Skip to main content

Neutrophils as Determinants of Vascular Stability in the Injured Spinal Cord

  • Chapter
  • First Online:
Vascular Mechanisms in CNS Trauma

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR,volume 5))

  • 1425 Accesses

Abstract

While a number of studies have examined the complex roles of leukocytes in the acute and chronically injured cord, few have specifically focused on neutrophils, where we have only recently begun to appreciate their involvement in both vascular pathogenesis and early wound healing. Here we address the mechanisms underlying neutrophil-mediated endothelial destabilization, their synergism with monocytes in modulating permeability, and their putative role as initiators of angiogenesis in the acutely injured spinal cord. Neutrophils contain a variety of bioactive molecules that are stored in granules. Studies have shown that certain of these molecules, and most notably proteases, contribute to endothelial destabilization as neutrophils degranulate during their transmigration across this front. Neutrophils have historically been regarded as detrimental to the acutely injured cord. However, there is growing evidence that this may be an oversimplified view as it fails to take into account their ability to release proteases that degrade the extracellular matrix, releasing latent growth factors that may in turn support early angiogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Beck KD et al (2010) Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 133(Pt 2):433–447

    Article  PubMed  Google Scholar 

  2. Stirling DP, Yong VW (2008) Dynamics of the inflammatory response after murine spinal cord injury revealed by flow cytometry. J Neurosci Res 86(9):1944–1958

    Article  PubMed  CAS  Google Scholar 

  3. Hall JC et al (2012) Docosahexaenoic acid, but not eicosapentaenoic acid, reduces the early inflammatory response following compression spinal cord injury in the rat. J Neurochem 121(5):738–750

    Article  PubMed  CAS  Google Scholar 

  4. Bartholdi D, Schwab ME (1997) Expression of pro-inflammatory cytokine and chemokine mRNA upon experimental spinal cord injury in mouse: an in situ hybridization study. Eur J Neurosci 9(7):1422–1438

    Article  PubMed  CAS  Google Scholar 

  5. Kigerl KA, McGaughy VM, Popovich PG (2006) Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. J Comp Neurol 494(4):578–594

    Article  PubMed  Google Scholar 

  6. Hawthorne AL, Popovich PG (2011) Emerging concepts in myeloid cell biology after spinal cord injury. Neurotherapeutics 8(2):252–261

    Article  PubMed  Google Scholar 

  7. Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57(2):173–185

    Article  PubMed  CAS  Google Scholar 

  8. Schmidt EP et al (2011) On, around, and through: neutrophil-endothelial interactions in innate immunity. Physiology (Bethesda) 26(5):334–347

    Article  PubMed  CAS  Google Scholar 

  9. Weinbaum S, Tarbell JM, Damiano ER (2007) The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9:121–167

    Article  PubMed  CAS  Google Scholar 

  10. Curry FR (2005) Microvascular solute and water transport. Microcirculation 12(1):17–31

    Article  PubMed  CAS  Google Scholar 

  11. Bazzoni G, Dejana E (2004) Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84(3):869–901

    Article  PubMed  CAS  Google Scholar 

  12. Johnson-Leger C, Aurrand-Lions M, Imhof BA (2000) The parting of the endothelium: miracle, or simply a junctional affair? J Cell Sci 113(Pt 6):921–933

    PubMed  CAS  Google Scholar 

  13. Noble LJ, Mautes AE, Hall JJ (1996) Characterization of the microvascular glycocalyx in normal and injured spinal cord in the rat. J Comp Neurol 376(4):542–556

    Article  PubMed  CAS  Google Scholar 

  14. Potter DR, Jiang J, Damiano ER (2009) The recovery time course of the endothelial cell glycocalyx in vivo and its implications in vitro. Circ Res 104(11):1318–1325

    Article  PubMed  CAS  Google Scholar 

  15. Gane J, Stockley R (2011) Mechanisms of neutrophil transmigration across the vascular endothelium in COPD. Thorax 67(6):553–561

    Article  PubMed  Google Scholar 

  16. Greenwood J et al (2011) Review: leucocyte-endothelial cell crosstalk at the blood-brain barrier: a prerequisite for successful immune cell entry to the brain. Neuropathol Appl Neurobiol 37(1):24–39

    Article  PubMed  CAS  Google Scholar 

  17. Anthony D et al (1998) CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown. Curr Biol 8(16):923–926

    Article  PubMed  CAS  Google Scholar 

  18. Benton RL et al (2008) Griffonia simplicifolia isolectin B4 identifies a specific subpopulation of angiogenic blood vessels following contusive spinal cord injury in the adult mouse. J Comp Neurol 507(1):1031–1052

    Article  PubMed  Google Scholar 

  19. Amulic B et al (2012) Neutrophil function: from mechanisms to disease. Annu Rev Immunol 30:459–489

    Article  PubMed  CAS  Google Scholar 

  20. Cepinskas G, Sandig M, Kvietys PR (1999) PAF-induced elastase-dependent neutrophil transendothelial migration is associated with the mobilization of elastase to the neutrophil surface and localization to the migrating front. J Cell Sci 112(Pt 12):1937–1945

    PubMed  CAS  Google Scholar 

  21. Hermant B et al (2003) Identification of proteases involved in the proteolysis of vascular endothelium cadherin during neutrophil transmigration. J Biol Chem 278(16):14002–14012

    Article  PubMed  CAS  Google Scholar 

  22. Ionescu CV et al (2003) Neutrophils induce sequential focal changes in endothelial adherens junction components: role of elastase. Microcirculation 10(2):205–220

    PubMed  CAS  Google Scholar 

  23. Borregaard N (2010) Neutrophils, from marrow to microbes. Immunity 33(5):657–670

    Article  PubMed  CAS  Google Scholar 

  24. Ardi VC et al (2007) Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A 104(51):20262–20267

    Article  PubMed  CAS  Google Scholar 

  25. Angelillo-Scherrer A (2012) Leukocyte-derived microparticles in vascular homeostasis. Circ Res 110(2):356–369

    Article  PubMed  CAS  Google Scholar 

  26. Reichel CA et al (2008) Gelatinases mediate neutrophil recruitment in vivo: evidence for stimulus specificity and a critical role in collagen IV remodeling. J Leukoc Biol 83(4):864–874

    Article  PubMed  CAS  Google Scholar 

  27. Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22(5):E4

    Article  PubMed  Google Scholar 

  28. de Castro RC Jr et al (2000) Metalloproteinase increases in the injured rat spinal cord. Neuroreport 11(16):3551–3554

    Article  PubMed  Google Scholar 

  29. Lee SM et al (2011) Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. J Neurotrauma 28(9):1893–1907

    Article  PubMed  Google Scholar 

  30. Fleming JC et al (2006) The cellular inflammatory response in human spinal cords after injury. Brain 129(Pt 12):3249–3269

    Article  PubMed  Google Scholar 

  31. Whetstone WD et al (2003) Blood-spinal cord barrier after spinal cord injury: relation to revascularization and wound healing. J Neurosci Res 74(2):227–239

    Article  PubMed  CAS  Google Scholar 

  32. Noble LJ et al (2002) Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 22(17):7526–7535

    PubMed  CAS  Google Scholar 

  33. Yu F et al (2008) Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury. J Neurotrauma 25(3):184–195

    Article  PubMed  Google Scholar 

  34. Lee JY et al (2012) Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury. Brain 135(Pt 8):2375–2389

    Article  PubMed  Google Scholar 

  35. Lee JY et al (2012) Valproic acid attenuates blood-spinal cord barrier disruption by inhibiting matrix metalloprotease-9 activity and improves functional recovery after spinal cord injury. J Neurochem 121(5):818–829

    Article  PubMed  CAS  Google Scholar 

  36. Pannu R et al (2007) Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. J Neurochem 101(1):182–200

    Article  PubMed  CAS  Google Scholar 

  37. Asahi M et al (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 21(19):7724–7732

    PubMed  CAS  Google Scholar 

  38. Caron A, Desrosiers RR, Beliveau R (2005) Ischemia injury alters endothelial cell properties of kidney cortex: stimulation of MMP-9. Exp Cell Res 310(1):105–116

    Article  PubMed  CAS  Google Scholar 

  39. Taoka Y et al (1998) Role of neutrophil elastase in compression-induced spinal cord injury in rats. Brain Res 799(2):264–269

    Article  PubMed  CAS  Google Scholar 

  40. Taoka Y et al (1997) Gabexate mesilate, a synthetic protease inhibitor, prevents compression-induced spinal cord injury by inhibiting activation of leukocytes in rats. Crit Care Med 25(5):874–879

    Article  PubMed  CAS  Google Scholar 

  41. Tonai T et al (2001) A neutrophil elastase inhibitor (ONO-5046) reduces neurologic damage after spinal cord injury in rats. J Neurochem 78(5):1064–1072

    Article  PubMed  CAS  Google Scholar 

  42. Shappell SB et al (1990) Comparison of antioxidant and nonantioxidant lipoxygenase inhibitors on neutrophil function. Implications for pathogenesis of myocardial reperfusion injury. J Pharmacol Exp Ther 252(2):531–538

    PubMed  CAS  Google Scholar 

  43. Nakauchi K et al (1996) Effects of lecithinized superoxide dismutase on rat spinal cord injury. J Neurotrauma 13(10):573–582

    PubMed  CAS  Google Scholar 

  44. Kubota K et al (2012) Myeloperoxidase exacerbates secondary injury by generating highly reactive oxygen species and mediating neutrophil recruitment in experimental spinal cord injury. Spine (Phila Pa 1976) 37(16):1363–1369

    Article  Google Scholar 

  45. Allen C et al (2012) Neutrophil cerebrovascular transmigration triggers rapid neurotoxicity through release of proteases associated with decondensed DNA. J Immunol 189(1):381–392

    Article  PubMed  CAS  Google Scholar 

  46. Gupta AK et al (2010) Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett 584(14):3193–3197

    Article  PubMed  CAS  Google Scholar 

  47. Phillipson M et al (2006) Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med 203(12):2569–2575

    Article  PubMed  CAS  Google Scholar 

  48. Davenpeck KL, Sterbinsky SA, Bochner BS (1998) Rat neutrophils express alpha4 and beta1 integrins and bind to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Blood 91(7):2341–2346

    PubMed  CAS  Google Scholar 

  49. Shanley TP et al (1998) Requirements for alpha d in IgG immune complex-induced rat lung injury. J Immunol 160(2):1014–1020

    PubMed  CAS  Google Scholar 

  50. Yednock TA et al (1995) Alpha 4 beta 1 integrin-dependent cell adhesion is regulated by a low affinity receptor pool that is conformationally responsive to ligand. J Biol Chem 270(48):28740–28750

    Article  PubMed  CAS  Google Scholar 

  51. Bao F et al (2008) An integrin inhibiting molecule decreases oxidative damage and improves neurological function after spinal cord injury. Exp Neurol 214(2):160–167

    Article  PubMed  CAS  Google Scholar 

  52. Fleming JC et al (2008) Alpha4beta1 integrin blockade after spinal cord injury decreases damage and improves neurological function. Exp Neurol 214(2):147–159

    Article  PubMed  CAS  Google Scholar 

  53. Gris D et al (2004) Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J Neurosci 24(16):4043–4051

    Article  PubMed  CAS  Google Scholar 

  54. Bao F et al (2004) Early anti-inflammatory treatment reduces lipid peroxidation and protein nitration after spinal cord injury in rats. J Neurochem 88(6):1335–1344

    Article  PubMed  CAS  Google Scholar 

  55. Geremia NM et al (2012) CD11d Antibody Treatment Improves Recovery in Spinal Cord-Injured Mice. J Neurotrauma 29(3):539–550

    Article  PubMed  Google Scholar 

  56. Hamada Y et al (1996) Involvement of an intercellular adhesion molecule 1-dependent pathway in the pathogenesis of secondary changes after spinal cord injury in rats. J Neurochem 66(4):1525–1531

    Article  PubMed  CAS  Google Scholar 

  57. Isaksson J, Farooque M, Olsson Y (2000) Spinal cord injury in ICAM-1-deficient mice: assessment of functional and histopathological outcome. J Neurotrauma 17(4):333–344

    Article  PubMed  CAS  Google Scholar 

  58. Scapini P et al (2001) Neutrophils produce biologically active macrophage inflammatory protein-3alpha (MIP-3alpha)/CCL20 and MIP-3beta/CCL19. Eur J Immunol 31(7):1981–1988

    Article  PubMed  CAS  Google Scholar 

  59. Yoshimura T, Takahashi M (2007) IFN-gamma-mediated survival enables human neutrophils to produce MCP-1/CCL2 in response to activation by TLR ligands. J Immunol 179(3):1942–1949

    PubMed  CAS  Google Scholar 

  60. McTigue DM et al (1998) Selective chemokine mRNA accumulation in the rat spinal cord after contusion injury. J Neurosci Res 53(3):368–376

    Article  PubMed  CAS  Google Scholar 

  61. Stammers AT, Liu J, Kwon BK (2012) Expression of inflammatory cytokines following acute spinal cord injury in a rodent model. J Neurosci Res 90(4):782–790

    Article  PubMed  CAS  Google Scholar 

  62. Chertov O et al (1997) Identification of human neutrophil-derived cathepsin G and azurocidin/CAP37 as chemoattractants for mononuclear cells and neutrophils. J Exp Med 186(5):739–747

    Article  PubMed  CAS  Google Scholar 

  63. De Y et al (2000) LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med 192(7):1069–1074

    Article  Google Scholar 

  64. Soehnlein O et al (2008) Neutrophil secretion products pave the way for inflammatory monocytes. Blood 112(4):1461–1471

    Article  PubMed  CAS  Google Scholar 

  65. Territo MC et al (1989) Monocyte-chemotactic activity of defensins from human neutrophils. J Clin Invest 84(6):2017–2020

    Article  PubMed  CAS  Google Scholar 

  66. Janardhan KS, Sandhu SK, Singh B (2006) Neutrophil depletion inhibits early and late monocyte/macrophage increase in lung inflammation. Front Biosci 11:1569–1576

    Article  PubMed  CAS  Google Scholar 

  67. Kim JV et al (2009) Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457(7226):191–195

    Article  PubMed  CAS  Google Scholar 

  68. Zhang H et al (2011) Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury. Neurotherapeutics 8(2):206–220

    Article  PubMed  CAS  Google Scholar 

  69. Stirling DP et al (2009) Depletion of Ly6G/Gr-1 leukocytes after spinal cord injury in mice alters wound healing and worsens neurological outcome. J Neurosci 29(3):753–764

    Article  PubMed  CAS  Google Scholar 

  70. Casella GT et al (2002) New vascular tissue rapidly replaces neural parenchyma and vessels destroyed by a contusion injury to the rat spinal cord. Exp Neurol 173(1):63–76

    Article  PubMed  Google Scholar 

  71. Loy DN et al (2002) Temporal progression of angiogenesis and basal lamina deposition after contusive spinal cord injury in the adult rat. J Comp Neurol 445(4):308–324

    Article  PubMed  Google Scholar 

  72. Gregory AD, Houghton AM (2011) Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res 71(7):2411–2416

    Article  PubMed  CAS  Google Scholar 

  73. Shojaei F et al (2008) Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci U S A 105(7):2640–2645

    Article  PubMed  CAS  Google Scholar 

  74. Hao Q et al (2007) Neutrophil depletion decreases VEGF-induced focal angiogenesis in the mature mouse brain. J Cereb Blood Flow Metab 27(11):1853–1860

    Article  PubMed  CAS  Google Scholar 

  75. Benelli R et al (2002) Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J 16(2):267–269

    PubMed  CAS  Google Scholar 

  76. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867

    Article  PubMed  CAS  Google Scholar 

  77. McCourt M et al (1999) Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch Surg 134(12):1325–1331, discussion 1331-2

    Article  PubMed  CAS  Google Scholar 

  78. Rennekampff HO et al (2000) Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J Surg Res 93(1):41–54

    Article  PubMed  CAS  Google Scholar 

  79. Van den Steen PE et al (2000) Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 96(8):2673–2681

    PubMed  Google Scholar 

  80. Lee WL, Downey GP (2001) Leukocyte elastase: physiological functions and role in acute lung injury. Am J Respir Crit Care Med 164(5):896–904

    Article  PubMed  CAS  Google Scholar 

  81. Nozawa H, Chiu C, Hanahan D (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci U S A 103(33):12493–12498

    Article  PubMed  CAS  Google Scholar 

  82. Bergers G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737–744

    Article  PubMed  CAS  Google Scholar 

  83. Popovich PG et al (1996) A quantitative spatial analysis of the blood-spinal cord barrier. I. Permeability changes after experimental spinal contusion injury. Exp Neurol 142(2):258–275

    Article  PubMed  CAS  Google Scholar 

  84. Noble LJ, Wrathall JR (1988) Blood-spinal cord barrier disruption proximal to a spinal cord transection in the rat: time course and pathways associated with protein leakage. Exp Neurol 99(3):567–578

    Article  PubMed  CAS  Google Scholar 

  85. Noble LJ, Ellison JA (1989) Effect of transection on the blood-spinal cord barrier of the rat after isolation from descending sources. Brain Res 487(2):299–310

    Article  PubMed  CAS  Google Scholar 

  86. Noble LJ, Wrathall JR (1989) Distribution and time course of protein extravasation in the rat spinal cord after contusive injury. Brain Res 482(1):57–66

    Article  PubMed  CAS  Google Scholar 

  87. Cohen DM et al (2009) Blood-spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced MRI. NMR Biomed 22(3):332–341

    Article  PubMed  Google Scholar 

  88. Baldwin SA et al (1998) The presence of 4-hydroxynonenal/protein complex as an indicator of oxidative stress after experimental spinal cord contusion in a rat model. J Neurosurg 88(5):874–883

    Article  PubMed  CAS  Google Scholar 

  89. Borregaard N, Sorensen OE, Theilgaard-Monch K (2007) Neutrophil granules: a library of innate immunity proteins. Trends Immunol 28(8):340–345

    Article  PubMed  CAS  Google Scholar 

  90. Ditor DS et al (2006) A therapeutic time window for anti-CD 11d monoclonal antibody treatment yielding reduced secondary tissue damage and enhanced behavioral recovery following severe spinal cord injury. J Neurosurg Spine 5(4):343–352

    Article  PubMed  Google Scholar 

  91. Saville LR et al (2004) A monoclonal antibody to CD11d reduces the inflammatory infiltrate into the injured spinal cord: a potential neuroprotective treatment. J Neuroimmunol 156(1–2):42–57

    Article  PubMed  CAS  Google Scholar 

  92. Fleming JC et al (2009) Timing and duration of anti-alpha4beta1 integrin treatment after spinal cord injury: effect on therapeutic efficacy. J Neurosurg Spine 11(5):575–587

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alpa Trivedi .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Trivedi, A., Lee, S.M., Zhang, H., Noble-Haeusslein, L.J. (2014). Neutrophils as Determinants of Vascular Stability in the Injured Spinal Cord. In: Lo, E., Lok, J., Ning, M., Whalen, M. (eds) Vascular Mechanisms in CNS Trauma. Springer Series in Translational Stroke Research, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8690-9_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-8690-9_16

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-8689-3

  • Online ISBN: 978-1-4614-8690-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics