Vascular Inflammation in Ischemic Stroke: Adhesion Receptors Controlling Leukocyte–Endothelial Interactions

  • Stephen F. Rodrigues
  • D. Neil Granger
Part of the Springer Series in Translational Stroke Research book series (SSTSR, volume 6)


The contribution of leukocytes to the pathogenesis of ischemic stroke has been extensively studied and thoroughly documented. In this chapter, different aspects of leukocyte involvement in the lesion formation caused by ischemic stroke are highlighted, including the inflammatory agents that mediate leukocyte recruitment to the site of injury, the primary leukocyte populations that contribute to tissue damage, and the adhesion receptors that control leukocyte–endothelial cell interactions in post-ischemic brain. Agents that interfere with leukocyte recruitment in the brain are also addressed as potential therapeutic interventions for ischemic stroke.


Ischemic Stroke Middle Cerebral Artery Occlusion Infarct Volume Neutrophil Elastase Leukocyte Recruitment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ (2006) Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367:1747–57PubMedCrossRefGoogle Scholar
  2. 2.
    Strong K, Mathers C, Bonita R (2007) Preventing stroke: saving lives around the world. Lancet Neurol 6:182–7PubMedCrossRefGoogle Scholar
  3. 3.
    Murphy J (2003) Pharmacological treatment of acute ischemic stroke. Crit Care Nurs Q 26(4):276–82PubMedCrossRefGoogle Scholar
  4. 4.
    Adams HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Marler JR, Woolson RF, Zivin JA (1994) Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Circulation 90:1588–601PubMedCrossRefGoogle Scholar
  5. 5.
    Khaja AM, Grotta JC (2007) Established treatments for acute ischaemic stroke. Lancet 27:319–30CrossRefGoogle Scholar
  6. 6.
    Liesz A, Zhou W, Mracskó É, Karcher S, Bauer H, Schwarting S, Sun L, Bruder D, Stegemann S, Cerwenka A, Sommer C, Dalpke AH, Veltkamp R (2011) Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain 134:704–20PubMedCrossRefGoogle Scholar
  7. 7.
    del Zoppo GJ (2010) Acute anti-inflammatory approaches to ischemic stroke. Ann N Y Acad Sci 1207:143–8PubMedCrossRefGoogle Scholar
  8. 8.
    Yilmaz G, Granger DN (2010) Leukocyte recruitment and ischemic brain injury. Neuromolecular Med 12(2):193–204PubMedCrossRefGoogle Scholar
  9. 9.
    Ziegler G, Freyer D, Harhausen D, Khojasteh U, Nietfeld W, Trendelenburg G (2011) Blocking TLR2 in vivo protects against accumulation of inflammatory cells and neuronal injury in experimental stroke. J Cereb Blood Flow Metab 31:757–66PubMedCrossRefGoogle Scholar
  10. 10.
    Connolly ES Jr, Winfree CJ, Prestigiacomo CJ, Kim SC, Choudhri TF, Hoh BL, Naka Y, Solomon RA, Pinsky DJ (1997) Exacerbation of cerebral injury in mice that express the P-selectin gene: identification of P-selectin blockade as a new target for the treatment of stroke. Circ Res 81:304–10PubMedCrossRefGoogle Scholar
  11. 11.
    Ishikawa M, Cooper D, Arumugam TV, Zhang JH, Nanda A, Granger DN (2004) Platelet-leukocyteendothelial cell interactions after middle cerebral artery occlusion and reperfusion. J Cereb Blood Flow Metab 24:907–15PubMedCrossRefGoogle Scholar
  12. 12.
    Ren X, Akiyoshi K, Vandenbark AA, Hurn PD, Offner H (2011) Programmed death-1 pathway limits central nervous system inflammation and neurologic deficits in murine experimental stroke. Stroke 42:2578–83PubMedCrossRefGoogle Scholar
  13. 13.
    Barone FC, Schmidt DB, Hillegass LM, Price WJ, White RF, Feuerstein GZ, Clark RK, Lee EV, Griswold DE, Sarau HM (1992) Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke 23:1337–47PubMedCrossRefGoogle Scholar
  14. 14.
    Choi IY, Lee JC, Ju C, Hwang S, Cho GS, Lee HW, Choi WJ, Jeong LS, Kim WK (2011) A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. Am J Pathol 179:2042–52PubMedCrossRefGoogle Scholar
  15. 15.
    Choi JS, Park J, Suk K, Moon C, Park YK, Han HS (2011) Mild hypothermia attenuates intercellular adhesion molecule-1 induction via activation of extracellular signal-regulated kinase-1/2 in a focal cerebral ischemia model. Stroke Res Treat 2011:846716PubMedGoogle Scholar
  16. 16.
    Ritter LS, Orozco JA, Coull BM, McDonagh PF, Rosenblum WI (2000) Leukocyte accumulation and hemodynamic changes in the cerebral microcirculation during early reperfusion after stroke. Stroke 31:1153–61PubMedCrossRefGoogle Scholar
  17. 17.
    Akopov SE, Simonian NA, Grigorian GS (1996) Dynamics of polymorphonuclear leukocyte accumulation in acute cerebral infarction and their correlation with brain tissue damage. Stroke 27:1739–43PubMedCrossRefGoogle Scholar
  18. 18.
    Buck BH, Liebeskind DS, Saver JL, Bang OY, Yun SW, Starkman S, Ali LK, Kim D, Villablanca JP, Salamon N, Razinia T, Ovbiagele B (2008) Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke 39:355–60PubMedCrossRefGoogle Scholar
  19. 19.
    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 Commun 11:93–9Google Scholar
  20. 20.
    Iadecola C, Alexander M (2001) Cerebral ischemia and inflammation. Curr Opin Neurol 14:89–94PubMedCrossRefGoogle Scholar
  21. 21.
    Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT (2009) Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J 276:13–26PubMedCrossRefGoogle Scholar
  22. 22.
    Hayward NJ, Elliott PJ, Sawyer SD, Bronson RT, Bartus RT (1996) Lack of evidence for neutrophil participation during infarct formation following focal cerebral ischemia in the rat. Exp Neurol 139:188–202PubMedCrossRefGoogle Scholar
  23. 23.
    Zhang RL, Chopp M, Chen H, Garcia JH (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 Neurol Sci 125(1):3–10PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang RL, Chopp M, Li Y, Zaloga C, Jiang N, Jones ML, Miyasaka M, Ward PA (1994) Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 44:1747–51PubMedCrossRefGoogle Scholar
  25. 25.
    Brait VH, Arumugam TV, Drummond GR, Sobey CG (2012) Importance of T lymphocytes in brain injury, immunodeficiency, and recovery after cerebral ischemia. J Cereb Blood Flow Metab 32:598–611PubMedCrossRefGoogle Scholar
  26. 26.
    Clark RK, Lee EV, White RF, Jonak ZL, Feuerstein GZ, Barone FC (1994) Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue. Brain Res Bull 35:387–92PubMedCrossRefGoogle Scholar
  27. 27.
    Kriz J (2006) Inflammation in ischemic brain injury: timing is important. Crit Rev Neurobiol 18:145–57PubMedCrossRefGoogle Scholar
  28. 28.
    Yilmaz G, Arumugam TV, Stokes KY, Granger DN (2006) Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 113:2105–12PubMedCrossRefGoogle Scholar
  29. 29.
    Breckwoldt MO, Chen JW, Stangenberg L, Aikawa E, Rodriguez E, Qiu S, Moskowitz MA, Weissleder R (2008) Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase. Proc Natl Acad Sci USA 105:18584–9PubMedCrossRefGoogle Scholar
  30. 30.
    Connolly ES Jr, Winfree CJ, Springer TA, Naka Y, Liao H, Yan SD, Stern DM, Solomon RA, Gutierrez-Ramos JC, Pinsky DJ (1996) Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke. J Clin Invest 97:209–16PubMedCrossRefGoogle Scholar
  31. 31.
    Stevens SL, Bao J, Hollis J, Lessov NS, Clark WM, Stenzel-Poore MP (2002) The use of flow cytometry to evaluate temporal changes in inflammatory cells following focal cerebral ischemia in mice. Brain Res 932:110–9PubMedCrossRefGoogle Scholar
  32. 32.
    Matsuo Y, Onodera H, Shiga Y, Nakamura M, Ninomiya M, Kihara T, Kogure K (1994) Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemia brain injury in the rat. Stroke 25:1469–75PubMedCrossRefGoogle Scholar
  33. 33.
    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 656:344–52PubMedCrossRefGoogle Scholar
  34. 34.
    Barone FC, Hillegass LM, Tzimas MN, Schmidt DB, Foley JJ, White RF, Price WJ, Feuerstein GZ, Clark RK, Griswold DE et al (1995) Time related changes in myeloperoxidase activity and leukotriene B4 receptor binding reflect leukocyte influx in cerebral focal stroke. Mol Chem Neuropathol 24:13–30PubMedCrossRefGoogle Scholar
  35. 35.
    Jander S, Kraemer M, Schroeter M, Witte OW, 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 15:42–51PubMedCrossRefGoogle Scholar
  36. 36.
    Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15:192–9PubMedCrossRefGoogle Scholar
  37. 37.
    Ren X, Akiyoshi K, Vandenbark AA, Hurn PD, Offner H (2011) CD4+FoxP3+ regulatory T-cells in cerebral ischemic stroke. Metab Brain Dis 26:87–90PubMedCrossRefGoogle Scholar
  38. 38.
    Ren X, Akiyoshi K, Dziennis S, Vandenbark AA, Herson PS, Hurn PD, Offner H (2011) Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. J Neurosci 31:8556–63PubMedCrossRefGoogle Scholar
  39. 39.
    Kubes P, Suzuki M, Granger DN (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 88:4651–5PubMedCrossRefGoogle Scholar
  40. 40.
    Gidday JM, Park TS, Shah AR, Gonzales ER (1998) Modulation of basal and postischemic leukocyte-endothelial adherence by nitric oxide. Stroke 29:1423–9PubMedCrossRefGoogle Scholar
  41. 41.
    Tan J, Town T, Mori T, Obregon D, Wu Y, DelleDonne A, Rojiani A, Crawford F, Flavell RA, Mullan M (2002) CD40 is expressed and functional on neuronal cells. EMBO J 21:643–52PubMedCrossRefGoogle Scholar
  42. 42.
    Omari KM, Dorovini-Zis K (2003) CD40 expressed by human brain endothelial cells regulates CD4+ T cell adhesion to endothelium. J Neuroimmunol 134:166–78PubMedCrossRefGoogle Scholar
  43. 43.
    Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–4PubMedCrossRefGoogle Scholar
  44. 44.
    Monaco C, Andreakos E, Young S, Feldmann M, Paleolog ET (2002) Cellmediated signaling to vascular endothelium: induction of cytokines, chemokines, and tissue factor. J Leukoc Biol 71:659–68PubMedGoogle Scholar
  45. 45.
    Ishikawa M, Vowinkel T, Stokes KY, Arumugam TV, Yilmaz G, Nanda A, Granger DN (2005) CD40/CD40 ligand signaling in mouse cerebral microvasculature after focal ischemia/reperfusion. Circulation 111:1690–6PubMedCrossRefGoogle Scholar
  46. 46.
    Caolo V, Molin DG, Post MJ (2012) Notch regulation of hematopoiesis, endothelial precursor cells, and blood vessel formation: orchestrating the vasculature. Stem Cells Int 2012:805602PubMedGoogle Scholar
  47. 47.
    Chi Z, Zhang J, Tokunaga A, Harraz MM, Byrne ST, Dolinko A, Xu J, Blackshaw S, Gaiano N, Dawson TM, Dawson VL (2012) Botch promotes neurogenesis by antagonizing Notch. Dev Cell 22(4):707–20PubMedCrossRefGoogle Scholar
  48. 48.
    Arumugam TV, Chan SL, Jo DG, Yilmaz G, Tang SC, Cheng A, Gleichmann M, Okun E, Dixit VD, Chigurupati S, Mughal MR, Ouyang X, Miele L, Magnus T, Poosala S, Granger DN, Mattson MP (2006) Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke. Nat Med 12:621–3PubMedCrossRefGoogle Scholar
  49. 49.
    Carr MW, Roth SJ, Luther E, Rose SS, Springer TA (1994) Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci USA 91:3652–6PubMedCrossRefGoogle Scholar
  50. 50.
    Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–15PubMedCrossRefGoogle Scholar
  51. 51.
    Xia M, Sui Z (2009) Recent developments in CCR2 antagonists. Expert Opin Ther Pat 19:295–303PubMedCrossRefGoogle Scholar
  52. 52.
    Liu L, Kubes P (2003) Molecular mechanisms of leukocyte recruitment: organ-specific mechanisms of action. Thromb Haemost 89:213–20PubMedGoogle Scholar
  53. 53.
    Barkalow FJ, Goodman MJ, Gerritsen ME, Mayadas TN (1996) Brain endothelium lack one of two pathways of P-selectin-mediated neutrophil adhesion. Blood 88:4585–93PubMedGoogle Scholar
  54. 54.
    Granger DN, Stokes KY (2005) Differential regulation of leukocyte-endothelial cell interactions. In: Aird WC (ed) Endothelial cells in health and disease. Taylor & Francis, Boca Raton, FL, pp 229–43CrossRefGoogle Scholar
  55. 55.
    Zhang R, Chopp M, Zhang Z, Jiang N, Powers C (1998) The expression of P- and E-selectins in three models of middle cerebral artery occlusion. Brain Res 785(2):207–14PubMedCrossRefGoogle Scholar
  56. 56.
    Stanimirovic D, Shapiro A, Wong J, Hutchison J, Durkin J (1997) The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion. J Neuroimmunol 76:193–205PubMedCrossRefGoogle Scholar
  57. 57.
    Tamaru M, Tomura K, Sakamoto S, Tezuka K, Tamatani T, Narumi S (1998) Interleukin-1beta induces tissue- and cell type-specific expression of adhesion molecules in vivo. Arterioscler Thromb Vasc Biol 18(8):1292–303PubMedCrossRefGoogle Scholar
  58. 58.
    Carvalho-Tavares J, Hickey MJ, Hutchison J, Michaud J, Sutcliffe IT, Kubes P (2000) A role for platelets and endothelial selectins in tumor necrosis factor-alphainduced leukocyte recruitment in the brain microvasculature. Circ Res 87:1141–8PubMedCrossRefGoogle Scholar
  59. 59.
    Hu XM, Zhang Y, Zeng FD (2004) Effects of sodium beta-aescin on expression of adhesion molecules and migration of neutrophils after middle cerebral artery occlusion in rats. Acta Pharmacol Sin 25:869–75PubMedGoogle Scholar
  60. 60.
    Zhang RL, Chopp M, Zhang ZG, Phillips ML, Rosenbloom CL, Cruz R, Manning A (1996) E-selectin in focal cerebral ischemia and reperfusion in the rat. J Cereb Blood Flow Metab 16:1126–36PubMedCrossRefGoogle Scholar
  61. 61.
    Huang J, Choudhri TF, Winfree CJ, McTaggart RA, Kiss S, Mocco J, Kim LJ, Protopsaltis TS, Zhang Y, Pinsky DJ, Connolly ES Jr (2000) Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke. Stroke 31:3047–53PubMedCrossRefGoogle Scholar
  62. 62.
    Mocco J, Choudhri T, Huang J, Harfeldt E, Efros L, Klingbeil C, Vexler V, Hall W, Zhang Y, Mack W, Popilskis S, Pinsky DJ, Connolly ES Jr (2002) HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ Res 91:907–14PubMedCrossRefGoogle Scholar
  63. 63.
    Fassbender K, Mössner R, Motsch L, Kischka U, Grau A, Hennerici M (1995) Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke 26(8):1361–4PubMedCrossRefGoogle Scholar
  64. 64.
    Kasahara Y, Taguchi A, Uno H, Nakano A, Nakagomi T, Hirose H, Stern DM, Matsuyama T (2010) Telmisartan suppresses cerebral injury in a murine model of transient focal ischemia. Brain Res 1340:70–80PubMedCrossRefGoogle Scholar
  65. 65.
    Love S, Barber R (2001) Expression of P-selectin and intercellular adhesion molecule-1 in human brain after focal infarction or cardiac arrest. Neuropathol Appl Neurobiol 27:465–73PubMedCrossRefGoogle Scholar
  66. 66.
    Suzuki H, Abe K, Tojo SJ, Kitagawa H, Kimura K, Mizugaki M, Itoyama Y (1999) Reduction of ischemic brain injury by anti-P-selectin monoclonal antibody after permanent middle cerebral artery occlusion in rat. Neurol Res 21(3):269–76PubMedGoogle Scholar
  67. 67.
    Jin AY, Tuor UI, Rushforth D, Kaur J, Muller RN, Petterson JL, Boutry S, Barber PA (2010) Reduced blood brain barrier breakdown in P-selectin deficient mice following transient ischemic stroke: a future therapeutic target for treatment of stroke. BMC Neurosci 11:12PubMedCrossRefGoogle Scholar
  68. 68.
    Ruehl ML, Orozco JA, Stoker MB, McDonagh PF, Coull BM, Ritter LS (2002) Protective effects of inhibiting both blood and vascular selectins after stroke and reperfusion. Neurol Res 24:226–32PubMedCrossRefGoogle Scholar
  69. 69.
    Htun P, Fateh-Moghadam S, Tomandl B, Handschu R, Klinger K, Stellos K, Garlichs C, Daniel W, Gawaz M (2006) Course of platelet activation and platelet-leukocyte interaction in cerebrovascular ischemia. Stroke 37:2283–7PubMedCrossRefGoogle Scholar
  70. 70.
    Wei YS, Lan Y, Meng LQ, Nong LG (2011) The association of L-selectin polymorphisms with L-selectin serum levels and risk of ischemic stroke. J Thromb Thrombolysis 32:110–5PubMedCrossRefGoogle Scholar
  71. 71.
    Yenari MA, Sun GH, Kunis DM, Onley D, Vexler V (2001) L-selectin inhibition does not reduce injury in a rabbit model of transient focal cerebral ischemia. Neurol Res 23:72–8PubMedCrossRefGoogle Scholar
  72. 72.
    Arumugam TV, Salter JW, Chidlow JH, Ballantyne CM, Kevil CG, Granger DN (2004) Contributions of LFA-1 and Mac-1 to brain injury and microvascular dysfunction induced by transient middle cerebral artery occlusion. Am J Physiol Heart Circ Physiol 287:H2555–60PubMedCrossRefGoogle Scholar
  73. 73.
    Chen H, Chopp M, Zhang RL, Bodzin G, Chen Q, Rusche JR, Todd RF 3rd (1994) Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 35:458–63PubMedCrossRefGoogle Scholar
  74. 74.
    Fiszer U, Korczak-Kowalska G, Palasik W, Korlak J, Górski A, Członkowska A (1998) Increased expression of adhesion molecule CD18 (LFA-1beta) on the leukocytes of peripheral blood in patients with acute ischemic stroke. Acta Neurol Scand 97:221–4PubMedCrossRefGoogle Scholar
  75. 75.
    Khan M, Sekhon B, Giri S, Jatana M, Gilg AG, Ayasolla K, Elango C, Singh AK, Singh I (2005) S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke. J Cereb Blood Flow Metab 25:177–92PubMedCrossRefGoogle Scholar
  76. 76.
    Kim JS, Chopp M, Chen H, Levine SR, Carey JL, Welch KM (1995) Adhesive glycoproteins CD11a and CD18 are upregulated in the leukocytes from patients with ischemic stroke and transient ischemic attacks. J Neurol Sci 128:45–50PubMedCrossRefGoogle Scholar
  77. 77.
    Prestigiacomo CJ, Kim SC, Connolly ES Jr, Liao H, Yan SF, Pinsky DJ (1999) CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke. Stroke 30:1110–7PubMedCrossRefGoogle Scholar
  78. 78.
    Soriano SG, Coxon A, Wang YF, Frosch MP, Lipton SA, Hickey PR, Mayadas TN (1999) Mice deficient in Mac-1 (CD11b/CD18) are less susceptible to cerebral ischemia/reperfusion injury. Stroke 30:134–9PubMedCrossRefGoogle Scholar
  79. 79.
    Okada Y, Copeland BR, Mori E, Tung MM, Thomas WS, del Zoppo GJ (1994) P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion. Stroke 25:202–11PubMedCrossRefGoogle Scholar
  80. 80.
    Lindsberg PJ, Carpén O, Paetau A, Karjalainen-Lindsberg ML, Kaste M (1996) Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 94:939–45PubMedCrossRefGoogle Scholar
  81. 81.
    Chen H, Song YS, Chan PH (2009) Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion. J Cereb Blood Flow Metab 29:1262–72PubMedCrossRefGoogle Scholar
  82. 82.
    Ding YH, Young CN, Luan X, Li J, Rafols JA, Clark JC, McAllister JP 2nd, Ding Y (2005) Exercise preconditioning ameliorates inflammatory injury in ischemic rats during reperfusion. Acta Neuropathol 109:237–46PubMedCrossRefGoogle Scholar
  83. 83.
    Zhang RL, Zhang ZG, Chopp M, Zivin JA (1999) Thrombolysis with tissue plasminogen activator alters adhesion molecule expression in the ischemic rat brain. Stroke 30:624–9PubMedCrossRefGoogle Scholar
  84. 84.
    Zhang RL, Zhang ZG, Chopp M (1999) Increased therapeutic efficacy with rt-PA and anti-CD18 antibody treatment of stroke in the rat. Neurology 52:273–9PubMedCrossRefGoogle Scholar
  85. 85.
    Vemuganti R, Dempsey RJ, Bowen KK (2004) Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 35:179–84PubMedCrossRefGoogle Scholar
  86. 86.
    Brait VH, Jackman KA, Walduck AK, Selemidis S, Diep H, Mast AE, Guida E, Broughton BR, Drummond GR, Sobey CG (2010) Mechanisms contributing to cerebral infarct size after stroke: gender, reperfusion, T lymphocytes, and Nox2-derived superoxide. J Cereb Blood Flow Metab 30:1306–17PubMedCrossRefGoogle Scholar
  87. 87.
    Hoyte LC, Brooks KJ, Nagel S, Akhtar A, Chen R, Mardiguian S, McAteer MA, Anthony DC, Choudhury RP, Buchan AM, Sibson NR (2010) Molecular magnetic resonance imaging of acute vascular cell adhesion molecule-1 expression in a mouse model of cerebral ischemia. J Cereb Blood Flow Metab 30:1178–87PubMedCrossRefGoogle Scholar
  88. 88.
    Wang J, Zhao Y, Liu C, Jiang C, Zhao C, Zhu Z (2011) Progesterone inhibits inflammatory response pathways after permanent middle cerebral artery occlusion in rats. Mol Med Rep 4:319–24PubMedGoogle Scholar
  89. 89.
    Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM (1994) Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 25:1794–8PubMedCrossRefGoogle Scholar
  90. 90.
    Justicia C, Martín A, Rojas S, Gironella M, Cervera A, Panés J, Chamorro A, Planas AM (2006) Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice. J Cereb Blood Flow Metab 26:421–32PubMedCrossRefGoogle Scholar
  91. 91.
    Petrovic-Djergovic D, Hyman MC, Ray JJ, Bouis D, Visovatti SH, Hayasaki T, Pinsky DJ (2012) Tissue-resident ecto-5′ nucleotidase (CD73) regulates leukocyte trafficking in the ischemic brain. J Immunol 188(5):2387–98PubMedCrossRefGoogle Scholar
  92. 92.
    Jin G, Tsuji K, Xing C, Yang YG, Wang X, Lo EH (2009) CD47 gene knockout protects against transient focal cerebral ischemia in mice. Exp Neurol 217:165–70PubMedCrossRefGoogle Scholar
  93. 93.
    Wang X, Xu L, Wang H, Zhan Y, Puré E, Feuerstein GZ (2002) CD44 deficiency in mice protects brain from cerebral ischemia injury. J Neurochem 83:1172–9PubMedCrossRefGoogle Scholar
  94. 94.
    Airas L, Lindsberg PJ, Karjalainen-Lindsberg ML, Mononen I, Kotisaari K, Smith DJ, Jalkanen S (2008) Vascular adhesion protein-1 in human ischaemic stroke. Neuropathol Appl Neurobiol 34:394–402PubMedCrossRefGoogle Scholar
  95. 95.
    Kim JB, Sig Choi J, Yu YM, Nam K, Piao CS, Kim SW, Lee MH, Han PL, Park JS, Lee JK (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26:6413–21PubMedCrossRefGoogle Scholar
  96. 96.
    Fujioka M, Nakano T, Hayakawa K, Irie K, Akitake Y, Sakamoto Y, Mishima K, Muroi C, Yonekawa Y, Banno F, Kokame K, Miyata T, Nishio K, Okuchi K, Iwasaki K, Fujiwara M, Siesjö BK (2012) ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury. Neurol Sci 33:1107–15PubMedCrossRefGoogle Scholar
  97. 97.
    Kim ID, Shin JH, Lee HK, Jin YC, Lee JK (2012) Intranasal delivery of HMGB1-binding heptamer peptide confers a robust neuroprotection in the postischemic brain. Neurosci Lett 525:179–83PubMedCrossRefGoogle Scholar
  98. 98.
    Cao CX, Yang QW, Lv FL, Cui J, Fu HB, Wang JZ (2007) Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun 353:509–14PubMedCrossRefGoogle Scholar
  99. 99.
    Yang QW, Li JC, Lu FL, Wen AQ, Xiang J, Zhang LL, Huang ZY, Wang JZ (2008) Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. J Cereb Blood Flow Metab 28:1588–96PubMedCrossRefGoogle Scholar
  100. 100.
    Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I, Sekiya T, Ooboshi H, Kitazono T, Yanagawa T, Ishii T, Takahashi H, Mori S, Nishibori M, Kuroda K, Akira S, Miyake K, Yoshimura A (2012) Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 18:911–7PubMedCrossRefGoogle Scholar
  101. 101.
    Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 15:946–50PubMedCrossRefGoogle Scholar
  102. 102.
    Terao S, Yilmaz G, Stokes KY, Russell J, Ishikawa M, Kawase T, Granger DN (2008) Blood cell-derived RANTES mediates cerebral microvascular dysfunction, inflammation, and tissue injury after focal ischemia-reperfusion. Stroke 39:2560–70PubMedCrossRefGoogle Scholar
  103. 103.
    Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29:1020–30PubMedCrossRefGoogle Scholar
  104. 104.
    Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, Chan PH, Park TS (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289:H558–68PubMedCrossRefGoogle Scholar
  105. 105.
    Belaaouaj A, Kim KS, Shapiro SD (2000) Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase. Science 289:1185–8PubMedCrossRefGoogle Scholar
  106. 106.
    Hermant B, Bibert S, Concord E, Dublet B, Weidenhaupt M, Vernet T, Gulino-Debrac D (2003) Identification of proteases involved in the proteolysis of vascular endothelium cadherin during neutrophil transmigration. J Biol Chem 278:14002–12PubMedCrossRefGoogle Scholar
  107. 107.
    Ishikawa N, Oda M, Kawaguchi M, Tsunezuka Y, Watanabe G (2003) The effects of a specific neutrophil elastase inhibitor (ONO-5046) in pulmonary ischemia-reperfusion injury. Transpl Int 16:341–6PubMedCrossRefGoogle Scholar
  108. 108.
    Ikegame Y, Yamashita K, Hayashi S, Yoshimura S, Nakashima S, Iwama T (2010) Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema. Hypertens Res 33:703–7PubMedCrossRefGoogle Scholar
  109. 109.
    Frenkel D, Huang Z, Maron R, Koldzic DN, Moskowitz MA, Weiner HL (2005) Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke. J Neurol Sci 233:125–32PubMedCrossRefGoogle Scholar
  110. 110.
    Goussev AV, Zhang Z, Anderson DC, Chopp M (1998) P-selectin antibody reduces hemorrhage and infarct volume resulting from MCA occlusion in the rat. J Neurosci 161:16–22Google Scholar
  111. 111.
    Morikawa E, Zhang SM, Seko Y, Toyoda T, Kirino T (1996) Treatment of focal cerebral ischemia with synthetic oligopeptide corresponding to lectin domain of selectin. Stroke 27:951–5PubMedCrossRefGoogle Scholar
  112. 112.
    Takeda H, Spatz M, Ruetzler C, McCarron R, Becker K, Hallenbeck J (2002) Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats. Stroke 33:2156–63PubMedCrossRefGoogle Scholar
  113. 113.
    Ishibashi S, Maric D, Mou Y, Ohtani R, Ruetzler C, Hallenbeck JM (2009) Mucosal tolerance to E-selectin promotes the survival of newly generated neuroblasts via regulatory T-cell induction after stroke in spontaneously hypertensive rats. J Cereb Blood Flow Metab 29:606–20PubMedCrossRefGoogle Scholar
  114. 114.
    Yenari MA, Kunis D, Sun GH, Onley D, Watson L, Turner S, Whitaker S, Steinberg GK (1998) Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia. Exp Neurol 153(2):223–33PubMedCrossRefGoogle Scholar
  115. 115.
    Bednar MM, Wright SD, Raymond-Russell SJ, Kohut JJ, Gross CE (1996) IB4, a monoclonal antibody against the CD18 leukocyte adhesion protein, reduces intracranial pressure following thromboembolic stroke in the rabbit. Neurol Res 18:171–5PubMedGoogle Scholar
  116. 116.
    Mori E, del Zoppo GJ, Chambers JD, Copeland BR, Arfors KE (1992) Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 23:712–8PubMedCrossRefGoogle Scholar
  117. 117.
    Zhang L, Zhang ZG, Zhang RL, Lu M, Krams M, Chopp M (2003) Effects of a selective CD11b/CD18 antagonist and recombinant human tissue plasminogen activator treatment alone and in combination in a rat embolic model of stroke. Stroke 34:1790–5PubMedCrossRefGoogle Scholar
  118. 118.
    Becker KJ (2002) Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6.5) in acute stroke. Curr Med Res Opin 18:18–22CrossRefGoogle Scholar
  119. 119.
    Jiang N, Chopp M, Chahwala S (1998) Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat. Brain Res 788:25–34PubMedCrossRefGoogle Scholar
  120. 120.
    Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA, ASTIN Study Investigators (2003) Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke 34(11):2543–8PubMedCrossRefGoogle Scholar
  121. 121.
    Jones R (2000) Rovelizumab (ICOS Corp). IDrugs 3:442–6PubMedGoogle Scholar
  122. 122.
    Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM, Anderson DC (1995) Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 26:1438–42, discussion 1443PubMedCrossRefGoogle Scholar
  123. 123.
    Bowes MP, Rothlein R, Fagan SC, Zivin JA (1995) Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurology 45:815–9PubMedCrossRefGoogle Scholar
  124. 124.
    Enlimomab Acute Stroke Trial Investigators (2001) Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57:1428–34CrossRefGoogle Scholar
  125. 125.
    Furuya K, Takeda H, Azhar S, McCarron RM, Chen Y, Ruetzler CA, Wolcott KM, DeGraba TJ, Rothlein R, Hugli TE, del Zoppo GJ, Hallenbeck JM (2001) Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine anti-human intercellular adhesion molecule-1 antibody: a bedside-to-bench study. Stroke 32:2665–74PubMedCrossRefGoogle Scholar
  126. 126.
    Vuorte J, Lindsberg PJ, Kaste M, Meri S, Jansson SE, Rothlein R, Repo H (1999) Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in whole blood. J Immunol 162(4):2353–7PubMedGoogle Scholar
  127. 127.
    Barone FC, Feuerstein GZ (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19(8):819–34Google Scholar
  128. 128.
    Arumugam TV, Cheng YL, Choi Y, Choi YH, Yang S, Yun YK, Park JS, Yang DK, Thundyil J, Gelderblom M, Karamyan VT, Tang SC, Chan SL, Magnus T, Sobey CG, Jo DG (2011) Evidence that gamma-secretase-mediated Notch signaling induces neuronal cell death via the nuclear factor-kappaB-Bcl-2-interacting mediator of cell death pathway in ischemic stroke. Mol Pharmacol 80(1):23–31Google Scholar
  129. 129.
    Schilling M, Strecker JK, Schäbitz WR, Ringelstein EB, Kiefer R (2009) Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice. Neuroscience 161(3):806–12Google Scholar
  130. 130.
    Wang H, Zhan Y, Xu L, Feuerstein GZ, Wang X (2001) Use of suppression subtractive hybridization for differential gene expression in stroke: discovery of CD44 gene expression and localization in permanent focal stroke in rats. Stroke 32(4):1020–7Google Scholar
  131. 131.
    Gidday JM, Park TS, Gonzales ER, Beetsch JW (1997) CD18-dependent leukocyte adherence and vascular injury in pig cerebral circulation after ischemia. Am J Physiol 272(6 Pt 2):H2622–9Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Clinical and Toxicological AnalysesUniversity of Sao PauloSao PauloBrazil
  2. 2.Molecular and Cellular PhysiologyLouisiana State University Health Sciences CenterBaton RougeUSA

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