Chemokines in ischemia and reperfusion

Summary

Chemokine signaling plays an important role in the postischemic inflammatory response. Overlapping pathways involving reactive oxygen intermediates,Toll-like receptor (TLR) activation, the complement cascade and the nuclear factor (NF)- κ B system induce both CXC and CC chemokines in ischemic tissues. Reperfusion accentuates chemokine expression promoting an intense inflammatory reaction. ELR-containing CXC chemokines regulate neutrophil infiltration in the ischemic area, whereas CXCR3 ligands may mediate recruitment of Th1 cells. CC chemokines, on the other hand, induce mononuclear cell infiltration and macrophage activation.Evidence suggests that chemokine signaling mediates actions beyond leukocyte chemotaxis and activation, regulating angiogenesis and fibrous tissue deposition. Effective repair of ischemic tissue is dependent on a wellorchestrated cellular response and on timely induction and suppression of chemokines in a locally restricted manner. This manuscript reviews the evidence suggesting a role for chemokine- mediated effects in ischemia/reperfusion and discusses the potential significance of these interactions in injury and repair of ischemic tissues.

Keywords

Chemokine - ischemia - reperfusion - leukocyte - inflammation

• References

• 1 Gross GJ, Auchampach JA. Reperfusion injury: Does it exist?. J Mol Cell Cardiol 2007; 42: 12-18.
• 2 Frangogiannis NG. Chemokines in the ischemic myocardium: from inflammation to fibrosis. Inflamm Res 2004; 53: 585-595.
• 3 Jaeschke H. Mechanisms of liver injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions. Am J Physiol Gastrointest Liver Physiol 2006; 290: G1083-1088.
• 4 Minami M, Satoh M. Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury. Life Sci 2003; 74: 321-327.
• 5 Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001; 02: 108-115.
• 6 Zlotnik A. et al. Recent advances in chemokines and chemokine receptors. Crit Rev Immunol 1999; 19: 1-47.
• 7 Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000; 12: 121-127.
• 8 Ceradini DJ. et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858-864.
• 9 Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005; 115: 500-508.
• 10 Becker LB. New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res 2004; 61: 461-470.
• 11 Hensley K. et al. Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med 2000; 28: 1456-1462.
• 12 Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS. Circulation 2003; 108: 1912-1916.
• 13 Sen CK, Packer L. Antioxidant and redox regulation of gene transcription. FASEB J 1996; 10: 709-720.
• 14 Nossuli TO, Frangogiannis NG. et al. Brief murine myocardial I/R induces chemokines in a TNF-alpha-independent manner: role of oxygen radicals. Am J Physiol Heart Circ Physiol 2001; 281: H2549-2558.
• 15 Lakshminarayanan V. et al. Reactive oxygen intermediates induce monocyte chemotactic protein-1 in vascular endothelium after brief ischemia. Am J Pathol 2001; 159: 1301-1311.
• 16 Maekawa N. et al. Improved myocardial ischemia/ reperfusion injury in mice lacking tumor necrosis factor- alpha. J Am Coll Cardiol 2002; 39: 1229-1235.
• 17 Chandrasekar B. et al. Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation 2001; 103: 2296-2302.
• 18 Colletti LM. et al. Chemokine expression during hepatic ischemia/reperfusion-induced lung injury in the rat. The role of epithelial neutrophil activating protein. J Clin Invest 1995; 95: 134-141.
• 19 Kato A. et al. Specific role of interleukin-1 in hepatic neutrophil recruitment after ischemia/reperfusion. Am J Pathol 2002; 161: 1797-1803.
• 20 Frangogiannis NG. et al. Resident cardiac mast cells degranulate and release preformed TNF-alpha, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion. Circulation 1998; 98: 699-710.
• 21 Somasundaram P. et al. Mast cell tryptase may modulate endothelial cell phenotype in healing myocardial infarcts. J Pathol 2005; 205: 102-111.
• 22 Nijmeijer R. et al. CRP, a major culprit in complement- mediated tissue damage in acute myocardial infarction?. Int Immunopharmacol 2001; 01: 403-414.
• 23 Fujita T. Evolution of the lectin-complement pathway and its role in innate immunity. Nat Rev Immunol 2002; 02: 346-353.
• 24 Rossen RD. et al. Mechanism of complement activation after coronary artery occlusion: evidence that myocardial ischemia in dogs causes release of constituents of myocardial subcellular origin that complex with human C1q in vivo. Circ Res 1988; 62: 572-584.
• 25 Hill JH, Ward PA. The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J Exp Med 1971; 133: 885-900.
• 26 Kilgore KS. et al. Attenuation of interleukin-8 expression in C6-deficient rabbits after myocardial ischemia/ reperfusion. J Mol Cell Cardiol 1998; 30: 75-85.
• 27 de Vries B. et al. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J Immunol 2003; 170: 3883-3889.
• 28 Beg AA. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002; 23: 509-512.
• 29 McKee CM. et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest 1996; 98: 2403-2413.
• 30 Taylor KR. et al. Hyaluronan fragments stimulate dermal endothelial recognition of injury through TLR4. J Biol Chem 2004; 279: 17079-17084.
• 31 Taylor KR. et al. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J Biol Chem 2004; 279: 17079-17084.
• 32 Zhai Y. et al. Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol 2004; 173: 7115-7119.
• 33 Oyama J. et al. Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 2004; 109: 784-789.
• 34 Boyd JH. et al. Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NFkappaB dependent inflammatory response. Cardiovasc Res 2006; 72: 384-393.
• 35 Lenardo MJ, Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 1989; 58: 227-229.
• 36 Stancovski I, Baltimore D. NF-kappaB activation: the I kappaB kinase revealed?. Cell 1997; 91: 299-302.
• 37 Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002; 03: 221-227.
• 38 Misra A. et al. Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction. Circulation 2003; 108: 3075-3078.
• 39 Kupatt C. et al. Retroinfusion of NFkappaB decoy oligonucleotide extends cardioprotection achieved by CD18 inhibition in a preclinical study of myocardial ischemia and retroinfusion in pigs. Gene Ther 2002; 09: 518-526.
• 40 Lawrence T. et al. Possible new role for NF-kappaB in the resolution of inflammation. Nat Med 2001; 07: 1291-1297.
• 41 Bizzarri C. et al. ELR+ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets. Pharmacol Ther 2006; 112: 139-149.
• 42 Rollins BJ. Chemokines. Blood 1997; 90: 909-928.
• 43 Clark-Lewis I. et al. Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2-terminal residues and evidence for uncoupling of neutrophil chemotaxis, exocytosis, and receptor binding activities. J Biol Chem 1991; 266: 23128-23134.
• 44 Clark-Lewis I. et al. Structure-activity relationships of chemokines. J Leukoc Biol 1995; 57: 703-711.
• 45 Kukielka GL. et al. Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo. J Clin Invest 1995; 95: 89-103.
• 46 Ivey CL. et al. Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8. J Clin Invest 1995; 95: 2720-2728.
• 47 Sekido N. et al. Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature 1993; 365: 654-657.
• 48 Matsumoto T. et al. Prevention of cerebral edema and infarct in cerebral reperfusion injury by an antibody to interleukin-8. Lab Invest 1997; 77: 119-125.
• 49 Boyle Jr EM. et al. Inhibition of interleukin-8 blocks myocardial ischemia-reperfusion injury. J Thorac Cardiovasc Surg 1998; 116: 114-121.
• 50 Kocher AA. et al. Myocardial homing and neovascularization by human bone marrow angioblasts is regulated by IL-8/Gro CXC chemokines. J Mol Cell Cardiol 2006; 40: 455-464.
• 51 Anisowicz A. et al. Constitutive overexpression of a growth-regulated gene in transformed Chinese hamster and human cells. Proc Natl Acad Sci USA 1987; 84: 7188-7192.
• 52 Cochran BH. et al. Molecular cloning of gene sequences regulated by platelet-derived growth factor. Cell 1983; 33: 939-947.
• 53 Riaz AA. et al. Oxygen radical-dependent expression of CXC chemokines regulate ischemia/reperfusion- induced leukocyte adhesion in the mouse colon. Free Radic Biol Med 2003; 35: 782-789.
• 54 Daemen MA. et al. Apoptosis and chemokine induction after renal ischemia-reperfusion. Transplantation 2001; 71: 1007-1011.
• 55 Miura M. et al. Neutralization of Gro alpha and macrophage inflammatory protein-2 attenuates renal ischemia/reperfusion injury. Am J Pathol 2001; 159: 2137-2145.
• 56 Lentsch AB. et al. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells. Hepatology 1998; 27: 507-512.
• 57 Tarzami ST. et al. Opposing effects mediated by the chemokine receptor CXCR2 on myocardial ischemiareperfusion injury: recruitment of potentially damaging neutrophils and direct myocardial protection. Circulation 2003; 108: 2387-2392.
• 58 Souza DG. et al. Repertaxin, a novel inhibitor of rat CXCR2 function, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury. Br J Pharmacol 2004; 143: 132-142.
• 59 Cugini D. et al. Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion. Kidney Int 2005; 67: 1753-1761.
• 60 Fiorina P. et al. Role of CXC chemokine receptor 3 pathway in renal ischemic injury. J Am Soc Nephrol 2006; 17: 716-723.
• 61 Strieter RM. et al. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 1995; 270: 27348-27357.
• 62 Strieter RM, Polverini PJ, Arenberg DA. et al. Role of C-X-C chemokines as regulators of angiogenesis in lung cancer. J Leukoc Biol 1995; 57: 752-762.
• 63 Shiraha H. et al. IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity. J Cell Biol 1999; 146: 243-254.
• 64 Waeckel L. et al. Impairment in postischemic neovascularization in mice lacking the CXC chemokine receptor 3. Circ Res 2005; 96: 576-582.
• 65 Frangogiannis NG. et al. Induction and suppression of interferon-inducible protein 10 in reperfused myocardial infarcts may regulate angiogenesis. FASEB J 2001; 15: 1428-1430.
• 66 Frangogiannis NG. et al. Induction of the synthesis of the C-X-C chemokine interferon-gamma-inducible protein- 10 in experimental canine endotoxemia. Cell Tissue Res 2000; 302: 365-376.
• 67 Frangogiannis NG. et al. IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury. J Immunol 2000; 165: 2798-2808.
• 68 Birdsall HH. et al. Complement C5a, TGF-beta 1, and MCP-1, in sequence, induce migration of monocytes into ischemic canine myocardium within the first one to five hours after reperfusion. Circulation 1997; 95: 684-692.
• 69 Nagasawa T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635-638.
• 70 Salvucci O. et al. Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1. Blood 2002; 99: 2703-2711.
• 71 Salcedo R. et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol 1999; 154: 1125-1135.
• 72 Aiuti A. et al. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 1997; 185: 111-120.
• 73 Jo DY. et al. Chemotaxis of primitive hematopoietic cells in response to stromal cell-derived factor-1. J Clin Invest 2000; 105: 101-111.
• 74 Peled A. et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999; 283: 845-848.
• 75 Togel F. et al. Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Kidney Int 2005; 67: 1772-1784.
• 76 Pillarisetti K, Gupta SK. Cloning and relative expression analysis of rat stromal cell derived factor-1 (SDF-1)1: SDF-1 alpha mRNA is selectively induced in rat model of myocardial infarction. Inflammation 2001; 25: 293-300.
• 77 Askari AT. et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003; 362: 697-703.
• 78 Schober A. et al. SDF-1alpha-mediated tissue repair by stem cells: a promising tool in cardiovascular medicine?. Trends Cardiovasc Med 2006; 16: 103-108.
• 79 Hristov M, Weber C. Endothelial progenitor cells: characterization, pathophysiology, and possible clinical relevance. J Cell Mol Med 2004; 08: 498-508.
• 80 Yamaguchi J. et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 2003; 107: 1322-1328.
• 81 Rollins BJ. Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease. Mol Med Today 1996; 02: 198-204.
• 82 Gu L. et al. Monocyte chemoattractant protein-1. Chem Immunol 1999; 72: 7-29.
• 83 Nelken NA. et al. Monocyte chemoattractant protein- 1 in human atheromatous plaques. J Clin Invest 1991; 88: 1121-1127.
• 84 Gu L. et al. In vivo properties of monocyte chemoattractant protein-1. J Leukoc Biol 1997; 62: 577-580.
• 85 Koch AE. et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 1992; 90: 772-779.
• 86 Tesch GH. et al. Monocyte chemoattractant protein- 1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis. J Clin Invest 1999; 103: 73-80.
• 87 Kakio T. et al. Roles and relationship of macrophages and monocyte chemotactic and activating factor/ monocyte chemoattractant protein-1 in the ischemic and reperfused rat heart. Lab Invest 2000; 80: 1127-1136.
• 88 Tarzami ST. et al. Chemokine expression in myocardial ischemia: MIP-2 dependent MCP-1 expression protects cardiomyocytes from cell death. J Mol Cell Cardiol 2002; 34: 209-221.
• 89 Furuichi K. et al. CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol 2003; 14: 2503-2515.
• 90 Che X. et al. Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res 2001; 902: 171-177.
• 91 Kumar AG. et al. Induction of monocyte chemoattractant protein-1 in the small veins of the ischemic and reperfused canine myocardium. Circulation 1997; 95: 693-700.
• 92 Ono K. et al. Prevention of myocardial reperfusion injury in rats by an antibody against monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. Lab Invest 1999; 79: 195-203.
• 93 Dewald O. et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res 2005; 96: 881-889.
• 94 Geissmann F. et al. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003; 19: 71-82.
• 95 Weber C. et al. Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol 2000; 67: 699-704.
• 96 Gavrilin MA. et al. Monocyte chemotactic protein 1 upregulates IL-1beta expression in human monocytes. Biochem Biophys Res Commun 2000; 277: 37-42.
• 97 Jiang Y. et al. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol 1992; 148: 2423-2428.
• 98 Tabata T. et al. Monocyte chemoattractant protein-1 induces scavenger receptor expression and monocyte differentiation into foam cells. Biochem Biophys Res Commun 2003; 305: 380-385.
• 99 Kaikita K. et al. Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction. Am J Pathol 2004; 165: 439-447.
• 100 Morimoto H. et al. Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction. Circ Res 2006; 99: 891-899.
• 101 Wang X. et al. Molecular cloning and expression of the rat monocyte chemotactic protein-3 gene: a possible role in stroke. Brain Res Mol Brain Res 1999; 71: 304-312.
• 102 Schenk S. et al. Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor. Stem Cells 2007; 25: 245-251.
• 103 Uguccioni M. et al. Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes. Eur J Immunol 1995; 25: 64-68.
• 104 Dewald O. et al. Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. Am J Pathol 2004; 164: 665-677.
• 105 Kim JS. et al. Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein- 1 after focal cerebral ischemia in the rat. J Neuroimmunol 1995; 56: 127-134.
• 106 Krishnadasan B. et al. Beta-chemokine function in experimental lung ischemia-reperfusion injury. Ann Thorac Surg 2004; 77: 1056-1062.
• 107 Schall TJ. Biology of the RANTES/SIS cytokine family. Cytokine 1991; 03: 165-183.
• 108 Schall TJ. et al. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature 1990; 347: 669-671.
• 109 Parissis JT. et al. Serum profiles of C-C chemokines in acute myocardial infarction: possible implication in postinfarction left ventricular remodeling. J Interferon Cytokine Res 2002; 22: 223-229.
• 110 Lemay S. et al. Prominent and sustained up-regulation of gp130-signaling cytokines and the chemokine MIP-2 in murine renal ischemia-reperfusion injury. Transplantation 2000; 69: 959-963.
• 111 Furuichi K. et al. Chemokine receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury. Am J Pathol 2006; 169: 372-387.
• 112 Soriano SG. et al. Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury. J Neuroimmunol 2002; 125: 59-65.
• 113 Jennings RB. et al. Development of cell injury in sustained acute ischemia. Circulation 1990; 82 II: 2-12.
• 114 Frangogiannis NG. The mechanistic basis of infarct healing. Antioxid Redox Signal 2006; 08: 1907-1939.
• 115 Frangogiannis NG. Targeting the inflammatory response in healing myocardial infarcts. Curr Med Chem 2006; 13: 1877-1893.
• 116 Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2006 doi:10.1016/j.cardiores. 2006.10.002
• 117 Dobaczewski M. et al. Extracellular matrix remodeling in canine and mouse myocardial infarcts. Cell Tissue Res 2006; 324: 475-488.
• 118 White HD. et al. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987; 76: 44-51.
• 119 Hayashidani S. et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2003; 108: 2134-2140.
• 120 Frangogiannis NG. et al. The critical role of endogenous Thrombospondin (TSP)-1 in preventing expansion of healing myocardial infarcts. Circulation 2005; 111: 2935-2942.
• 121 Zymek P. et al. The role of platelet-derived growth factor signaling in healing myocardial infarcts. J Am Coll Cardiol 2006; 48: 2315-2323.
• 122 Dewald O. et al. Development of murine ischemic cardiomyopathy is associated with a transient inflammatory reaction and depends on reactive oxygen species. Proc Natl Acad Sci USA 2003; 100: 2700-2705.
• 123 Frangogiannis NG. et al. Critical role of Monocyte Chemoattractant Protein (MCP)-1/CCL2 in the pathogenesis of ischemic cardiomyopathy. Circulation 2007; 115: 584-592.
• 124 Quan TE. et al. Circulating fibrocytes: collagensecreting cells of the peripheral blood. Int J Biochem Cell Biol 2004; 36: 598-606.
• 125 Moore BB. et al. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol 2005; 166: 675-684.
• 126 Frangogiannis NG. et al. Evidence for an active inflammatory process in the hibernating human myocardium. Am J Pathol 2002; 160: 1425-1433.
• 127 Frangogiannis NG. et al. Active interstitial remodeling: an important process in the hibernating human myocardium. J Am Coll Cardiol 2002; 39: 1468-1474.
• 128 Zhou L. et al. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ Res 2006; 98: 1177-1185.
• 129 Bidzhekov K. et al. MCP-1 induces a novel transcription factor with proapoptotic activity. Circ Res 2006; 98: 1107-1109.
• 130 Araki M. et al. Expression of IL-8 during reperfusion of renal allografts is dependent on ischemic time. Transplantation 2006; 81: 783-788.
• 131 Jaeschke H. et al. Superoxide generation by neutrophils and Kupffer cells during in vivo reperfusion after hepatic ischemia in rats. J Leukoc Biol 1992; 52: 377-382.
• 132 Colletti LM. et al. The ratio of ELR+ to ELR- CXC chemokines affects the lung and liver injury following hepatic ischemia/ reperfusion in the rat. Hepatology 2000; 31: 435-445.