Targeting neutrophils in ischemic stroke: Translational insights from experimental studies

Journal of Cerebral Blood Flow and Metabolism

Volumn 35, Issue 6, 2015, Pages 888-901

  Jickling, Glen C ^a   Liu, DaZhi ^a   Ander, Bradley P ^a   Stamova, Boryana ^a   Zhan, Xinhua ^a   Sharp, Frank R ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

atherosclerosis; cerebral ischemia; immune system; neutrophil; stroke; thrombus

Indexed keywords

CD11B ANTIGEN; CHEMOKINE; CYTOKINE; GELATINASE B; INTERCELLULAR ADHESION MOLECULE 1; LEUKOCYTE ELASTASE; LYMPHOCYTE FUNCTION ASSOCIATED ANTIGEN 1; OXIDIZED LOW DENSITY LIPOPROTEIN; REACTIVE OXYGEN METABOLITE; SELECTIN; TOLL LIKE RECEPTOR;

APOPTOSIS; ATHEROSCLEROSIS; BLOOD BRAIN BARRIER; BLOOD CLOTTING; BRAIN EDEMA; BRAIN INFARCTION SIZE; BRAIN INJURY; BRAIN ISCHEMIA; CELL ADHESION; CELL DAMAGE; CELL MIGRATION; CEREBROVASCULAR ACCIDENT; EXPERIMENTAL STUDY; EXTRACELLULAR TRAP; HUMAN; LEUKOCYTE ACTIVATION; MICROGLIA; NEUROPROTECTION; NEUTROPHIL; NEUTROPHIL COUNT; NONHUMAN; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; TARGET CELL; THROMBOCYTE AGGREGATION; ANIMAL; BRAIN; COMPLICATION; IMMUNOLOGY; PATHOLOGY; STROKE; THROMBOSIS;

ANIMALS; ATHEROSCLEROSIS; BRAIN; BRAIN ISCHEMIA; HUMANS; NEUTROPHILS; STROKE; THROMBOSIS;

EID: 84930179351     PISSN: 0271678X     EISSN: 15597016     Source Type: Journal    
DOI: 10.1038/jcbfm.2015.45     Document Type: Review

References (160)

1. Segel GB, Halterman MW, Lichtman MA. The paradox of the neutrophil's role in tissue injury. J Leukoc Biol 2011; 89: 359-372.
2. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13: 159-175.
3. Ruf W, Ruggeri ZM. Neutrophils release brakes of coagulation. Nat Med 2010; 16: 851-852.
4. Carbone F, Nencioni A, Mach F, Vuilleumier N, Montecucco F. Pathophysiological role of neutrophils in acute myocardial infarction. Thromb Haemost 2013; 110: 501-514.
5. Mocsai A. Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med 2013; 210: 1283-1299.
6. Ross AM, Hurn P, Perrin N, Wood L, Carlini W, Potempa K. Evidence of the peripheral inflammatory response in patients with transient ischemic attack. J Stroke Cerebrovasc Dis 2007; 16: 203-207.
7. Kim J, Song TJ, Park JH, Lee HS, Nam CM, Nam HS et al. Different prognostic value of white blood cell subtypes in patients with acute cerebral infarction. Atherosclerosis 2012; 222: 464-467.
8. Buck BH, Liebeskind DS, Saver JL, Bang OY, Yun SW, Starkman S et al. Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke 2008; 39: 355-360.
9. Kumar AD, Boehme AK, Siegler JE, Gillette M, Albright KC, Martin-Schild S. Leukocytosis in patients with neurologic deterioration after acute ischemic stroke is associated with poor outcomes. J Stroke Cerebrovasc Dis 2012; 22: e111-e117.
10. Gokhan S, Ozhasenekler A, Mansur Durgun H, Akil E, Ustundag M, Orak M. Neutrophil lymphocyte ratios in stroke subtypes and transient ischemic attack. Eur Rev Med Pharmacol Sci 2013; 17: 653-657.
11. Tsai NW, Chang WN, Shaw CF, Jan CR, Lu CH. Leucocyte apoptosis in patients with acute ischaemic stroke. Clin Exp Pharmacol Physiol 2010; 37: 884-888.
12. Kataoka H, Kim SW, Plesnila N. Leukocyte-endothelium interactions during permanent focal cerebral ischemia in mice. J Cereb Blood Flow Metab 2004; 24: 668-676.
13. Hallenbeck JM, Dutka AJ, Tanishima T, Kochanek PM, Kumaroo KK, Thompson CB et al. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 1986; 17: 246-253.
14. Garcia JH, Liu KF, Yoshida Y, Lian J, Chen S, del Zoppo GJ. Influx of leukocytes and platelets in an evolving brain infarct (Wistar rat). Am J Pathol 1994; 144: 188-199.
15. Watcharotayangul J, Mao L, Xu H, Vetri F, Baughman VL, Paisansathan C et al. Post-ischemic vascular adhesion protein-1 inhibition provides neuroprotection in a rat temporary middle cerebral artery occlusion model. J Neurochem 2012; 123: 116-124.
16. Barone FC, Hillegass LM, Tzimas MN, Schmidt DB, Foley JJ, White RF et al. Timerelated changes in myeloperoxidase activity and leukotriene B4 receptor binding reflect leukocyte influx in cerebral focal stroke. Mol Chem Neuropathol 1995; 24: 13-30.
17. Tu XK, Yang WZ, Shi SS, Wang CH, Zhang GL, Ni TR et al. Spatio-Temporal distribution of inflammatory reaction and expression of TLR2/4 signaling pathway in rat brain following permanent focal cerebral ischemia. Neurochem Res 2010; 35: 1147-1155.
18. Akopov SE, Simonian NA, Grigorian GS. Dynamics of polymorphonuclear leukocyte accumulation in acute cerebral infarction and their correlation with brain tissue damage. Stroke 1996; 27: 1739-1743.
19. Emerich DF, Dean RL, 3rd, Bartus RT. The role of leukocytes following cerebral ischemia: pathogenic variable or bystander reaction to emerging infarct? Exp Neurol 2002; 173: 168-181.
20. Dimasi D, Sun WY, Bonder CS. Neutrophil interactions with the vascular endothelium. Int Immunopharmacol 2013; 17: 1167-1175.
21. Eash KJ, Greenbaum AM, Gopalan PK, Link DC. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest 2010; 120: 2423-2431.
22. Sadik CD, Kim ND, Luster AD. Neutrophils cascading their way to inflammation. Trends Immunol 2011; 32: 452-460.
23. Sanz MJ, Kubes P. Neutrophil-Active chemokines in in vivo imaging of neutrophil trafficking. Eur J Immunol 2012; 42: 278-283.
24. Losy J, Zaremba J, Skrobanski P. CXCL1 (GRO-Alpha) chemokine in acute ischaemic stroke patients. Folia Neuropathol 2005; 43: 97-102.
25. Zaremba J, Skrobanski P, Losy J. The level of chemokine CXCL5 in the cerebrospinal fluid is increased during the first 24 hours of ischaemic stroke and correlates with the size of early brain damage. Folia Morphol (Warsz) 2006; 65: 1-5.
26. Reichel CA, Khandoga A, Anders HJ, Schlondorff D, Luckow B, Krombach F. Chemokine receptors Ccr1, Ccr2, and Ccr5 mediate neutrophil migration to postischemic tissue. J Leukoc Biol 2006; 79: 114-122.
27. Copin JC, da Silva RF, Fraga-Silva RA, Capettini L, Quintao S, Lenglet S et al. Treatment with Evasin-3 reduces atherosclerotic vulnerability for ischemic stroke, but not brain injury in mice. J Cereb Blood Flow Metab 2013; 33: 490-498.
28. Villa P, Triulzi S, Cavalieri B, Di Bitondo R, Bertini R, Barbera S et al. The interleukin-8 (IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-Term inflammation in permanent and transient cerebral ischemia in rats. Mol Med 2007; 13: 125-133.
29. Brait VH, Rivera J, Broughton BR, Lee S, Drummond GR, Sobey CG. Chemokinerelated gene expression in the brain following ischemic stroke: no role for CXCR2 in outcome. Brain Res 2011; 1372: 169-179.
30. Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV. Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 2007; 38: 1345-1353.
31. Dewas C, Dang PM, Gougerot-Pocidalo MA, El-Benna J. TNF-Alpha induces phosphorylation of p47(phox) in human neutrophils: partial phosphorylation of p47phox is a common event of priming of human neutrophils by TNF-Alpha and granulocyte-macrophage colony-stimulating factor. J Immunol 2003; 171: 4392-4398.
32. Lambertsen KL, Biber K, Finsen B. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab 2012; 32: 1677-1698.
33. Rothwell N. Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav Immun 2003; 17: 152-157.
34. Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005; 76: 1366-1372.
35. Lavine SD, Hofman FM, Zlokovic BV. Circulating antibody against tumor necrosis factor-Alpha protects rat brain from reperfusion injury. J Cereb Blood Flow Metab 1998; 18: 52-58.
36. Gary DS, Bruce-Keller AJ, Kindy MS, Mattson MP. Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J Cereb Blood Flow Metab 1998; 18: 1283-1287.
37. Rane MJ, Gozal D, Butt W, Gozal E, Pierce WM, Jr., Guo SZ et al. Gamma-Amino butyric acid type B receptors stimulate neutrophil chemotaxis during ischemia-reperfusion. J Immunol 2005; 174: 7242-7249.
38. Prince LR, Whyte MK, Sabroe I, Parker LC. The role of TLRs in neutrophil activation. Curr Opin Pharmacol 2011; 11: 397-403.
39. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464: 104-107.
40. Shichita T, Hasegawa E, Kimura A, Morita R, Sakaguchi R, Takada I et al. Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat Med 2012; 18: 911-917.
41. Hayakawa K, Mishima K, Irie K, Hazekawa M, Mishima S, Fujioka M et al. Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism. Neuropharmacology 2008; 55: 1280-1286.
42. Brea D, Blanco M, Sobrino T, Ramos-Cabrer P, Castillo J. [The levels of expression of toll-like receptors 2 and 4 in neutrophils are associated with the prognosis of ischaemic stroke patients]. Rev Neurol 2011; 52: 12-19.
43. Kilic U, Kilic E, Matter CM, Bassetti CL, Hermann DM. TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. Neurobiol Dis 2008; 31: 33-40.
44. Lindsberg PJ, Siren AL, Feuerstein GZ, Hallenbeck JM. Antagonism of neutrophil adherence in the deteriorating stroke model in rabbits. J Neurosurg 1995; 82: 269-277.
45. Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM et al. Antiintercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 1995; 26: 1438-1442, discussion 1443.
46. Kitagawa K, Matsumoto M, Mabuchi T, Yagita Y, Ohtsuki T, Hori M et al. Deficiency of intercellular adhesion molecule 1 attenuates microcirculatory disturbance and infarction size in focal cerebral ischemia. J Cereb Blood Flow Metab 1998; 18: 1336-1345.
47. Enlimomab Acute Stroke Trial Investigators. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 2001; 57: 1428-1434.
48. Becker KJ. Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6.5) in acute stroke. Curr Med Res Opin 2002; 18: s18-s22.
49. Furuya K, Takeda H, Azhar S, McCarron RM, Chen Y, Ruetzler CA et al. 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 2001; 32: 2665-2674.
50. Soriano SG, Coxon A, Wang YF, Frosch MP, Lipton SA, Hickey PR et al. Mice deficient in Mac-1 (CD11b/CD18) are less susceptible to cerebral ischemia/ reperfusion injury. Stroke 1999; 30: 134-139.
51. Yenari MA, Kunis D, Sun GH, Onley D, Watson L, Turner S et al. Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia. Exp Neurol 1998; 153: 223-233.
52. Jiang N, Moyle M, Soule HR, Rote WE, Chopp M. Neutrophil inhibitory factor is neuroprotective after focal ischemia in rats. Ann Neurol 1995; 38: 935-942.
53. Zhang L, Zhang ZG, Zhang RL, Lu M, Krams M, Chopp M. 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 2003; 34: 1790-1795.
54. Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279, 276 in acute ischemic stroke. Stroke 2003; 34: 2543-2548.
55. Mocco J, Choudhri T, Huang J, Harfeldt E, Efros L, Klingbeil C et al. HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ Res 2002; 91: 907-914.
56. Huang J, Choudhri TF, Winfree CJ, McTaggart RA, Kiss S, Mocco J et al. Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke. Stroke 2000; 31: 3047-3053.
57. Jin AY, Tuor UI, Rushforth D, Kaur J, Muller RN, Petterson JL et al. Reduced blood brain barrier breakdown in P-selectin deficient mice following transient ischemic stroke: a future therapeutic target for treatment of stroke. BMC Neurosci 2010; 11: 12.
58. Bargatze RF, Kurk S, Butcher EC, Jutila MA. Neutrophils roll on adherent neutrophils bound to cytokine-induced endothelial cells via L-selectin on the rolling cells. J Exp Med 1994; 180: 1785-1792.
59. Bednar MM, Gross CE, Russell SR, Fuller SP, Ellenberger CL, Schindler E et al. Humanized anti-L-selectin monoclonal antibody DREG200 therapy in acute thromboembolic stroke. Neurol Res 1998; 20: 403-408.
60. Jin G, Tsuji K, Xing C, Yang YG, Wang X, Lo EH. CD47 gene knockout protects against transient focal cerebral ischemia in mice. Exp Neurol 2009; 217: 165-170.
61. Petrovic-Djergovic D, Hyman MC, Ray JJ, Bouis D, Visovatti SH, Hayasaki T et al. Tissue-resident ecto-5' nucleotidase (CD73) regulates leukocyte trafficking in the ischemic brain. J Immunol 2012; 188: 2387-2398.
62. Chou WH, Choi DS, Zhang H, Mu D, McMahon T, Kharazia VN et al. Neutrophil protein kinase Cdelta as a mediator of stroke-reperfusion injury. J Clin Invest 2004; 114: 49-56.
63. Gangaraju S, Sultan K, Whitehead SN, Nilchi L, Slinn J, Li X et al. Cerebral endothelial expression of Robo1 affects brain infiltration of polymorphonuclear neutrophils during mouse stroke recovery. Neurobiol Dis 2013; 54: 24-31.
64. Allen C, Thornton P, Denes A, McColl BW, Pierozynski A, Monestier M et al. Neutrophil cerebrovascular transmigration triggers rapid neurotoxicity through release of proteases associated with decondensed DNA. J Immunol 2012; 189: 381-392.
65. Enzmann G, Mysiorek C, Gorina R, Cheng YJ, Ghavampour S, Hannocks MJ et al. The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol 2013; 125: 395-412.
66. Petrault O, Ouk T, Gautier S, Laprais M, Gele P, Bastide M et al. Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion. Br J Pharmacol 2005; 144: 1051-1058.
67. Fernandez-Cadenas I, Rio-Espinola AD, Domingues-Montanari S, Mendioroz M, Fernandez-Morales J, Penalba A et al. Genes involved in hemorrhagic transformations that follow recombinant t-PA treatment in stroke patients. Pharmacogenomics 2013; 14: 495-504.
68. Gautier S, Ouk T, Petrault O, Caron J, Bordet R. Neutrophils contribute to intracerebral haemorrhages after treatment with recombinant tissue plasminogen activator following cerebral ischaemia. Br J Pharmacol 2009; 156: 673-679.
69. McColl BW, Rothwell NJ, Allan SM. Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1-And neutrophil-dependent mechanisms. J Neurosci 2007; 27: 4403-4412.
70. Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab 1999; 19: 624-633.
71. Kelly PJ, Morrow JD, Ning M, Koroshetz W, Lo EH, Terry E et al. Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study. Stroke 2008; 39: 100-104.
72. Tang Y, Xu H, Du X, Lit L, Walker W, Lu A et al. Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study. J Cereb Blood Flow Metab 2006; 26: 1089-1102.
73. Stamova B, Xu H, Jickling G, Bushnell C, Tian Y, Ander BP et al. Gene expression profiling of blood for the prediction of ischemic stroke. Stroke 2010; 41: 2171-2177.
74. Castellanos M, Sobrino T, Millan M, Garcia M, Arenillas J, Nombela F et al. Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory study. Stroke 2007; 38: 1855-1859.
75. Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 2008; 39: 1121-1126.
76. Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD et al. Leukocytederived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 2005; 289: H558-H568.
77. Wang G, Guo Q, Hossain M, Fazio V, Zeynalov E, Janigro D et al. Bone marrowderived cells are the major source of MMP-9 contributing to blood-brain barrier dysfunction and infarct formation after ischemic stroke in mice. Brain Res 2009; 1294: 183-192.
78. Ludewig P, Sedlacik J, Gelderblom M, Bernreuther C, Korkusuz Y, Wagener C et al. CEACAM1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke. Circ Res 2013; 113: 1013-1022.
79. Lapchak PA. Hemorrhagic transformation following ischemic stroke: significance, causes, and relationship to therapy and treatment. Curr Neurol Neurosci Rep 2002; 2: 38-43.
80. Fan X, Lo EH, Wang X. Effects of minocycline plus tissue plasminogen activator combination therapy after focal embolic stroke in type 1 diabetic rats. Stroke 2013; 44: 745-752.
81. Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 2006; 12: 441-445.
82. Gautier S, Ouk T, Tagzirt M, Lefebvre C, Laprais M, Petrault O et al. Impact of the neutrophil response to granulocyte colony-stimulating factor on the risk of hemorrhage when used in combination with tissue plasminogen activator during the acute phase of experimental stroke. J Neuroinflammation 2014; 11: 96.
83. Ikegame Y, Yamashita K, Hayashi S, Yoshimura S, Nakashima S, Iwama T. Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema. Hypertens Res 2010; 33: 703-707.
84. Stowe AM, Adair-Kirk TL, Gonzales ER, Perez RS, Shah AR, Park TS et al. Neutrophil elastase and neurovascular injury following focal stroke and reperfusion. Neurobiol Dis 2009; 35: 82-90.
85. Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-Associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab 2001; 21: 1393-1400.
86. Chen H, Song YS, Chan PH. Inhibition of NADPH oxidase is neuroprotective after ischemia-reperfusion. J Cereb Blood Flow Metab 2009; 29: 1262-1272.
87. Tang XN, Zheng Z, Giffard RG, Yenari MA. Significance of marrow-derived nicotinamide adenine dinucleotide phosphate oxidase in experimental ischemic stroke. Ann Neurol 2011; 70: 606-615.
88. Lapchak PA, Araujo DM, Song D, Wei J, Purdy R, Zivin JA. Effects of the spin trap agent disodium-[tert-butylimino)methyl]benzene-1, 3-disulfonate N-oxide (generic NXY-059) on intracerebral hemorrhage in a rabbit Large clot embolic stroke model: combination studies with tissue plasminogen activator. Stroke 2002; 33: 1665-1670.
89. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007; 357: 562-571.
90. Asahi M, Asahi K, Wang X, Lo EH. Reduction of tissue plasminogen activatorinduced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2000; 20: 452-457.
91. Lapchak PA, Chapman DF, Zivin JA. Pharmacological effects of the spin trap agents N-T-butyl-phenylnitrone (PBN) and 2, 2, 6, 6-Tetramethylpiperidine-N-oxyl (TEMPO) in a rabbit thromboembolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 2001; 32: 147-153.
92. Yamashita T, Kamiya T, Deguchi K, Inaba T, Zhang H, Shang J et al. Dissociation and protection of the neurovascular unit after thrombolysis and reperfusion in ischemic rat brain. J Cereb Blood Flow Metab 2009; 29: 715-725.
93. Mishina M, Komaba Y, Kobayashi S, Kominami S, Fukuchi T, Mizunari T et al. Administration of free radical scavenger edaravone associated with higher frequency of hemorrhagic transformation in patients with cardiogenic embolism. Neurol Med Chir (Tokyo) 2008; 48: 292-297.
94. Matsubara M, Akizuki O, Ikeda J, Saeki K, Yao K, Sasaki K. Benidipine, an antihypertensive drug, inhibits reactive oxygen species production in polymorphonuclear leukocytes and oxidative stress in salt-loaded stroke-prone spontaneously hypertensive rats. Eur J Pharmacol 2008; 58s0: 201-213.
95. Jickling GC, Liu D, Stamova B, Ander BP, Zhan X, Lu A et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab 2014; 34: 185-199.
96. Dirnagl U. Pathobiology of injury after stroke: the neurovascular unit and beyond. Ann NY Acad Sci 2012; 1268: 21-25.
97. McColl BW, Rothwell NJ, Allan SM. Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci 2008; 28: 9451-9462.
98. Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol 2012; 5: 354-366.
99. Christoffersson G, Vagesjo E, Vandooren J, Liden M, Massena S, Reinert RB et al. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue. Blood 2012; 120: 4653-4662.
100. Cauwe B, Martens E, Proost P, Opdenakker G. Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase B/MMP-9 substrates. Integr Biol (Camb) 2009; 1: 404-426.
101. Taichman NS, Young S, Cruchley AT, Taylor P, Paleolog E. Human neutrophils secrete vascular endothelial growth factor. J Leukoc Biol 1997; 62: 397-400.
102. Gong Y, Koh DR. Neutrophils promote inflammatory angiogenesis via release of preformed VEGF in an in vivo corneal model. Cell Tissue Res 2010; 339: 437-448.
103. Cuartero MI, Ballesteros I, Moraga A, Nombela F, Vivancos J, Hamilton JA et al. N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARgamma agonist rosiglitazone. Stroke 2013; 44: 3498-3508.
104. Easton AS. Neutrophils and stroke-Can neutrophils mitigate disease in the central nervous system? Int Immunopharmacol 2013; 17: 1218-1225.
105. Harris AK, Ergul A, Kozak A, Machado LS, Johnson MH, Fagan SC. Effect of neutrophil depletion on gelatinase expression, edema formation and hemorrhagic transformation after focal ischemic stroke. BMC Neurosci 2005; 6: 49.
106. Moriya Y, Mizuma A, Uesugi T, Ohnuki Y, Nagata E, Takahashi W et al. Phase I study of intravenous low-dose granulocyte colony-stimulating factor in acute and subacute ischemic stroke. J Stroke Cerebrovasc Dis 2012; 22: 1088-1097.
107. Schabitz WR, Laage R, Vogt G, Koch W, Kollmar R, Schwab S et al. AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 2010; 41: 2545-2551.
108. Gelderblom M, Weymar A, Bernreuther C, Velden J, Arunachalam P, Steinbach K et al. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood 2012; 120: 3793-3802.
109. Ren X, Akiyoshi K, Dziennis S, Vandenbark AA, Herson PS, Hurn PD et al. Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. J Neurosci 2011; 31: 8556-8563.
110. Soehnlein O, Lindbom L. Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol 2010; 10: 427-439.
111. Soehnlein O, Zernecke A, Eriksson EE, Rothfuchs AG, Pham CT, Herwald H et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood 2008; 112: 1461-1471.
112. Wu TH, Chien KL, Lin HJ, Hsu HC, Su TC, Chen MF et al. Total white blood cell count or neutrophil count predict ischemic stroke events among adult Taiwanese: report from a community-based cohort study. BMC Neurol 2013; 13: 7.
113. Zia E, Melander O, Bjorkbacka H, Hedblad B, Engstrom G. Total and differential leucocyte counts in relation to incidence of stroke subtypes and mortality: a prospective cohort study. J Intern Med 2012; 272: 298-304.
114. Grau AJ, Boddy AW, Dukovic DA, Buggle F, Lichy C, Brandt T et al. Leukocyte count as an independent predictor of recurrent ischemic events. Stroke 2004; 35: 1147-1152.
115. Ertas G, Sonmez O, Turfan M, Kul S, Erdogan E, Tasal A et al. Neutrophil/lymphocyte ratio is associated with thromboembolic stroke in patients with nonvalvular atrial fibrillation. J Neurol Sci 2013; 324: 49-52.
116. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013; 61: 404-410.
117. Plante H, Picard S, Mancini J, Borgeat P. 5-Lipoxygenase-Activating protein homodimer in human neutrophils: evidence for a role in leukotriene biosynthesis. Biochem J 2006; 393: 211-218.
118. Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004; 36: 233-239.
119. Darbousset R, Thomas GM, Mezouar S, Frere C, Bonier R, Mackman N et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood 2012; 120: 2133-2143.
120. von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835.
121. Jin R, Yu S, Song Z, Zhu X, Wang C, Yan J et al. Soluble CD40 ligand stimulates CD40-dependent activation of the beta2 integrin Mac-1 and protein kinase C Zeda (PKCzeta) in neutrophils: implications for neutrophil-platelet interactions and neutrophil oxidative burst. PLoS One 2013; 8: e64631.
122. McCabe DJ, Harrison P, Mackie IJ, Sidhu PS, Purdy G, Lawrie AS et al. Increased platelet count and leucocyte-platelet complex formation in acute symptomatic compared with asymptomatic severe carotid stenosis. J Neurol Neurosurg Psychiatry 2005; 76: 1249-1254.
123. Hallevi H, Hazan-Halevy I, Paran E. Modification of neutrophil adhesion to human endothelial cell line in acute ischemic stroke by dipyridamole and candesartan. Eur J Neurol 2007; 14: 1002-1007.
124. Vickers JD. Binding of polymerizing fibrin to integrin alpha(IIb)beta(3) on chymotrypsin-Treated rabbit platelets decreases phosphatidylinositol 4, 5-bisphosphate and increases cytoskeletal actin. Platelets 1999; 10: 228-237.
125. Gavins FN, Russell J, Senchenkova EL, De Almeida Paula L, Damazo AS, Esmon CT et al. Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S. Blood 2011; 117: 4125-4133.
126. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16: 887-896.
127. Faraday N, Schunke K, Saleem S, Fu J, Wang B, Zhang J et al. Cathepsin g-dependent modulation of platelet thrombus formation in vivo by blood neutrophils. PLoS One 2013; 8: e71447.
128. Khan MM, Motto DG, Lentz SR, Chauhan AK. ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice. J Thromb Haemost 2012; 10: 1665-1671.
129. Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 1777-1783.
130. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, Jr. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
131. Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10: 136-144.
132. Fischer S, Preissner KT. Extracellular nucleic acids as novel alarm signals in the vascular system. Mediators of defence and disease. Hamostaseologie 2013; 33: 37-42.
133. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473: 317-325.
134. Johnson RC, Chapman SM, Dong ZM, Ordovas JM, Mayadas TN, Herz J et al. Absence of P-selectin delays fatty streak formation in mice. J Clin Invest 1997; 99: 1037-1043.
135. Nageh MF, Sandberg ET, Marotti KR, Lin AH, Melchior EP, Bullard DC et al. Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1997; 17: 1517-1520.
136. Braunersreuther V, Zernecke A, Arnaud C, Liehn EA, Steffens S, Shagdarsuren E et al. Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2007; 27: 373-379.
137. Doring Y, Drechsler M, Wantha S, Kemmerich K, Lievens D, Vijayan S et al. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ Res 2012; 110: 1052-1056.
138. Wantha S, Alard JE, Megens RT, van der Does AM, Doring Y, Drechsler M et al. Neutrophil-derived cathelicidin promotes adhesion of classical monocytes. Circ Res 2013; 112: 792-801.
139. Mazor R, Shurtz-Swirski R, Farah R, Kristal B, Shapiro G, Dorlechter F et al. Primed polymorphonuclear leukocytes constitute a possible link between inflammation and oxidative stress in hyperlipidemic patients. Atherosclerosis 2008; 197: 937-943.
140. Dorweiler B, Torzewski M, Dahm M, Kirkpatrick CJ, Lackner KJ, Vahl CF. Subendothelial infiltration of neutrophil granulocytes and liberation of matrixdestabilizing enzymes in an experimental model of human neo-intima. Thromb Haemost 2008; 99: 373-381.
141. Laxton RC, Hu Y, Duchene J, Zhang F, Zhang Z, Leung KY et al. A role of matrix metalloproteinase-8 in atherosclerosis. Circ Res 2009; 105: 921-929.
142. Lenglet S, Mach F, Montecucco F. Role of matrix metalloproteinase-8 in atherosclerosis. Mediators Inflamm 2013; 2013: 659282.
143. Nakamura K, Sasaki T, Cheng XW, Iguchi A, Sato K, Kuzuya M. Statin prevents plaque disruption in apoE-knockout mouse model through pleiotropic effect on acute inflammation. Atherosclerosis 2009; 206: 355-361.
144. Ionita MG, van den Borne P, Catanzariti LM, Moll FL, de Vries JP, Pasterkamp G et al. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler Thromb Vasc Biol 2010; 30: 1842-1848.
145. Sen S, Hinderliter A, Sen PK, Simmons J, Beck J, Offenbacher S et al. Aortic arch atheroma progression and recurrent vascular events in patients with stroke or transient ischemic attack. Circulation 2007; 116: 928-935.
146. Nasr N, Ruidavets JB, Arnal JF, Sie P, Larrue V. Association of neutrophil count with microembolization in patients with symptomatic carotid artery stenosis. Atherosclerosis 2009; 207: 519-523.
147. Tsai NW, Chang WN, Shaw CF, Jan CR, Huang CR, Chen SD et al. The value of leukocyte adhesion molecules in patients after ischemic stroke. J Neurol 2009; 256: 1296-1302.
148. Cojocaru IM, Cojocaru M, Burcin C. Evaluation of granulocyte elastase as a sensitive diagnostic parameter of inflammation in first ischemic stroke. Rom J Intern Med 2006; 44: 317-321.
149. Elneihoum AM, Falke P, Axelsson L, Lundberg E, Lindgarde F, Ohlsson K. Leukocyte activation detected by increased plasma levels of inflammatory mediators in patients with ischemic cerebrovascular diseases. Stroke 1996; 27: 1734-1738.
150. Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003; 107: 598-603.
151. Ning M, Furie KL, Koroshetz WJ, Lee H, Barron M, Lederer M et al. Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 2006; 66: 1550-1555.
152. Tuttolomondo A, Pinto A, Corrao S, Di Raimondo D, Fernandez P, Di Sciacca R et al. Immuno-inflammatory and thrombotic/fibrinolytic variables associated with acute ischemic stroke diagnosis. Atherosclerosis 2009; 203: 503-508.
153. Intiso D, Zarrelli MM, Lagioia G, Di Rienzo F, Checchia De Ambrosio C, Simone P et al. Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients. Neurol Sci 2004; 24: 390-396.
154. Domac FM, Misirli H. The role of neutrophils and interleukin-8 in acute ischemic stroke. Neurosciences (Riyadh) 2008; 13: 136-141.
155. Breckwoldt MO, Chen JW, Stangenberg L, Aikawa E, Rodriguez E, Qiu S et al. Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase. Proc Natl Acad Sci USA 2008; 105: 18584-18589.
156. Weston RM, Jones NM, Jarrott B, Callaway JK. Inflammatory cell infiltration after endothelin-1-induced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. J Cereb Blood Flow Metab 2007; 27: 100-114.
157. Anwaar I, Gottsater A, Ohlsson K, Mattiasson I, Lindgarde F. Increasing levels of leukocyte-derived inflammatory mediators in plasma and cAMP in platelets during follow-up after acute cerebral ischemia. Cerebrovasc Dis 1998; 8: 310-317.
158. Matsuo Y, Onodera H, Shiga Y, Shozuhara H, Ninomiya M, Kihara T et al. Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 1994; 656: 344-352.
159. Bowes MP, Rothlein R, Fagan SC, Zivin JA. Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurology 1995; 45: 815-819.
160. Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK. Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1999; 19: 778-787.