Información del artículo
Abstract
Hepatic ischemia-reperfusion injury is an underlying complication that occurs in clinical conditions such as hepatic resection surgery, liver transplantation and the states of shock. Such injury has classically been attributed to the joint deleterious action of both neutrophils and reactive oxygen species. However, there is increasing evidence that T lymphocytes are also key players in the acute reperfusion injury of diverse organs. They seem to act mainly by promoting the recruitment of inflammatory cells. The purpose of this review is to summarize the molecular and cellular mechanisms that participate in the pathophysiology of liver reperfusion injury.
Keywords:
Liver ischemia
Reperfusion injury
Kupffer cells
T lymphocytes
Neutrophils
Cytokines
Reactive oxygen species
Nitric oxide
Resumen
El fenómeno de isquemia-reperfusión subyace a la lesión hepática que acontece en situaciones clínicas tales como la cirugía de resección hepática, el trasplante hepático y los estados de shock. Esta lesión se ha atribuido clásicamente a la acción deletérea conjunta de neutrófilos y especies reactivas de oxígeno. Sin embargo, diversos estudios llevados a cabo en la última década han mostrado un papel cada vez más relevante de los linfocitos T en los fenómenos de isquemia-reperfusión, que activan el reclutamiento de células inflamatorias y causan daño en los tejidos afectados. El objeto de esta revisión es mostrar los mecanismos moleculares y celulares implicados en la fisiopatología de esta lesión.
Palabras clave:
Isquemia hepática
Lesión por reperfusión
Células de Kupffer
Linfocitos T
Neutrófilos
Citocinas
Especies reactivas de oxígeno
Óxido nítrico
El Texto completo está disponible en PDF
References
[1.]
J. Pringle.
Notes on the arrest of hepatic hemorrhage due to trauma.
Annals of Surgery, 48 (1908), pp. 541-549
[2.]
D.L. Liu, B. Jeppsson, C.H. Hakansson, R. Odselius.
Multiplesystem organ damage resulting from prolonged hepatic inflow interruption.
Archives of Surgery, 131 (1996), pp. 442-447
[3.]
J.C. Caldwell-Kenkel, R.T. Currin, Y. Tanaka, R.G. Thurman, J.J. Lemasters.
Kupffer cell activation and endothelial cell damage after storage of rat livers: Effects of reperfusion.
Hepatology, 13 (1991), pp. 83-95
[4.]
M. Deschenes, S.H. Belle, R.A. Krom, R.K. Zetterman, J.R. Lake.
Early allograft dysfunction after liver transplantation: A definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Data- base.
Transplantation, 66 (1998), pp. 302-310
[5.]
P.A. Clavien, P.R. Harvey, S.M. Strasberg.
Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies.
Transplantation, 53 (1992), pp. 957-978
[6.]
P.-M. Huet, M.R. Nagaoka, G. Desbiens, E. Tarrab, A. Brault, M.-P. Bralet, et al.
Sinusoidal endothelial cell and hepatocyte death following cold ischemia-warm reperfusion of the rat liver.
Hepatology, 39 (2004), pp. 1110-1119
[7.]
B. Fellstrom, L.M. Akuyrek, U. Backman, E. Larsson, J. Melin, L. Zezina.
Postischemic reperfusion injury and allograft arteriosclerosis.
Transplantation Proceedings, 30 (1998), pp. 4278-4280
[8.]
J. Busquets, T. Serrano, J. Figueras, E. Ramos, J. Torras, A. Rafecas, et al.
Influence of donor postreperfusion changes on graft evolution after liver transplant.
Transplantation Proceedings, 34 (2002), pp. 252-253
[9.]
Y. Yamakawa, M. Takano, M. Patel, N. Tien, T. Takada, G.B. Bulkley.
Interaction of platelet activating factor, reactive oxygen species generated by xanthine oxidase, and leukocytes in the generation of hepatic injury after shock/resuscitation.
Annals of Surgery, 231 (2000), pp. 387-398
[10.]
N. Okano, S. Miyoshi, R. Owada, N. Fujita, Y. Kadoi, S. Saito, et al.
Impairment of hepatosplanchnic oxygenation and increase of serum hyaluronate during normothermic and mild hypothermic cardiopulmonarybypass.
Anesthesia and Analgesia, 95 (2002), pp. 278-286
[11.]
G.K. Glantzounis, A.D. Tselepis, A.P. Tambaki, T.A. Trikalinos, A.D. Manataki, D.A. Galaris, et al.
Laparoscopic surgery-induced changes inoxidative stress markers in human plasma.
Surgical Endoscopy, 15 (2001), pp. 1315-1319
[12.]
G.K. Glantzounis, I. Tsimaris, A.D. Tselepis, C. Thomas, D.A. Galaris, E.C. Tsimoyiannis.
Alterations in plasma oxidative stress markers after laparoscopic operations of the upper and lower abdomen.
Angiology, 56 (2005), pp. 459-465
[13.]
J.B. Rezende-Neto, E.E. Moore, T. Masuno, P.K. Moore, J.L. Johnson, F.R. Sheppard, et al.
The abdominal compartment syndrome as a second insult during systemic neutrophil priming provokes multiple organ injury.
Shock, 20 (2003), pp. 303-308
[14.]
M. Bilzer, A.L. Gerbes.
Preservation injury of the liver: Mechanisms and novel therapeutic strategies.
Journal of Hepatology, 32 (2000), pp. 508-515
[15.]
B. González-Flecha, J.C. Cutrin, A. Boveris.
Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion.
The Journal of Clinical Investigation, 91 (1993), pp. 456-464
[16.]
H. Blum, M.D. Osbakken, R.G. Johnson Jr.
Sodium flux and bioenergetics in the ischemic rat liver.
Magnetic Resonance in Medicine, 18 (1991), pp. 348-357
[17.]
D.K. Dhar, Y. Takemoto, N. Nagasue, M. Uchida, T. Ono, T. Nakamura.
FK506 maintains cellular calcium homeostasis in ischemia-reperfusion injury of the canine liver.
The Journal of Surgical Research, 60 (1996), pp. 142-146
[19.]
K. Ishii, S. Suita, H. Sumimoto.
Effect of verapamil on conversion of xanthine dehydrogenase to oxidase in ischemic rat liver.
Researchin Experimental Medicine, 190 (1990), pp. 389-399
[20.]
H. Jaeschke.
Molecular mechanisms of hepatic ischemiareperfusion injury and preconditioning.
American Journal of Physiology-Gastrointestinal & Liver Physiology, 284 (2003), pp. G15-G26
[21.]
H. Jaeschke, A. Farhood.
Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver.
The American Journal of Physiology, 260 (1991), pp. G355-G362
[22.]
T. Ikeda, K. Yanaga, K. Kishikawa, S. Kakizoe, M. Shimada, K. Sugimachi.
Ischemic injury in liver transplantation: Difference in injury sites between warm and cold ischemia in rats.
Hepatology, 16 (1992), pp. 454-461
[23.]
C. Fondevila, R.W. Busuttil, J.W. Kupiec-Weglinski.
Hepatic ischemia/reperfusion injury—a freshlook.
Experimental & Molecular Pathology, 74 (2003), pp. 86-93
[24.]
S.J. Weiss.
Tissue destruction by neutrophils.
New England Journal of Medicine, 320 (1989), pp. 365-376
[25.]
H. Jaeschke.
Reactive oxygen and mechanisms of inflammatory liver injury. [Abstract] [86 refs].
Journal of Gastroenterology & Hepatology, 15 (2000), pp. 718-724
[26.]
G. Ardizzone, C. Stratta, S. Valzan, M. Crucitti, M. Gallo, E. Cerutti.
Acute blood leukocyte reduction after liver reperfusion: A marker of ischemic injury.
Transplantation Proceedings, 38 (2006), pp. 1076-1077
[27.]
D. Galaris, A. Barbouti, P. Korantzopoulos.
Oxidative stress in hepatic ischemia-reperfusion injury: The role of antioxidants and iron chelating compounds.
Current Pharmaceutical Design, 12 (2006), pp. 2875-2890
[28.]
M. Taniguchi, M. Uchinami, K. Doi, M. Yoshida, H. Sasaki, K. Tamagawa, et al.
Edaravone reduces ischemia-reperfusion injury mediators in rat liver.
Journal of Surgical Research, 137 (2007), pp. 69-74
[29.]
L.M. Colletti, D.G. Remick, G.D. Burtch, S.L. Kunkel, R.M. Strieter, D.A. Campbell Jr.
Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat.
The Journal of Clinical Investigation, 85 (1990), pp. 1936-1943
[30.]
R.F. Schwabe, D.A. Brenner.
Mechanisms of liver injury.I. TNF-alpha-induced liver injury: Role of IKK, JNK, and ROS path-ways.
American Journal of Physiology-Gastrointestinal & Liver Physiology, 290 (2006), pp. G583-G589
[31.]
S. Suzuki, L.H. Toledo-Pereyra.
Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury.
The Journal of Surgical Research, 57 (1994), pp. 253-258
[32.]
W. Zhou, M.O. McCollum, B.A. Levine, M.S. Olson.
Inflammation and platelet-activating factor production during hepatic ischemia/reperfusion.
Hepatology, 16 (1992), pp. 1236-1240
[33.]
T.L. Husted, A.B. Lentsch.
The role of cytokines in pharmacological modulation of hepatic ischemia/reperfusion injury.
Current Pharmaceutical Design, 12 (2006), pp. 2867-2873
[34.]
J.Y. Scoazec, F. Durand, C. Degott, D. Delautier, J. Bernuau, J. Belghiti, et al.
Expression of cytokine-dependent adhesion molecules in postreperfusion biopsy specimens of liver allografts.
Gastroenterology, 107 (1994), pp. 1094-1102
[35.]
A. Koo, H. Komatsu, G. Tao, M. Inoue, P.H. Guth, N. Kaplowitz.
Contribution of no-reflow phenomenon to hepatic injury after ischemia-reperfusion: Evidence for a role for superoxide anion.
Hepatology, 15 (1992), pp. 507-514
[36.]
H. Jaeschke.
Mechanisms of liver injury. II. Mechanisms of neutrophil-induced liver celli njury during hepatic ischemiareperfusion and other acute inflammatory conditions.
American Journal of Physiology, 290 (2006), pp. G1083-G1088
[37.]
S.K.J.H. Ramaiah.
Role of neutrophils in the pathogenesis of acute inflammatory liver injury.
Toxicologic Pathology, 35 (2007), pp. 757-766
[38.]
H. Jaeschke, J.J. Lemasters.
Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury.
Gastroenterology, 125 (2003), pp. 1246-1257
[39.]
T.G. Lehmann, M.D. Wheeler, R.F. Schwabe, H.D. Connor, R. Schoon-hoven, H. Bunzendahl, et al.
Gene delivery of Cu/Zn-superoxide dismutase improves graft function after transplantation of fatty livers in the rat.
Hepatology, 32 (2000), pp. 1255-1264
[40.]
D.F.I. Pevni, D. Schwartz, I. Schwartz, T. Chernichovski, A. Kramer, Y. Ben-Gal, et al.
New evidence for the role of TNF-alpha in liver ischaemic/reperfusion injury.
Eur J Clin Invest, 38 (2008), pp. 649-655
[41.]
lH. Noh, L. Gille, A. Kozlov, K. Staniek.
Are mitochondria a spontaneous and permanent source of reactive oxygen species?.
Redox Report, 8 (2003), pp. 135-141
[42.]
G.K. Glantzounis, H.J. Salacinski, W. Yang, B.R. Davidson, A.M. Seifalian.
The contemporary role of antioxidant therapy in attenuating liver ischemia-reperfusion injury: A review.
Liver Transplantation, 11 (2005), pp. 1031-1047
[43.]
H. Ischiropoulos, L. Zhu, J.S. Beckman.
Peroxy nitrite formation from macrophage-derived nitricoxide.
Archives of Biochemistry and Biophysics, 298 (1992), pp. 446-451
[44.]
M. Bilzer, G. Paumgartner, A.L. Gerbes.
Glutathione protects the rat liver against reperfusion injury after hypothermic preservation.
Gastroenterology, 117 (1999), pp. 200-210
[45.]
A.L. Nieminen, A.M. Byrne, B. Herman, J.J. Lemasters.
Mitochondrial permeability transition in hepatocy tesinduced by t-BuOOH: NAD(P)H and reactive oxygen species.
The American Journal of Physiology, 272 (1997), pp. C1286-C1294
[46.]
A.B. Lentsch, A. Kato, H. Yoshidome, K.M. McMasters, M.J. Edwards.
Inflammatory mechanisms and therapeutic strategies for warm hepaticischemia/reperfusion injury.
Hepatology, 32 (2000), pp. 169-173
[47.]
O.D. Saugstad, A.O. Aasen.
Plasma hypoxanthine concentrations in pigs. A prognostic aid inhypoxia. European Surgical Research.
Europaische Chirurgische Forschung, 12 (1980), pp. 123-129
[48.]
O.D. Saugstad.
Role of xanthine oxidase and its inhibitor in hypoxia: Reoxygenation injury.
Pediatrics, 98 (1996), pp. 103-107
[49.]
F. Stirpe, E. Della Corte.
The regulation of rat liver xanthine oxidase. Conversion in vitro of the enzyme activity from dehydrogenase (type D) to oxidase (type O).
The Journal of Biological Chemistry, 244 (1969), pp. 3855-3863
[50.]
C. Fan, R.M. Zwacka, J.F. Engelhardt.
Therapeutic approaches for ischemia/reperfusion injury in the liver.
Journal of Molecular Medicine, 77 (1999), pp. 577-592
[51.]
D. Adkison, M.E. Hollwarth, J.N. Benoit, D.A. Parks, J.M. McCord, D.N. Granger.
Role of free radicals in ischemia-reperfusion injury to the liver.
Acta Physiologica Scandinavica, 548 (1986), pp. 101-107
[52.]
R.J. Wanders, S. Denis.
Identification of superoxide dismutase in rat liver peroxisomes.
Biochimicaet Biophysica Acta, 1115 (1992), pp. 259-262
[53.]
A.E. Simpson.
The cytochrome P450 4 (CYP4) family.
General Pharmacology, 28 (1997), pp. 351-359
[54.]
K. Pahan, B.T. Smith, A.K. Singh, I. Singh.
Cytochrome P-450 2E1 in rat liver peroxisomes: Downregulation by ischemia/reperfusion-induced oxidative stress.
Free Radical Biology & Medicine, 23 (1997), pp. 963-971
[55.]
T.Z. Liu, K.T. Lee, C.L. Chern, J.T. Cheng, A. Stern, L.Y. Tsai.
Free radical-triggered hepatic injury of experimental obstructive jaundice of rats involves over production of proinflammatory cytokines and enhanced activation of nuclear factor kappaB.
Annals of Clinical and Laboratory Science, 31 (2001), pp. 383-390
[56.]
R.M. Zwacka, Y. Zhang, W. Zhou, J. Halldorson, J.F. Engelhardt.
Ischemia/reperfusion injury in the liver of BALB/c mice activates AP-1 and nuclear factor kappaB independently of IkappaB degradation.
Hepatology, 28 (1998), pp. 1022-1030
[57.]
N. Harada, Y. Iimuro, T. Nitta, M. Yoshida, H. Uchinami, T. Nishio, et al.
Inactivation of the small GTPase Rac1 protects the liver from ischemia/reperfusion injury in the rat.
Surgery, 134 (2003), pp. 480-491
[58.]
H.A. Rudiger, P.A. Clavien.
Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver.
Gastroenterology, 122 (2002), pp. 202-210
[59.]
M. Bauer, I. Bauer.
Heme oxygenase-1: Redox regulation and role in the hepatic response to oxidative stress.
Antioxidants & Redox Signaling, 4 (2002), pp. 749-758
[60.]
M. Paxian, H. Rensing, A. Rickauer, S. Schonhofen, J. Schmeck, B.H. Pannen, et al.
Kupffer cells and neutrophils as paracrine regulators of the heme oxygenase-1 gene in hepatocytes after hemorrhagic shock.
Shock, 15 (2001), pp. 438-445
[61.]
H. Jaeschke, A.P. Bautista, Z. Spolarics, J.J. Spitzer.
Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia.
Free Radical Research Communications, 15 (1991), pp. 277-284
[62.]
M.K. Mittal, T.K. Gupta, F.Y. Lee, C.C. Sieber, R.J. Groszmann.
Nitric oxide modulates hepatic vascular tone in normal ratl iver.
The American Journal of Physiology, 267 (1994), pp. G416-G422
[63.]
R.S. McCuskey.
Morphological mechanisms for regulating blood flow through hepatic sinusoids.
Liver, 20 (2000), pp. 3-7
[64.]
S. Cuzzocrea, D.P. Riley, A.P. Caputi, D. Salvemini.
Antioxidant therapy: A new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury.
Pharmacological Reviews, 53 (2001), pp. 135-159
[65.]
G.M. Hur, Y.S. Ryu, H.Y. Yun, B.H. Jeon, Y.M. Kim, J.H. Seok, et al.
Hepatic ischemia/reperfusion in rats induces iNOS gene transcription by activation of NF-kappaB.
Biochemical and Biophysical Research Communications, 261 (1999), pp. 917-922
[66.]
N. Chida, Y. Hirasawa, T. Ohkawa, Y. Ishii, Y. Sudo, K. Tamura, et al.
Pharmacological profile of FR260330, a novel orally active inducible nitricoxide synthase inhibitor.
European Journal of Pharmacology, 509 (2005), pp. 71-76
[67.]
S. Tsuchihashi, F. Kaldas, N. Chida, Y. Sudo, K. Tamura, Y. Zhai, et al.
FK330, a novel inducible nitricoxide synthase inhibitor, prevents ischemia and reperfusion injury in rat liver transplantation.
American Journal of Transplantation, 6 (2006), pp. 2013-2022
[68.]
M. Meguro, T. Katsuramaki, M. Nagayama, H. Kimura, M. Isobe, Y. Kimura, et al.
A novel inhibitor ofi nducible nitricoxide synthase (ONO-1714) prevents critical warm ischemiareperfusion injury in the pig liver.
Transplantation, 73 (2002), pp. 1439-1446
[69.]
C.-M. Hsu, J.-S. Wang, C.-H. Liu, L.-W. Chen.
Kupffer cells protect liver from ischemia-reperfusion injury by an inducible nitric oxide synthase-dependent mechanism.
Shock, 17 (2002), pp. 280-285
[70.]
I.N. Hines, S. Kawachi, H. Harada, K.P. Pavlick, J.M. Hoffman, S. Bharwani, et al.
Role of nitric oxide in liver ischemia and reperfusion injury.
Molecular & Cellular Biochemistry, 234-235 (2002), pp. 229-237
[71.]
O. Le Moine, H. Louis, A. Demols, F. Desalle, F. Demoor, E. Quertinmont, et al.
Cold liver ischemia-reperfusion injury critically depends on liver T cells and is improved by donor pretreatment with interleukin 10 in mice.
Hepatology, 31 (2000), pp. 1266-1274
[72.]
P.A. Clavien, P.R. Harvey, J.R. Sanabria, R. Cywes, G.A. Levy, S.M. Strasberg.
Lymphocyte adherence in the reperfused rat liver: Mechanisms and effects.
Hepatology, 17 (1993), pp. 131-142
[73.]
T. Shigematsu, R.E. Wolf, D.N. Granger.
T-lymphocytes modulate the microvascular and inflammatory responses to intestinal ischemia-reperfusion.
Microcirculation, 9 (2002), pp. 99-109
[74.]
Y. Okuaki, H. Miyazaki, M. Zeniya, T. Ishikawa, Y. Ohkawa, S. Tsuno, et al.
Splenectomy-reduced hepatic injury induced by ischemia/reperfusion in the rat.
Liver, 16 (1996), pp. 188-194
[75.]
M.R. Weiser, J.P. Williams, F.D. Moore Jr, L. Kobzik, M. Ma, H.B. Hechtman, et al.
Reperfusion injury of ischemic skeletal muscle ismediated by natural antibody and complement.
The Journal of Experimental Medicine, 183 (1996), pp. 2343-2348
[76.]
J.P. Williams, T.T. Pechet, M.R. Weiser, R. Reid, L. Kobzik, F.D. Moore Jr, et al.
Intestinal reperfusion injury is mediated by IgM and complement.
Journal of Applied Physiology, 86 (1999), pp. 938-942
[77.]
M.J. Burne-Taney, D.B. Ascon, F. Daniels, L. Racusen, W. Baldwin, H. Rabb.
B cell deficiency confers protection from renal ischemia reperfusion injury.
Journal of Immunology, 171 (2003), pp. 3210-3215
[78.]
M.J. Burne-Taney, N. Yokota-Ikeda, H. Rabb.
Effects of combined T-and B-cell deficiency on murine ischemia reperfusion injury.
American Journal of Transplantation, 5 (2005), pp. 1186-1193
[79.]
R.M. Zwacka, Y. Zhang, J. Halldorson, H. Schlossberg, L. Dudus, J.F. Engelhardt.
CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver.
The Journal of Clinical Investigation, 100 (1997), pp. 279-289
[80.]
M.Z.S. Hanschen, F. Krombach, A. Khandoga.
Reciprocal activation between CD4+ T cells and Kupffer Cells during hepatic ischemia-reperfusion.
Transplantation, 86 (2008), pp. 710-718
[81.]
D.M. Anselmo, F.F. Amersi, X.-D. Shen, F. Gao, M. Katori, C. Lassman, et al.
FTY720 pretreatment reduces warm hepatic ischemia reperfusion injury through inhibition of T-lymphocyte infiltration.
American Journal of Transplantation, 2 (2002), pp. 843-849
[82.]
C.C. Caldwell, T. Okaya, A. Martignoni, T. Husted, R. Schuster, A.B. Lentsch.
Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemiareperfusion.
American Journal of Physiology-Gastrointestinal & Liver Physiology, 289 (2005), pp. G969-G976
[83.]
A.K. Abbas, K.M. Murphy, A. Sher.
Functional diversity of helper T lymphocytes.
Nature, 383 (1996), pp. 787-793
[84.]
E. González-Rey, A. Chorny, M. Delgado.
Regulation of immune tolerance by anti-inflammatory neuropeptides.
Nat Rev Immunol, 7 (2007), pp. 52-63
[85.]
C.T. Weaver, L.E. Harrington, P.R. Mangan, M. Gavrieli, K.M. Murphy.
Th17: An effector CD4T cell lineage with regulatory T cell ties.
Immunity, 24 (2006), pp. 677-688
[86.]
S.L. Reiner.
Development in motion: Helper T cells at work.
Cell, 129 (2007), pp. 33-36
[87.]
V.P. Márques, G.M. Goncalves, C.Q. Feitoza, M.A. Cenedeze, A.P. Fernándes Bertocchi, M.J. Damiao, et al.
Influence of TH1/TH2 switched immune response on renal ischemia-reperfusion injury.
Nephron, 104 (2006), pp. e48-e56
[88.]
J. Arias-Díaz, J.A. Ildefonso, J.J. Muñoz, A. Zapata, E. Jiménez.
Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion.
Lab Invest, 89 (2009), pp. 433-445
Copyright © 2010. Asociación Española de Cirujanos
