Skip to main content

Advertisement

Log in

Local and systemic pro-inflammatory and anti-inflammatory cytokine patterns in patients with chronic subdural hematoma: a prospective study

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

Innate immune pro- and anti-inflammatory responses in patients with chronic subdural hematoma (CSDH) were investigated by measuring and comparing the systemic and subdural fluid levels of cytokines.

Materials and method

Cytokine values were analyzed in samples obtained during surgery of 56 adult patients who were operated on for unilateral CSDHs using a Multiplex antibody bead kit.

Results

There were significantly higher levels of the pro-inflammatory IL-2R (p = 0.004), IL-5 (p < 0.001), IL-6 (p < 0.001), and IL-7 (p < 0.001), and anti-inflammatory mediators IL-10 (p < 0.001) and IL-13 (p = 0.002) in CSDH fluid compared with systemic levels. The pro-inflammatory TNF-alpha (p < 0.001), IL-1beta (p < 0.001), IL-2 (p = 0.007) and IL-4 (p < 0.001) were significantly lower in hematoma fluid compared with systemic levels. The ratios between pro- versus anti-inflammatory cytokines were statistically significant higher in CSDH (7.8) compared with systemic levels (1.3).

Conclusions

The innate immune responses occur both locally at the site of CSDH, as well as systematically in patients with CSDH. The local hyper-inflammatory and low anti-inflammatory responses exist simultaneously. The findings suggest poorly coordinated innate immune responses at the site of CSDH that may lead to propagating of local inflammatory process and basically contribute to formation and progression of CSDH.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chen JC, Levy ML. Causes, epidemiology, and risk factors of chronic subdural hematoma. Neurosurg Clin North Am. 2000;11:399–406.

    CAS  Google Scholar 

  2. Weigel R, Schmiedek P, Krauss JK. Outcome of contemporary surgery for chronic subdural haematoma: evidence based review. J Neurol Neurosurg Psychiatry. 2003;74:937–43.

    Article  PubMed  CAS  Google Scholar 

  3. DE Haines, Harkey HL, al-Mefty O. The “subdural” space: a new look at an outdated concept. Neurosurgery. 1993;32:111–20.

    Article  PubMed  CAS  Google Scholar 

  4. Mack J, Squier W, Eastman JT. Anatomy and development of the meninges: implications for subdural collections and CSF circulation. Pediatr Radiol. 2009;39:200–10.

    Article  PubMed  Google Scholar 

  5. Reina MA, Casasola ODL, Lopez A, De Andres JA, Mora M, Fernandez A. The origin of the spinal subdural space: ultrastructure findings. Anesth Analg. 2002;94:991–5.

    Article  PubMed  Google Scholar 

  6. Frati A, Salvati M, Mainiero F, Ippoliti F, Rocchi G, Raco A, Caroli E, Cantore G, Delfini R. Inflammation markers and risk factors for recurrence in 35 patients with a posttraumatic chronic subdural hematoma: a prospective study. J Neurosurg. 2004;100:24–32.

    PubMed  Google Scholar 

  7. Hirashima Y, Endo S, Kato R, Ohmori T, Nagahori T, Nishijima M, Karasawa K, Nojima S, Takaku A. Platelet-activating factor (PAF) and the development of chronic subdural haematoma. Acta Neurochir (Wien). 1994;129:20–5.

    Article  Google Scholar 

  8. Hong HJ, Kim YJ, Yi HJ, Ko Y, Oh SJ, Kim JM. Role of angiogenic growth factors and inflammatory cytokine on recurrence of chronic subdural hematoma. Surg Neurol. 2009;71:161–6.

    Article  PubMed  Google Scholar 

  9. Suzuki M, Endo S, Inada K, Kudo A, Kitakami A, Kuroda K, Ogawa A. Inflammatory cytokines locally elevated in chronic subdural haematoma. Acta Neurochir (Wien). 1998;140:51–5.

    Article  CAS  Google Scholar 

  10. Wada T, Kuroda K, Yoshida Y. Local elevation of the anti-inflammatory interleukin-10 in the pathogenesis of chronic subdural hematoma. Neurosurg Rev. 2006;29:242–5.

    Article  PubMed  Google Scholar 

  11. Hohenstein A, Erber R, Schilling L, Weigel R. Increased mRNA expression of VEGF within the hematoma and imbalance of angiopoietin-1 and -2 mRNA within the neomembranes of chronic subdural hematoma. J Neurotrauma. 2005;22:518–28.

    Article  PubMed  Google Scholar 

  12. Katano H, Kamiya K, Mase M, Tanikawa M, Yamada K. Tissue plasminogen activator in chronic subdural hematomas as a predictor of recurrence. J Neurosurg. 2006;104:79–84.

    Article  PubMed  CAS  Google Scholar 

  13. Nanko N, Tanikawa M, Mase M, Fujita M, Tateyama H, Miyati T, Yamada K. Involvement of hypoxia-inducible factor-1α and vascular endothelial growth factor in the mechanism of development of chronic subdural hematoma. Neurol Med Chir (Tokyo). 2009;49:379–85.

    Article  Google Scholar 

  14. Shono T, Inamura T, Morioka T, Matsumoto K, Suzuki SO, Ikezaki K, Iwaki T, Fukui M. Vascular endothelial growth factor in chronic subdural haematomas. J Clin Neurosci. 2001;8:411–5.

    Article  PubMed  CAS  Google Scholar 

  15. Suzuki K, Takano S, Nose T, Doi M, Ohasi N. Increased concentration of vascular endothelial growth factor (VEGF) in chronic subdural hematoma. J Trauma. 1999;46:532–3. (Letter).

    Article  PubMed  CAS  Google Scholar 

  16. Vaquero J, Zurita M, Cincu R. Vascular endothelial growth-permeability factor in granulation tissue of chronic subdural haematomas. Acta Neurochir (Wien). 2002;144:343–7.

    Article  CAS  Google Scholar 

  17. Weigel R, Schilling L, Schmiedek P. Specific pattern of growth factor distribution in chronic subdural hematoma (CSH): evidence for an angiogenic disease. Acta Neurochir (Wien). 2001;143:811–9.

    Article  CAS  Google Scholar 

  18. Friede RL, Schachenmayer W. The origin of subdural neomembranes II. Fine structure of neomembranes. Am J Pathol. 1978;92:69–84.

    PubMed  CAS  Google Scholar 

  19. Moskala M, Gościński I, Kałuża J, Polar J, Krupa M, Adamek D, Pityński K, Miodoński AJ. Morphological aspects of the traumatic chronic subdural hematoma capsule: SEM studies. Microsc Microanal. 2007;13:211–9.

    Article  PubMed  CAS  Google Scholar 

  20. Yamashima T, Yamamoto S. The origin of inner membranes in chronic subdural hematomas. Acta Neuropathol. 1985;67:219–25.

    Article  PubMed  CAS  Google Scholar 

  21. Fujisawa H, Ito H, Kashiwagi S, Nomura S, Toyosawa M. Kallikrein-kinin system in chronic subdural haematomas: Its role in vascular permeability and regulation of fibrinolysis and coagulation. J Neurol Neurosurg Psychiatry. 1995;59:388–94.

    Article  PubMed  CAS  Google Scholar 

  22. Murakami H, Hirose Y, Sagoh M, Shimizu K, Kojima M, Gotoh K, Mine Y, Hayashi T, Kawase T. Why do chronic subdural hematomas continue to grow slowly and not coagulate? Role of thrombomodulin in the mechanism. J Neurosurg. 2002;96:877–84.

    Article  PubMed  Google Scholar 

  23. Nomura S, Kashiwagi S, Fujisawa H, Ito H, Nakamura K. Characterization of local hyperfibrinolysis in chronic subdural hematomas by SDS-PAGE and immunoblot. J Neurosurg. 1994;81:910–3.

    Article  PubMed  CAS  Google Scholar 

  24. Suzuki M, Kudo A, Kitakami A, Doi M, Kubo N, Kuroda K, Ogawa A. Local hypercoagulative activity precedes hyperfibrinolytic activity in the subdural space during development of chronic subdural haematoma from subdural effusion. Acta Neurochir (Wien). 1998;140:261–6.

    Article  CAS  Google Scholar 

  25. Weir B, Gordon P. Factors affecting coagulation: fibrinolysis in chronic subdural fluid collection. J Neurosurg. 1983;58:242–5.

    Article  PubMed  CAS  Google Scholar 

  26. Kawano N, Suzuki K. Presence of smooth-muscle cells in the subdural neomembrane. J Neurosurg. 1981;54:646–51.

    Article  PubMed  CAS  Google Scholar 

  27. Sarkar C, Lakhtakia R, Gill SS, Sharma MC, Mahapatra AK, Mehta VS. Chronic subdural haematoma and the enigmatic eosinophil. Acta Neurochir (Wien). 2002;144:983–8.

    Article  CAS  Google Scholar 

  28. Dinarello CA. Proinflammatory cytokines. Chest. 2000;118:503–8.

    Article  PubMed  CAS  Google Scholar 

  29. Li H, Lin X. Positive and negative signalling components involved in TNF-alpha-induced NF-kappaB activation. Cytokine. 2008;41:1–8.

    Article  PubMed  Google Scholar 

  30. Apte SH, Baz A, Kelso A, Kienzle N. Interferon-gamma and interleukin-4 reciprocally regulate CD8 expression in CD8+ T cells. Proc Natl Acad Sci USA. 2008;105:17475–80.

    Article  PubMed  CAS  Google Scholar 

  31. Arai K, Lee F, Miyajima A, Miyatake S, Arai N, Yokota T. Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem. 1990;59:783–836.

    Article  PubMed  CAS  Google Scholar 

  32. Boyman O, Ramsey C, Kim DM, Sprent J, Surh CD. Il-7/Anti-IL-7 mAb complexes restore T cell development and induce homeostatic T cell expansion without lymphopenia. J Immunol. 2008;180:7265–75.

    PubMed  CAS  Google Scholar 

  33. Fry TJ, Mackall CL. Interleukin-7: from bench to clinic. Blood. 2002;99:3892–904.

    Article  PubMed  CAS  Google Scholar 

  34. Nelson BH, Lord JD, Greenberg PD. Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature. 1994;369:333–6.

    Article  PubMed  CAS  Google Scholar 

  35. Schluns KS, Lefrançois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol. 2003;3:269–79.

    Article  PubMed  CAS  Google Scholar 

  36. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006;6:595–601.

    Article  PubMed  CAS  Google Scholar 

  37. Dubucquoi S, Desreumaux P, Janin A, Klein O, Goldman M, Tavernier J, Capron A, Capron M. Interleukin 5 synthesis by eosinophils: association with granules and immunoglobulin-dependent secretion. J Exp Med. 1994;179:703–8.

    Article  PubMed  CAS  Google Scholar 

  38. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1–78.

    Article  PubMed  CAS  Google Scholar 

  39. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–78.

    Article  PubMed  Google Scholar 

  40. Maruo N, Morita I, Shirao M, Murota S-I. IL-6 increases endothelial permeability in vitro. Endocrinology. 1992;131:710–4.

    Article  PubMed  CAS  Google Scholar 

  41. Strazynski M, Eble JA, Kresse H, Schönherr E. Interleukin (IL)-6 and IL-10 induce decorin mRNA in endothelial cells, but interaction with fibrillar collagen is essential for its translation. J Biol Chem. 2004;279:21266–70.

    Article  PubMed  CAS  Google Scholar 

  42. Tilg H, Trehu E, Atkins MB. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: Induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood. 1994;83:113–8.

    PubMed  CAS  Google Scholar 

  43. Trinchieri G. Interleukin-12 a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. J Immunol. 1995;13:251–76.

    Article  CAS  Google Scholar 

  44. Numasaki M, Fukushi JI, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101:2620–7.

    Article  PubMed  CAS  Google Scholar 

  45. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang Y-H, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.

    Article  PubMed  CAS  Google Scholar 

  46. Arend WP, Malyak M, Guthridge CJ, Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol. 1998;16:27–55.

    Article  PubMed  CAS  Google Scholar 

  47. Moore KW, O’Gara A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol. 1993;11:165–90.

    Article  PubMed  CAS  Google Scholar 

  48. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440.

    Article  PubMed  CAS  Google Scholar 

  49. Moore KW, de Waal MR, Coffman RI, O’Gara A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.

    Article  PubMed  CAS  Google Scholar 

  50. Seymour RM, Henderson B. Pro-inflammatory-anti-inflammatory cytokine dynamics mediated by cytokine-receptor dynamics in monocytes. IMA J Math Appl Med. 2001;18:159–92.

    Article  CAS  Google Scholar 

  51. Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21:425–56.

    Article  PubMed  CAS  Google Scholar 

  52. Minty A, Chalon P, Derocq JM, Dumont X, Guillemont JC, Kaghad M, Labit C, Leplatois P, Liauzun P, Miloux B, Minty C, Casellas P, Loison G, Lupker J, Schire D, Ferrara P, Caput D. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993;362:248–50.

    Article  PubMed  CAS  Google Scholar 

  53. Schlag G, Redl H. Mediators of injury and inflammation. World J Surg. 1996;20:406–10.

    Article  PubMed  CAS  Google Scholar 

  54. Stahel PF, Morganti-Kossmann MC, Kossmann T. The role of the complement system in traumatic brain injury. Brain Res Rev. 1998;27:243–56.

    Article  PubMed  CAS  Google Scholar 

  55. Keel M, Trentz O. Pathophysiology of polytrauma. Injury. 2005;36:691–709.

    Article  PubMed  Google Scholar 

  56. Schmidt OI, Heyde CE, Ertel W, Stahel PF. Closed head injury-an inflammatory disease? Brain Res Rev. 2005;48:388–99.

    Article  PubMed  Google Scholar 

  57. Liew FY, McInnes IB. The role of innate mediators in inflammatory response. Mol Immunol. 2002;38:887–90.

    Article  PubMed  CAS  Google Scholar 

  58. McInnes IB, Gracie JA. Interleukin-15: a new cytokine target for the treatment of inflammatory diseases. Curr Opin Pharmacol. 2004;4:392–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant from the Department of Neurosurgery, Oslo University Hospital, Oslo, Norway. We highly acknowledge Mrs Aina Mari Lian for excellent technical assistance and Mrs Annet Tøen for skilled database management.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Milo Stanisic.

Additional information

Responsible Editor: Claudia Kasserra.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stanisic, M., Aasen, A.O., Pripp, A.H. et al. Local and systemic pro-inflammatory and anti-inflammatory cytokine patterns in patients with chronic subdural hematoma: a prospective study. Inflamm. Res. 61, 845–852 (2012). https://doi.org/10.1007/s00011-012-0476-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-012-0476-0

Keywords

Navigation