Skip to main content

What has inflammation to do with traumatic brain injury?

Child's Nervous System volume 26, Article number: 221 (2010) Cite this article

Abstract

Introduction

Inflammation is an stereotypical response to tissue damage and has been extensively documented in experimental and clinical traumatic brain injury (TBI), including children.

Discussion

The initiation and orchestration of inflammation in TBI, as in other tissues, is complex and multifactorial encompassing pro- and anti-inflammatory cytokines, chemokines, adhesion molecules, complement factors, reactive oxygen and nitrogen species, and other undefined factors. It is evident that inflammation can have both beneficial and detrimental effects in TBI, but the mechanisms underlying this dichotomy are mostly unknown. Modification of the inflammatory response may be neuroprotective. Monitoring inflammation is now possible with techniques such as microdialysis; however, the prognostic value of measuring inflammatory mediators in TBI is still unclear with conflicting reports. Except for corticosteroids, no anti-inflammatory agents have been tested in TBI, and the negative results with these may have been flawed by their multiple side effects. Clinical trials with anti-inflammatory agents that target multiple or central and downstream pathways are warranted in adult and pediatric TBI. This review examines the mechanisms of inflammation after TBI, monitoring, and possible routes of intervention.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Arand M, Melzner H, Kinzl L, Brückner UB, Gebhard F (2001) Early inflammatory mediator response following isolated traumatic brain injury and other major trauma in humans. Langenbeck’s Arch Surg 386:241–248

    Article  CAS  Google Scholar 

  2. Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692

    Article  CAS  PubMed  Google Scholar 

  3. Badie B, Schartner JM, Hagar AR, Prabakaran S, Peebles TR, Bartley B, Lapsiwala S, Resnick DK, Vorpahl J (2003) Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation. Clin Cancer Res 9:872–877

    CAS  PubMed  Google Scholar 

  4. Bell MJ, Kochanek PM, Doughty LA, Carcillo JA, Adelson PD, Clark RS, Whalen MJ, DeKosky ST (1997) Comparison of the interleukin-6 and interleukin-10 response in children after severe traumatic brain injury or septic shock. Acta Neurochir Suppl 70:96–97

    CAS  PubMed  Google Scholar 

  5. Bellander BM, Singhrao SK, Ohlsson M, Mattsson P, Svensson M (2001) Complement activation in the human brain after traumatic head injury. J Neurotrauma 18:1295–1311

    Article  CAS  PubMed  Google Scholar 

  6. Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 2:788–794

    Article  CAS  PubMed  Google Scholar 

  7. Buttram SD, Wisniewski SR, Jackson EK, Adelson PD, Feldman K, Bayir H, Berger RP, Clark RS, Kochanek PM (2007) Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: effects of moderate hypothermia. J Neurotrauma 24:1707–1717

    Article  PubMed  Google Scholar 

  8. Cernak I, O’Connor C, Vink R (2001) Activation of cyclo-oxygenase-2 contributes to motor and cognitive dysfunction following diffuse traumatic brain injury in rats. Clin Exp Pharmacol Physiol 28:922–925

    Article  CAS  PubMed  Google Scholar 

  9. Csuka E, Morganti-Kossmann MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T (1999) IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood–brain barrier function. J Neuroimmunol 101:211–221

    Article  CAS  PubMed  Google Scholar 

  10. Dearden NM, Gibson JS, McDowall DG, Gibson RM, Cameron MM (1986) Effect of high-dose dexamethasone on outcome from severe head injury. J Neurosurg 64:81–88

    Article  CAS  PubMed  Google Scholar 

  11. Ehrlich LC, Hu S, Sheng WS, Sutton RL, Rockswold GL, Peterson PK, Chao CC (1998) Cytokine regulation of human microglial cell IL-8 production. J Immunol 160:1944–1948

    CAS  PubMed  Google Scholar 

  12. Fassbender K, Schneider S, Bertsch T, Schlueter D, Fatar M, Ragoschke A, Kühl S, Kischka U, Hennerici M (2000) Temporal profile of release of interleukin-1beta in neurotrauma. Neurosci Lett 284:135–138

    Article  CAS  PubMed  Google Scholar 

  13. Garcia-Segura LM, Balthazart J (2009) Steroids and neuroprotection: new advances. Front Neuroendocrinol 30:v–ix

    Article  PubMed  Google Scholar 

  14. Grzybicki D, Moore SA, Schelper R, Glabinski AR, Ransohoff RM, Murphy S (1998) Expression of monocyte chemoattractant protein (MCP-1) and nitric oxide synthase-2 following cerebral trauma. Acta Neuropathol 95:98–103

    Article  CAS  PubMed  Google Scholar 

  15. Hausmann EH, Berman NE, Wang YY, Meara JB, Wood GW, Klein RM (1998) Selective chemokine mRNA expression following brain injury. Brain Res 788:49–59

    Article  CAS  PubMed  Google Scholar 

  16. Hutchinson PJ, O’Connell MT, Rothwell NJ, Hopkins SJ, Nortje J, Carpenter KL, Timofeev I, Al-Rawi PG, Menon DK, Pickard JD (2007) Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra. J Neurotrauma 24:1545–1557

    Article  PubMed  Google Scholar 

  17. Juliet PA, Mao X, Del Bigio MR (2008) Proinflammatory cytokine production by cultured neonatal rat microglia after exposure to blood products. Brain Res 1210:230–239

    Article  CAS  PubMed  Google Scholar 

  18. Kalabalikis P, Papazoglou K, Gouriotis D, Papadopoulos N, Kardara M, Papageorgiou F, Papadatos J (1999) Correlation between serum IL-6 and CRP levels and severity of head injury in children. Intensive Care Med 25:288–292

    Article  CAS  PubMed  Google Scholar 

  19. Kossmann T, Hans VH, Imhof HG, Stocker R, Grob P, Trentz O, Morganti-Kossmann C (1995) Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock 4:311–317

    Article  CAS  PubMed  Google Scholar 

  20. Leinhase I, Schmidt OI, Thurman JM, Hossini AM, Rozanski M, Taha ME, Scheffler A, John T, Smith WR, Holers VM, Stahel PF (2006) Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury. Exp Neurol 199:454–464

    Article  CAS  PubMed  Google Scholar 

  21. Lenzlinger PM, Morganti-Kossmann MC, Laurer HL, McIntosh TK (2001) The duality of the inflammatory response to traumatic brain injury. Mol Neurobiol 24:169–181

    Article  CAS  PubMed  Google Scholar 

  22. Lloyd E, Somera-Molina K, Van Eldik LJ, Watterson DM, Wainwright MS (2008) Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury. Journal of Neuroinflammation 5:28

    Article  PubMed  Google Scholar 

  23. Longhi L, Perego C, Ortolano F, Zanier ER, Bianchi P, Stocchetti N, McIntosh TK, De Simoni MG (2009) C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice. Crit Care Med 37:659–665

    Article  CAS  PubMed  Google Scholar 

  24. Ma YL, Zhu X, Rivera PM, Tøien Ø, Barnes BM, LaManna JC, Smith MA, Drew KL (2005) Absence of cellular stress in brain after hypoxia induced by arousal from hibernation in Arctic ground squirrels. Am J Physiol Regul Integr Comp Physiol 289:R1297–R1306

    CAS  PubMed  Google Scholar 

  25. Maier B, Schwerdtfeger K, Mautes A, Holanda M, Müller M, Steudel WI, Marzi I (2001) Differential release of interleukines 6, 8, and 10 in cerebrospinal fluid and plasma after traumatic brain injury. Shock 15:421–426

    Article  CAS  PubMed  Google Scholar 

  26. Mathew P, Graham DI, Bullock R, Maxwell W, McCulloch J, Teasdale G (1994) Focal brain injury: histological evidence of delayed inflammatory response in a new rodent model of focal cortical injury. Acta Neurochir Suppl 60:428–430

    CAS  Google Scholar 

  27. McKeating EG, Andrews PJ, Signorini DF, Mascia L (1997) Transcranial cytokine gradients in patients requiring intensive care after acute brain injury. Br J Anaesth 78:520–523

    CAS  PubMed  Google Scholar 

  28. Moochhala SM, Lu J, Xing MC, Anuar F, Ng KC, Yang KL, Whiteman M, Atan S (2005) Mercaptoethylguanidine inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expressions induced in rats after fluid-percussion brain injury. J Trauma 59:450–457

    Article  PubMed  Google Scholar 

  29. Morganti-Kossman MC, Lenzlinger PM, Hans V, Stahel P, Csuka E, Ammann E, Stocker R, Trentz O, Kossmann T (1997) Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue. Mol Psychiatry 2:133–136

    Article  CAS  PubMed  Google Scholar 

  30. Morganti-Kossmann MC, Rancan M, Otto VI, Stahel PF, Kossmann T (2001) Role of cerebral inflammation after traumatic brain injury: a revisited concept. Shock 16:165–177

    Article  CAS  PubMed  Google Scholar 

  31. Moussaieff A, Shein NA, Tsenter J, Grigoriadis S, Simeonidou C, Alexandrovich AG, Trembovler V, Ben-Neriah Y, Schmitz ML, Fiebich BL, Munoz E, Mechoulam R, Shohami E (2008) Incensole acetate: a novel neuroprotective agent isolated from Boswellia carterii. J Cereb Blood Flow Metab 28:1341–1352

    Article  CAS  PubMed  Google Scholar 

  32. Nekludov M, Antovic J, Bredbacka S, Blombäck M (2007) Coagulation abnormalities associated with severe isolated traumatic brain injury: cerebral arterio-venous differences in coagulation and inflammatory markers. J Neurotrauma 24:174–180

    Article  PubMed  Google Scholar 

  33. Rock KL, Kono H (2008) The inflammatory response to cell death. Annu Rev Pathol 3:99–126

    Article  CAS  PubMed  Google Scholar 

  34. Singhal A, Baker AJ, Hare GM, Reinders FX, Schlichter LC, Moulton RJ (2002) Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury. J Neurotrauma 19:929–937

    Article  CAS  PubMed  Google Scholar 

  35. Sinz EH, Kochanek PM, Dixon CE, Clark RS, Carcillo JA, Schiding JK, Chen M, Wisniewski SR, Carlos TM, Williams D, DeKosky ST, Watkins SC, Marion DW, Billiar TR (1999) Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice. J Clin Invest 104:647–656

    Article  CAS  PubMed  Google Scholar 

  36. Stahel PF, Morganti-Kossmann MC, Kossmann T (1998) The role of the complement system in traumatic brain injury. Brain Res Brain Res Rev 27:243–256

    Article  CAS  PubMed  Google Scholar 

  37. Stefini R, Catenacci E, Piva S, Sozzani S, Valerio A, Bergomi R, Cenzato M, Mortini P, Latronico N (2008) Chemokine detection in the cerebral tissue of patients with posttraumatic brain contusions. J Neurosurg 108:958–962

    Article  CAS  PubMed  Google Scholar 

  38. Sullivan PG, Bruce-Keller AJ, Rabchevsky AG, Christakos S, Clair DK, Mattson MP, Scheff SW (1999) Exacerbation of damage and altered NF-kappaB activation in mice lacking tumor necrosis factor receptors after traumatic brain injury. J Neurosci 19:6248–6256

    CAS  PubMed  Google Scholar 

  39. Weil ZM, Norman GJ, DeVries AC, Nelson RJ (2008) The injured nervous system: a Darwinian perspective. Prog Neurobiol 86:48–59

    Article  PubMed  Google Scholar 

  40. Whalen MJ, Carlos TM, Kochanek PM, Wisniewski SR, Bell MJ, Clark RS, DeKosky ST, Marion DW, Adelson PD (2000) Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury. Crit Care Med 28:929–934

    Article  CAS  PubMed  Google Scholar 

  41. Winter CD, Pringle AK, Clough GF, Church MK (2004) Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain 127:315–320

    Article  PubMed  Google Scholar 

  42. You Z, Yang J, Takahashi K, Yager PH, Kim HH, Qin T, Stahl GL, Ezekowitz RA, Carroll MC, Whalen MJ (2007) Reduced tissue damage and improved recovery of motor function after traumatic brain injury in mice deficient in complement component C4. J Cereb Blood Flow Metab 27:1954–1964

    Article  CAS  PubMed  Google Scholar 

  43. Zhang X, Graham SH, Kochanek PM, Marion DW, Nathaniel PD, Watkins SC, Clark RS (2003) Caspase-8 expression and proteolysis in human brain after severe head injury. FASEB J 17:1367–1369

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by a SIDA grant GUN 2072790. The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Lund University Hospital, 221 85, Lund, Sweden

    David Cederberg & Peter Siesjö

Authors
  1. David Cederberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Siesjö
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Siesjö.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cederberg, D., Siesjö, P. What has inflammation to do with traumatic brain injury?. Childs Nerv Syst 26, 221 (2010). https://doi.org/10.1007/s00381-009-1029-x

Download citation

  • Received:

  • Published:

  • DOI: https://doi.org/10.1007/s00381-009-1029-x

Keywords

  • Traumatic brain injury
  • Inflammation
  • Children
  • Markers
  • Secondary injury