pica A, Occhiello A, Lorizio R, Mancini R et al (2008) Biophysical and biochemical characterization of a liposarcoma-derived recombinant MnSOD protein acting as an anticancer agent. Int J Cancer 123:2684–2695
Mari M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A et al (2006) Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab 4:185–198
Mari M, Colell A, Morales A, von Montfort C, Garcia-Ruiz C, Fernández-Checa JC (2010) Redox control of liver function in health and disease. Antioxid Redox Signal 12(11):1295–1331
Massip-Salcedo M, Roselló-Catafau J, Prieto J, Avíla MA, Peralta C (2007) The response of the hepatocyte to ischemia. Liver Int 27(1):6–16
Menger MD, Vollmar B (2000) Role of microcirculation in transplantation. Microcirculation 7:291–306
Melov S, Schneider JA, Day BJ, Hinerfeld D, Coskun P, Mirra SS, Crapo JD, Wallace DC (1998) A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. Nat Genet 18:159–163
Miller WL (2007) Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta 1771(6):663–676
Moon KH, Hood BL, Mukhopadhyay P, Rajesh M, Abdelmegeed MA, Kwon YI, Conrads TP, Veenstra TD, Song BJ, Pacher P (2008) Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion. Gastroenterology 135(4):1344–1357
Mori N, Horie Y, Yuji N, Wolf R, Granger N (2000) Hepatic microvesicular responses to ischemia-reperfusion in low-density lipoprotein receptor knockout mice. Am J Physiol 279:G1257–G1264
Mukhopadhyay P, Horváth B, Zsengellér Z, Zielonka J, Tanchian G, Holovac E, Kechrid M, Patel V, Stillman IE, Parikh SM, Joseph J, Kalyanaraman B, Pacher P (2012) Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy. Free Radic Biol Med 52(2):497–506
Muller FL, Roberts AG, Bowman MK, Kramer DM (2003) Architecture of the Qo site of the cytochrome bc1 complex probed by superoxide production. Biochemistry 42:6493–6499
Nguyen TT, Stevens MV, Kohr M, Steenberg C, Sack MN, Murphy E (2011) Cysteine 203 of cyclophilin D is critical for cyclophilin D activation of the mitochondrial permeability transition pore. J Biol Chem 286:40184–40192
Orr AL, Quinlan CL, Perevoshcchikova IV, Brand MD (2012) A refined analysis of superoxide production by mitochondria sn-glycerol 3-phosphate dehydrogenase. J Biol Chem 287:42921–42935
Pardo M, Budick-Harmeln N, Tirosh B, Tirosh O (2008) Antioxidant defense in hepatic ischemia-reperfusion injury is regulated by damage-associated molecular pattern signals molecules. Free Radic Biol Med 45:1073–1083
Parmar KM, Nambudiri V, Dai G, Larman HB, Gimbrone MA Jr, García-Cardeña G (2005) Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. J Biol Chem 280(29):26714–26719
Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (2003) The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 66(8):1499–1503
Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Orr AL, Brand MD (2013) Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biology 1:304–312
Relja B, Lehnert M, Seyboth K, Bormann F, Hohn C, Czerny C et al (2010) Simvastatin reduces mortality and hepatic injury after hemorrhage/resuscitation in rats. Shock 34:46–54
Ribas V, García-Ruiz C, Fernández-Checa JC (2014) Glutathione and mitochondria. Front Pharmacol 5:151
Robinson SM, Saif R, Sen G, French JJ, Jacques BC, Charnley RM, Manas DM, White SA (2013) N-acetylcysteine administration does not improve patient outcome after liver resection. HPB 15:457–462
Rüdiger HA, Clavien PA (2002) Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. Gastroenterology 122(1):202–210
Russo L, Gracia-Sancho J, García-Calderó H, Marrone G, García-Pagán JC, García-Cardeña G, Bosch J (2012) Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers. Hepatology 55(3):921–930
Scaloni A, Codarin E, Di Maso V, Arena S, Renzone G, Tiribelli C, Quadrifoglio F, Tell G (2009) Modern strategies to identify new molecular targets for the treatment of liver diseases: the promising role of proteomics and redox proteomics investigations. Proteomics Clin Appl 3:242–262
Sakon M, Ariyoshi H, Umeshita K, Monden M (2002) Ischemia-reperfusion injury of the liver with special reference to calcium-dependent mechanisms. Surg Today 32:1–12
Seizner M, Seizmer N, Jochum W, Graf R, Clavien PA (2007) Increased ischemic injury in old mouse liver: an ATP-dependent mechanism. Liver Transpl 13(3):382–390
Selzner M, Clavien PA (2001) Fatty liver in liver transplantation and surgery. Semin Liver Dis 21:105–113
Selzner N, Selzner M, Jochum W, Amann-Vesti B, Graf R, Clavien PA (2006) Mouse liver with macrosteatosis are more susceptible to normothermic ischemic injury than those with microsteatosis. J Hepatol 44:694–701
Shen XD, Ke B, Zhai Y, Gao F, Tsuchihashi S, Lassman CR, Busuttil RW, Kupiec-Weglinski JW (2007) Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. Liver Transpl 13(10):1435–1443
Soltys K, Dikdan G, Koneru B (2001) Oxidative stress in fatty livers of obese Zucker rats: rapid amelioration and improved tolerance to warm ischemia with tocopherol. Hepatology 34(1):13–18
Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, Beal MF (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24:7779–7788
St Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277:44784–44790
Strasberg SM (1997) Preservation injury and donor selection: it all starts here. Liver Transpl Surg 5(Suppl 1):S1–S7
Suetsugu H, Iimuro Y, Uehara T, Nishio T, Harada N, Yoshida M, Hatano E, Son G, Fujimoto J, Yamaoka Y (2005) Nuclear factor {kappa}B inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury. Gut 54(6):835–842
Sun K, Xie X, Liu Y, Han Z, Zhao X, Cai N, Zhang S, Song J, Wei L (2013) Autophagy lessens ischemic liver injury by reducing oxidative damage. Cell Biosci 3:26
Treberg JR, Quinlan CL, Brand MD (2011) Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I). J Biol Chem 286:27103–27110
Uchiyama A, Kim JS, Kon K, Jaeschke H, Ikejima K, Watanabe S, Lemasters JJ (2008) Translocation of iron from lysosomes into mitochondria is a key event during oxidative stress-induced hepatocellular injury. Hepatology 48:1644–1654
Urena MA, Ruiz-Delgado FC, Gonzalez EM, Segurola CL, Romero CJ, Garcia IG et al (1998) Assessing risk of the use of livers with macro and microsteatosis in a liver transplant program. Transplant Proc 30:3288–3291
Vascotto C, Cesaratto L, D'Ambrosio C, Scaloni A, Avellini C, Paron I, Baccarani U, Adani GL, Tiribelli C, Quadrifoglio F, Tell G (2006) Proteomic analysis of liver tissues subjected to early ischemia/reperfusion injury during human orthotopic liver transplantation. Proteomics 6(11):3455–3465
Venkatakrishnan P, Nakayasu ES, Almeida IC, Miller RT (2009) Absence of nitric-oxide synthase in sequentially purified rat liver mitochondria. J Biol Chem 284(30):19843–19855
Videla LA, Fernandez V (1988) Biochemical aspects of cellular oxidative stress. Arch Biol Med Exp 21:85–92
von Montfort C, Matías N, Fernandez A, Fucho R, Conde de la Rosa L, Martinez-Chantar ML, Mato JM, Machida K, Tsukamoto H, Murphy MP, Mansouri A, Kaplowitz N, Garcia-Ruiz C, Fernandez-Checa JC (2012) Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis. J Hepatol 57:852–859
Wang JH, Behrns KE, Leeuwenburgh C, Kim JS (2012) Critical role of autophage in ischemia/reperfusion injury to aged livers. Autophagy 8:140–141
Wang C, Chen K, Xia Y, Dai W, Wang F, Shen M, Cheng P, Wang J, Lu J, Zhang Y, Yang J, Zhu R, Zhang H, Li J, Zhou Y, Guo C (2014) N-acetylcysteine attenuates ischemia-reperfusion induced apoptosis and autophagy in mouse liver via regulation of the ROS/JNK/Bcl-2 pathway. PLoS ONE 9(9):e108855
Yang J, Marden JJ, Fan C, Sanlioglu S, Weiss RM, Ritchie TC, Davisson RL, Engelhardt JF (2003) Genetic redox preconditioning differentially modulates AP-1 and NF kappa B responses following cardiac ischemia/reperfusion injury and protects against necrosis and apoptosis. Mol Ther 7:341–353
Yoong KF, Gunson BK, Neil DA, Mirza DF, Mayer AD, Buckels JA et al (1999) Impact of donor liver microvesicular steatosis on the outcome of liver retransplantation. Transplant Proc 31:550–551
Zhai Y, Shen XD, O'Connell R, Gao F, Lassman C, Busuttil RW, Cheng G, Kupiec-Weglinski JW (2004) Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol 173(12):7115–7119
Zhou W, Zhang Y, Hosch MS, Lang A, Zwacka RM, Engelhardt JF (2001) Subcellular site of superoxide dismutase expression differentially controls AP-1 activity and injury in mouse liver following ischemia/reperfusion. Hepatology 33:902–914
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García-Ruíz, C., Morales, A., Fernández-Checa, J.C. (2015). Oxidative Stress and Liver Ischemia–Reperfusion Injury. In: Albano, E., Parola, M. (eds) Studies on Hepatic Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15539-5_7
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