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Do leukocytes play a role in focal ischemia in the brain? An objective review of the literature

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Book cover Inflammation and Stroke

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Three general lines of evidence have been put forth to support the role of neutrophil recruitment in ischemic cell death. These include (1) the presence of neutrophils within ischemic tissue at the approximate time that substantial cell death occurs, (2) the reduction of ischemia-induced cell loss following neutropenia, and (3) the observation that treatments which prevent neutrophil trafficking can be neuroprotective. Despite the numerous studies that have been conducted, this hypothesis remains controversial, for an objective assessment of the literature reveals great uncertainty for a pathogenic role of neutrophils in the brain damage associated with ischemia. The present chapter briefly summarizes and critically discusses the available data addressing this hypothesis.

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References

  1. Barone F, Hillegass L, Tzimas M, Schmidt D, Foley J, White R, Price W, Feuerstein G, Clark R, Griswold D, Sarau H (1995) Time-related changes in myeloperoxidase activity and leukotrine B4 receptor binding reflect leukocyte influx in cerebral focal stroke. Mol Chem Neuropathol 24: 13–30

    Article  PubMed  CAS  Google Scholar 

  2. Bednar M, Dooley R, Zamani M, Howard D, Gross C (1995) Neutrophil and platelet activity and quantification following delayed tPA therapy in a rabbit model of thromboembolic stroke. J Thrombosis Thrombolysis 1: 179–185

    Article  CAS  Google Scholar 

  3. Zoppo G del, Schmid-Schonbein G, Mori E, Copeland B, Chang C-M (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22: 1276–1283

    Article  PubMed  Google Scholar 

  4. Hallenbeck J, Dutka A, Tanishima T, Kochanek P, Kumaroo K, Thompson C, Obrenovitch T, Contreras T (1986) Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 17: 246–253

    Article  PubMed  CAS  Google Scholar 

  5. Jander S, Kraemer M, Schroeter M, Witte O, Stoll G (1995) Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab 15: 42–51

    Article  PubMed  CAS  Google Scholar 

  6. Ritter L, Orozco J, Coull B, McDonagh P (2000) Leukocyte accumulation and hemodynamic changes in the cerebral microcirculation during early reperfusion after stroke. Stroke 31: 1153–1161

    Article  PubMed  CAS  Google Scholar 

  7. Wang P-Y, Kao C-H, Mui M-Y, Wang S-J (1993) Leukocyte infiltration in acute hemispheric stroke. Stroke 24: 236–240

    Article  PubMed  CAS  Google Scholar 

  8. Hayward N, Elliott P, Sawyer S, Bronson R, Bartus R (1996) Lack of evidence for neutrophil participation during infarct formation following focal cerebral ischemia in the rat. Exp Neurol 139: 188–202

    Article  PubMed  CAS  Google Scholar 

  9. Akopov S, Simonian N, Grigorian G (1996) Dynamics of polymorphonuclear leukocyte accumulation in acute cerebral infarction and their correlation with brain tissue damage. Stroke 27: 1739–1743

    Article  PubMed  CAS  Google Scholar 

  10. Ahmed S-H, He Y, Nassief A, Xu J, Xu X, Hsu C (2000) Effects of lipopolysaccharide priming on acute ischemic brain injury. Stroke 31: 193–199

    Article  PubMed  CAS  Google Scholar 

  11. Barone F, Schmidt D, Hillegass L, Price W, White R, Feuerstein G, Clark R, Lee E, Griswold D, Sarau H (1992) Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke 23: 1337–1348

    Article  PubMed  CAS  Google Scholar 

  12. Clark R, Lee E, Fish C, White R, Price W, Jonak Z, Feuerstein G, Barone F (1993) Development of tissue damage, inflammation and resolution following stroke: An immunohistochemical and quantitative planimetric study. Brain Res Bull 31: 565–572

    Article  PubMed  CAS  Google Scholar 

  13. Clark R, Lee E, White R, Jonak Z, Feuerstein Z, Barone F (1994) Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue. Brain Res Bull 35: 387–392

    Article  CAS  Google Scholar 

  14. Dereski M, Chopp M, Knight R, Chen H, Garcia J (1992) Focal cerebral ischemia in the rat: Temporal profile of neutrophil responses. Neurosci Res Comm 11: 179–186

    Google Scholar 

  15. Garcia J, Kamijyo Y (1974) Cerebral infarction: Evolution of histopathological changes after occlusion of a middle cerebral artery in primates. J Neuropathol Exp Neurol 33: 408–421

    Article  PubMed  CAS  Google Scholar 

  16. Garcia J, Liu K, Yoshida Y, Lian J, Chen S, Zoppo G del (1994) Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol 144: 188–199

    PubMed  CAS  Google Scholar 

  17. Kato H, Kogure K, Liu X-H, Araki T, Itoyama Y (1996) Progressive expression of immunomolecules on activated microglia and invading leukocytes following focal cerebral ischemia in the rat. Brain Res 734: 203–212

    Article  PubMed  CAS  Google Scholar 

  18. Lehrmann E, Christensen T, Zimmer J, Diemer N, Finsen B (1997) Microglial and macrophage reactions mark progressive changes and define the penumbra in the rat neocortex and striatum after transient middle cerebral artery occusion. J Comp Neurol 386: 461–476

    Article  PubMed  CAS  Google Scholar 

  19. Linsdsberg P, Carpen O, Oaetau A, Karjalainen-Lindsberg M-L, Kaste M (1996) Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 94: 939–945

    Article  Google Scholar 

  20. Matsuo Y, Onodera H, Shiga Y, Nakamura M, Ninomiya M, Kihara T, Kogure K (1994) Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat: Effects of neutrophil depletion. Stroke 25: 1469–1475

    Article  PubMed  CAS  Google Scholar 

  21. Matsuo Y, Onodera H, Shiga Y, Shozuhara H, Ninomiya M, Kihara T, Tamatani T, Miyasaka M, Kogure K (1994) Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 656: 344–352

    Article  PubMed  CAS  Google Scholar 

  22. Pozzilli C, Lenzi G, Argentino C, Carolei A, Rasura M, Signore A, Bozzao L, Pozzilli P (1985) Imaging of leukocyte infiltration in human cerebral infarcts. Stroke 16: 251–255

    Article  PubMed  CAS  Google Scholar 

  23. Schroeter M, Jaonder S, Witte O, Stoll G (1994) Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion. J Neuroimmunol 55: 195–203

    Article  PubMed  CAS  Google Scholar 

  24. Yamasaki Y, Matsuo Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y, Kogure K (1995) Interleukin-1 as a pathogenic mediator of ischemic brain damage in rats. Stroke 26: 676–681

    Article  PubMed  CAS  Google Scholar 

  25. Zhang R-L, Chopp M, Chen H, Garcia J (1994) Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2H) middle cerebral artery occlusion in the rat. J Neurological Sci 125: 3–10

    Article  CAS  Google Scholar 

  26. Lopez O, Lanthorn T (1993) Anti-neutrophil antiserum reduces infarct volume after mouse permanent middle cerebral artery occlusion without producing neutropenia. Neurosci Res Comm 13: 45–53

    Google Scholar 

  27. Chen H, Chopp M, Bodzin G (1992) Neutropenia reduces the volume of cerebral infarct after transient middle cerebral artery occlusion in the rat. Neurosci Res Comm 11: 93–99

    Google Scholar 

  28. Dutka A, Kochanek P, Hallenbeck J (1989) Influence of granulocytopenia on canine cerebral ischemia induced by air embolism. Stroke 20: 390–395

    Article  PubMed  CAS  Google Scholar 

  29. Helps S, Gorman D (1991) Air embolism of the brain in rabbits pretreated with mechlorethamine. Stroke 22: 351–354

    Article  PubMed  CAS  Google Scholar 

  30. Shiga Y, Onodera Y, Kogure K, Yamasaki Y, Yashima Y, Syozuhara H, Sendo F (1991) Neutrophil as a mediator of ischemic edema formation in the brain. Neurosci Letts 125: 110–112

    Article  CAS  Google Scholar 

  31. Connolly E, Winfree C, Springer T, Naka Y, Liao H, Yan D, Stern D, Solomon R, Gutierrez-Ramos J-C, Pinsky D (1996) Cerebral protection in homozygous null ICAM1 mice after middle cerebral artery occlusion: Role of neutrophil adhesion in the pathogenesis of stroke. J Clin Invest 97: 209–216

    Article  PubMed  CAS  Google Scholar 

  32. Bednar M, Raymond S, McAuliffe T, Lodge P, Gross C (1991) The role of neutrophils and platelets in a rabbit model of thromboembolic stroke. Stroke 22: 44–50

    Article  PubMed  CAS  Google Scholar 

  33. Chabner B, Allegra C, Curt G, Calabresi P (1996) Antineoplastic agents. In: J Jardman et al (eds): Goodman and Gilman’s the pharmacological basis of therapeutics. McGraw Hill, 1233–1287

    Google Scholar 

  34. Härtl R, Schurer L, Schmid-Schonbein GW, Zoppo G del (1996) Experimental anti-leukocyte interventions in cerebral ischemia. J Cereb Blood Flow Metab 16: 1108–1119

    Article  PubMed  Google Scholar 

  35. Chopp M, Li Y, Jiang N, Zhang R, Prostak J (1996) Antibodies against adhesion molecules reduce apoptosis after transient middle cerebral artery occlusion in rat brain. J Cereb Blood Flow Metab 16: 578–584

    Article  CAS  Google Scholar 

  36. Shiga Y, Onodera H, Matsuo Y, Kogure K (1992) Cyclosporin A protects against ischemia-reperfusion injury in the brain. Brain Res 595: 145–148

    Article  PubMed  CAS  Google Scholar 

  37. Zhang R, Chopp M, Jiang N, Tang W, Prostak J, Manning A, Anderson D (1995) Anti-intercellular adhesion molecule-1 antibody reduces ischemic call damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 26: 1438–1443

    Article  PubMed  CAS  Google Scholar 

  38. Zhang R, Chopp M, Tang W, Zhang Z, Putney S, Starzyk R (1996) Synthetic peptide derived from the Bordetella pertussis bacterium reduces infarct volume after transient middle cerebral artery occlusion in the rat. Neurol 46: 1437–1441

    Article  CAS  Google Scholar 

  39. Kochanek P, Dutka A, Kumaroo K, Hallenbeck J (1987) Platelet activating factor receptor blockade enhances recovery after multifocal brain ischemia. Life Sci 41: 2639–2644

    Article  PubMed  CAS  Google Scholar 

  40. Bowes M, Zivin J, Rothlein R (1993) Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. Exp Neurol 119: 215–219

    Article  PubMed  CAS  Google Scholar 

  41. Bowes M, Rothlein R, Fagans S, Zivin J (1995) Monolconal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurol 45: 815–819

    Article  CAS  Google Scholar 

  42. Gross C, Howard D, Dooley R, Raymond S, Fuller S, Bednar M (1994) TGF-bl post-treatment in a rabbit model of cerebral ischaemia. Neurological Res 16: 465–470

    CAS  Google Scholar 

  43. Garcia J, Liu K-F, Bree M (1995) Effects of CD11b/18 monoclonal antibody on rats with permanent middle cerebral artery occlusion. Am J Pathol 148: 241–248

    Google Scholar 

  44. Garcia J, Liu K-F, Belton J (1995) Interleukin-1 receptor antagonist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion. Am J Pathol 147: 1477–1486

    PubMed  CAS  Google Scholar 

  45. Jiang N, Zhang R, Chen H, Chopp M (1994) Anti-CD11B monoclonal antibody reduces ischemic cell damage after transient (2h) but not after permanent MCA occlusion in the rat. Neurosci Res Comm 15: 85–93

    CAS  Google Scholar 

  46. Jiang N, Chopp M, Chahwala S (1998) Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat. Brain Res 788: 25–34

    Article  PubMed  CAS  Google Scholar 

  47. Takeshima R, Kirsch J, Koehler R, Gomoll A, Traystman R (1992) Monoclonal leukocyte antibody does not decrease the injury of transient focal cerebral ischemia in cats. Stroke 23: 247–252

    Article  PubMed  CAS  Google Scholar 

  48. Clark W, Madden K, Rothlein R, Zivin J (1991) Reduction of central nervous system ischemic injury by monoclonal antibody to intracellular adhesion molecule. J Neurosurg 75: 623–627

    Article  PubMed  CAS  Google Scholar 

  49. Clark W, Madden K, Rothlein R, Zivin J (1991) Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment. Stroke 22: 877–883

    Article  PubMed  CAS  Google Scholar 

  50. Zhang R, Chopp M, Li Y, Zaloga C, Jiang N, Jones M, Miyasaka M, Ward P (1994) Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurol 44: 1747–1751

    Article  CAS  Google Scholar 

  51. Zhang R, Zhang Z, Chopp M (1999) Increased therapeutic efficacy with rt-PA and antiCD18 antibody treatment of stroke in the rat. Neurol 52: 273–279

    Article  CAS  Google Scholar 

  52. Yanaka K, Camarata P, Spellman S, Skubitz A, Furcht L, Low W (1997) Laminin peptide ameliorates brain injury by inhibiting leukocyte accumulation in a rat model of transient focal cerebral ischemia. J Cereb Blood Flow Metab 17: 605–611

    Article  PubMed  CAS  Google Scholar 

  53. Yanaka K, Camarata P, Spellman S, McCarthy J, Furcht L, Low W (1997) Antagonism of leukocyte adherence by synthetic fibronectin peptide V in a rat model of transient focal cerebral ischemia. Neurosurg 40: 557–564

    CAS  Google Scholar 

  54. Yanaka K, Spellman S, McCarthy J, Low W, Camarata P (1996) Reduction of brain injury using heparin to inhibit leukocyte accuulation in a rat model of transient focal cerebral ischemia I: Protective mechanism. J Neurosurg 85: 1102–1107

    Article  PubMed  CAS  Google Scholar 

  55. Yanaka K, Spellman S, McCarthy J, Low W, Camarata P (1996) Reduction of brain injury using heparin to inhibit leukocyte accumulation in a rat model of transient focal cerebral ischemia II: Dose-response effect and the therapeutic window. J Neurosurg 85: 1108–1112

    Article  PubMed  CAS  Google Scholar 

  56. Toyoda T, Suzuki S, Kassell N, Lee K (1996) Intraischemic hypothermia attenuates neu-trophil infiltration in the rat neocortex after focal ischemia-reperfusion injury. Neurosurg 39: 1200–1205

    Article  CAS  Google Scholar 

  57. Spera P, Ellison J, Feuerstein G, Barone F (1998) IL-10 reduces rat brain injury following focal stroke. Neurosci Lett 251: 189–192

    Article  PubMed  CAS  Google Scholar 

  58. Shimakura A, Kamanaka Y, Ikeda Y, Kondo K, Suzuki Y, Umemura K (2000) Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion. Brain Res 858: 55–60

    Article  PubMed  CAS  Google Scholar 

  59. Relton J, Martin D, Thompson R, Russell D (1996) Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol 138: 206–213

    Article  PubMed  CAS  Google Scholar 

  60. Relton J, Rothwell N (1992) Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res Bull 29: 243–246

    Article  PubMed  CAS  Google Scholar 

  61. Prehn J, Backhauss C, Krieglstein J (1993) Transforming growth factor-B1 prevents gluatmate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J Cereb Blood Flow Metab 13: 521–525

    Article  PubMed  CAS  Google Scholar 

  62. Phillips J, Williams A, Adams J, Elliott P, Tortella F (2000) Proteasome inhibitor PS 519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia. Stroke 31: 1686–1693

    Article  PubMed  CAS  Google Scholar 

  63. Nawashiro H, Martin D, Hallenbeck J (1997) Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res 778: 265–271

    Article  PubMed  CAS  Google Scholar 

  64. Nawashiro H, Martin D, Hallenbeck J (1997) Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J Cereb Blood Flow Metab 17: 229–232

    Article  PubMed  CAS  Google Scholar 

  65. Mori E, Zoppo G del, Chambers J, Copeland B, Arfors K (1992) Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia. Stroke 23: 712–718

    Article  PubMed  CAS  Google Scholar 

  66. Matsumoto T, Ikeda K, Mukaida N, Harada A, Matsumoto Y, Yamashita J, Matsushima K (1997) Prevention of cerebral edema and infarct in cerebral reperfusion injury by an antibody to interleukin-8. Lab Invest 77: 119–125

    PubMed  CAS  Google Scholar 

  67. Loddick S, Bothwell N (1996) Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 16: 932–940

    Article  PubMed  CAS  Google Scholar 

  68. Kochanek P, Dutka A, Hallenbeck J (1987) Indomethacin, prostacyclin, and heparin improve postischemic cerebral blood flow without affecting early postischemic granulocyte accumulation. Stroke 18: 634–637

    Article  PubMed  CAS  Google Scholar 

  69. Jiang N, Moyle M, Soule H, Rote W, Chopp M (1995) Neutrophil inhibitory factor after focal ischemia in rats. Ann Neurol 38: 935–942

    Article  PubMed  CAS  Google Scholar 

  70. Gross C, Bednar M, Howard D, Sporn M (1993) Transforming growth factor-131 reduced infarct size after experimental cerebral ischemia in a rabbit model. Stroke 24: 558–562

    Article  PubMed  CAS  Google Scholar 

  71. Dawson D, Martin D, Hallenbeck J (1996) Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neurosci Lett 218: 41–44

    Article  CAS  Google Scholar 

  72. Chopp M, Zhang R, Chen H, Li Y, Jiang N, Rusche J (1994) Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25: 869–876

    Article  PubMed  CAS  Google Scholar 

  73. Chen H, Chopp M, Zhang R, Bodzin G, Chen Q, Rusche J, Todd R (1994) Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 35: 458–463

    Article  PubMed  Google Scholar 

  74. Bielenberg G, Wagener G, Beck T (1992) Infarct reduction by the platelet activating factor antagonist apafant in rats. Stroke 23: 98–103

    Article  PubMed  CAS  Google Scholar 

  75. Barone F, Arvin B, White R, Miller A, Webb C, Willette R, Lysko P, Feuerstein G (1997) Tumor necrosis factor-a: A mediator of focal ischemic brain injury. Stroke 28: 1233–1244

    Article  PubMed  CAS  Google Scholar 

  76. Kitagawa K, Matsumoto M, Mabuchi T, Yagita Y, Ohtsuki T, Hori M, Yanagihara T (1998) Deficiency of intercellular adhesion molecule-1 attenuates microcirculatory disturbance and infarction size in focal cerebral ischemia. J Cereb Blood Flow Metab 18: 1336–1345

    Article  PubMed  CAS  Google Scholar 

  77. Prestigiacomo C, Kim S, Connolly E, Liao H, Yan S, Pinsky D (1999) CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke. Stroke 30: 1110–1117

    Article  PubMed  CAS  Google Scholar 

  78. Soriano S, Lipton S, Wang Y, Xiao M, Springer T, Guiterrez-Ramos J-C, Hickey P (1996) Intercellular adhesion molecule-l-deficient mice are less susceptible to cerebral ischemia-reperfusion injury. Ann Neurol 39: 618–624

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Alkermes, Inc., 64 Sidney Street, Cambridge, MA, 02139, USA

    Dwaine F. Emerich, Reginald L. Dean III & Raymond T. Bartus

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  1. Dwaine F. Emerich
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  2. Reginald L. Dean III
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  1. Cardiovascular Diseases Research Experimental Station, DuPont Pharmaceuticals Company, Route 141 & Henry Clay Road, Wilmington, DE, 19880, USA

    Giora Z. Feuerstein

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Emerich, D.F., Dean, R.L., Bartus, R.T. (2001). Do leukocytes play a role in focal ischemia in the brain? An objective review of the literature. In: Feuerstein, G.Z. (eds) Inflammation and Stroke. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8297-2_7

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  • DOI: https://doi.org/10.1007/978-3-0348-8297-2_7

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9508-8

  • Online ISBN: 978-3-0348-8297-2

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