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Der Einfluss von Massentransfusion und Schädel-Hirn-Trauma auf die Seruminflammationsmarker TIMP‑1 und MMP‑9 bei polytraumatisierten Patienten

Influence of massive blood transfusion and traumatic brain injury on TIMP‑1 and MMP‑9 serum levels in polytraumatized patients

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Zusammenfassung

Hintergrund

Die Morbidität und Mortalität polytraumatisierter Patienten wird wesentlich durch das Ausmaß der posttraumatischen Inflammationsreaktion beeinflusst. In einer genomweiten mRNA-Microarray-Analyse konnte ein funktionelles Netzwerk an Genen, darunter die Matrixmetalloproteinase MMP‑9 und ihr Inhibitor TIMP‑1 (Tissue Inhibitor of Matrix Metalloproteinase‑1) identifiziert werden, welches in Abhängigkeit der klinischen Parameter „Massentransfusion (MT)“ sowie „Schädel-Hirn-Trauma (SHT)“ signifikant unterschiedlich exprimiert war.

Ziel der Arbeit

Ziel der vorliegenden Arbeit war es nun, die Serumkonzentrationen von TIMP‑1 und MMP‑9 in Abhängigkeit dieser klinischen Variablen in der frühen posttraumatischen Phase zu untersuchen.

Material und Methoden

In diese prospektive Studie wurden Patienten (≥18 Jahre) mit einem „Injury Severity Score“ (ISS) ≥ 16 Punkte eingeschlossen. Die Unterteilung des Kollektivs erfolgte anhand der klinischen Parameter MT (≥ 10EK/24 h) und SHT (CCT-positiv). Die Bestimmung der Serumkonzentrationen (0 h, 6 h, 12 h, 24 h, 48 h, 72 h) erfolgte mittels ELISA („Enzyme-linked Immunosorbent Assay“).

Ergebnisse

Massentransfundierte Patienten (n = 21; 50 ± 15,7 Jahre; ISS 39 ± 12,8 Punkte) zeigten eine insgesamt signifikant erhöhte TIMP‑1-Konzentration (p = 0,003) sowie signifikant höhere TIMP‑1-Level nach 12–72 h. SHT-Patienten (n = 28; 44 ± 19 Jahre; ISS 42 ± 10 Punkte) zeigten signifikant höhere MMP‑9-Konzentrationen im posttraumatischen Verlauf (p = 0,049).

Diskussion

Polytraumatisierte Patienten, die massentransfundiert wurden, wiesen signifikant höhere TIMP‑1-Konzentrationen auf als Nichtmassentransfundierte. Dies scheint Ausdruck einer massiv überschießenden Inflammationsreaktion zu sein und stellt so einen wesentlichen Faktor bei der Pathogenese der schweren posttraumatischen Immundysfunktion dieses Kollektivs dar. Der signifikante MMP‑9-Anstieg bei begleitendem SHT spiegelt die zentrale Rolle der Matrixmetalloproteinase in der Pathophysiologie des SHT wider.

Abstract

Background

The morbidity and mortality of polytrauma patients are substantially influenced by the extent of the posttraumatic inflammatory reaction. Studies have shown that TIMP‑1 and MMP‑9 play a major role in posttraumatic immune disorder in genome-wide mRNA microarray analyses. Furthermore, both showed differential gene expression profiles depending on the clinical parameters massive blood transfusion and traumatic brain injury.

Objective

The aim of this study was to evaluate TIMP‑1 and MMP‑9 serum concentrations in polytraumatized patients depending on the clinical parameters massive blood transfusion and traumatic brain injury in the early posttraumatic phase.

Material and methods

Polytrauma patients (≥18 years) with an „Injury Severity Score“ (ISS) ≥ 16 points were enrolled in this prospective study. Serum levels of TIMP‑1 and MMP‑9 were quantified (at 0 h, 6 h, 12 h, 24 h, 48 h and 72 h) using an enzyme-linked immunosorbent assay (ELISA). Groups were divided according to the clinical parameter massive blood transfusion (≥10 red blood cell units [RBC units] in the first 24-hour posttrauma) and traumatic brain injury (CCT postive [cranial computed tomography]).

Results

Following massive blood transfusion (n = 21; 50 ± 15.7 years; ISS 39 ± 12.8 points) patients showed overall significantly increased TIMP‑1 levels (p = 0.003) and significantly higher TIMP‑1 values after 12–72 h. Traumatic brain injury patients (n = 28; 44 ± 19 years; ISS 42 ± 10 points) showed significantly higher MMP‑9 levels (p = 0.049) in the posttraumatic period.

Conclusion

Polytraumatized patients who received massive blood transfusions following major trauma showed significantly higher TIMP‑1 levels than patients who did not receive massive transfusions. This seems to be an expression of a massively excessive inflammatory reaction and therefore represents a substantial factor in the pathogenesis of severe posttraumatic immune dysfunction in this collective. Furthermore, the significant increase in MMP‑9 with accompanying traumatic brain injury reflects the pivotal role of matrix metalloproteinases in the pathophysiology of traumatic brain injury.

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Literatur

  1. Abdul-Muneer PM, Chandra N, Haorah J (2015) Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury. Mol Neurobiol 51:966–979. https://doi.org/10.1007/s12035-014-8752-3

    Article  CAS  PubMed  Google Scholar 

  2. Biberthaler P, Bogner V, Baker HV et al (2005) Genome-wide monocytic mRNA expression in polytrauma patients for identification of clinical outcome. Shock 24:11–19

    Article  CAS  Google Scholar 

  3. Bilgin YM, van de Watering LMG, Eijsman L et al (2004) Double-blind, randomized controlled trial on the effect of leukocyte-depleted erythrocyte transfusions in cardiac valve surgery. Circulation 109:2755–2760. https://doi.org/10.1161/01.CIR.0000130162.11925.21

    Article  CAS  PubMed  Google Scholar 

  4. Bogner V, Baker HV, Kanz K‑G et al (2009) Hemorrhage and subsequent allogenic red blood cell transfusion are associated with characteristic monocyte messenger RNA expression patterns in patients after multiple injury-a genome wide view. J Trauma 67:792–801. https://doi.org/10.1097/TA.0b013e31819d9c04

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bogner V, Keil L, Kanz K‑G et al (2009) Very early posttraumatic serum alterations are significantly associated to initial massive RBC substitution, injury severity, multiple organ failure and adverse clinical outcome in multiple injured patients. Eur J Med Res 14:284–291. https://doi.org/10.1186/2047-783X-14-7-284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bogner V, Kirchhoff C, Baker HV et al (2007) Gene expression profiles are influenced by ISS, MOF, and clinical outcome in multiple injured patients: a genome-wide comparative analysis. Langenbecks Arch Surg 392:255–265. https://doi.org/10.1007/s00423-007-0182-5

    Article  CAS  PubMed  Google Scholar 

  7. Bogner V, Stoecklein V, Richter P et al (2012) Increased activation of the transcription factor c‑Jun by MAP kinases in monocytes of multiple trauma patients is associated with adverse outcome and mass transfusion. J Surg Res 178:385–389. https://doi.org/10.1016/j.jss.2011.12.035

    Article  CAS  PubMed  Google Scholar 

  8. Brumann M, Kusmenkov T, Ney L et al (2012) Concentration kinetics of serum MMP‑9 and TIMP‑1 after blunt multiple injuries in the early posttraumatic period. Mediators Inflamm. https://doi.org/10.1155/2012/435463

    Article  PubMed  PubMed Central  Google Scholar 

  9. Casault C, Al Sultan AS, Banoei M et al (2018) Cytokine responses in severe traumatic brain injury: where there is smoke, is there fire? Neurocrit Care 25:72–11. https://doi.org/10.1007/s12028-018-0522-z

    Article  CAS  Google Scholar 

  10. Chen Y, Swanson RA (2003) Astrocytes and brain injury. J Cereb Blood Flow Metab 23:137–149. https://doi.org/10.1097/01.WCB.0000044631.80210.3C

    Article  PubMed  Google Scholar 

  11. Copin J‑C, Rebetez MML, Turck N et al (2012) Matrix metalloproteinase 9 and cellular fibronectin plasma concentrations are predictors of the composite endpoint of length of stay and death in the intensive care unit after severe traumatic brain injury. Scand J Trauma Resusc Emerg Med 20:83. https://doi.org/10.1186/1757-7241-20-83

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dunn LK, Thiele RH, Ma JZ et al (2012) Duration of red blood cell storage and outcomes following orthotopic liver transplantation. Liver Transpl 18:475–481. https://doi.org/10.1002/lt.23379

    Article  PubMed  Google Scholar 

  13. Dunne JR, Malone DL, Tracy JK, Napolitano LM (2004) Allogenic blood transfusion in the first 24 hours after trauma is associated with increased systemic inflammatory response syndrome (SIRS) and death. Surg Infect (larchmt) 5:395–404. https://doi.org/10.1089/sur.2004.5.395

    Article  Google Scholar 

  14. Escobar GA, Cheng AM, Moore EE et al (2007) Stored packed red blood cell transfusion up-regulates inflammatory gene expression in circulating leukocytes. Ann Surg 246:129–134. https://doi.org/10.1097/01.sla.0000264507.79859.f9

    Article  PubMed  PubMed Central  Google Scholar 

  15. Fergusson D, Khanna MP, Tinmouth A, Hébert PC (2004) Transfusion of leukoreduced red blood cells may decrease postoperative infections: two meta-analyses of randomized controlled trials. Can J Anaesth 51:417–424. https://doi.org/10.1007/BF03018302

    Article  PubMed  Google Scholar 

  16. Gentile LF, Cuenca AG, Efron PA et al (2012) Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg 72:1491–1501. https://doi.org/10.1097/TA.0b013e318256e000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. von Gertten C, Holmin S, Mathiesen T, Nordqvist A‑CS (2003) Increases in matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 mRNA after cerebral contusion and depolarisation. J Neurosci Res 73:803–810. https://doi.org/10.1002/jnr.10729

    Article  CAS  Google Scholar 

  18. Ghajar J (2000) Traumatic brain injury. Lancet 356:923–929. https://doi.org/10.1016/S0140-6736(00)02689-1

    Article  CAS  PubMed  Google Scholar 

  19. Gill SE, Parks WC (2008) Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol 40:1334–1347. https://doi.org/10.1016/j.biocel.2007.10.024

    Article  CAS  PubMed  Google Scholar 

  20. Green RS, Erdogan M, Lacroix J et al (2018) Age of transfused blood in critically ill adult trauma patients: a prespecified nested analysis of the Age of Blood Evaluation randomized trial. Transfusion 58:1846–1854. https://doi.org/10.1111/trf.14640

    Article  PubMed  Google Scholar 

  21. Hästbacka J, Fredén F, Hult M et al (2015) Matrix metalloproteinases-8 and -9 and tissue inhibitor of metalloproteinase-1 in burn patients. A prospective observational study. PLoS ONE 10:e125918. https://doi.org/10.1371/journal.pone.0125918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hästbacka J, Linko R, Tervahartiala T et al (2014) Serum MMP-8 and TIMP‑1 in critically ill patients with acute respiratory failure: TIMP‑1 is associated with increased 90-day mortality. Anesth Analg 118:790–798. https://doi.org/10.1213/ANE.0000000000000120

    Article  CAS  PubMed  Google Scholar 

  23. Hoffmann U, Bertsch T, Dvortsak E et al (2006) Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP‑1 in severe sepsis. Scand J Infect Dis 38:867–872. https://doi.org/10.1080/00365540600702058

    Article  CAS  PubMed  Google Scholar 

  24. Hopewell S, Omar O, Hyde C et al (2013) A systematic review of the effect of red blood cell transfusion on mortality: evidence from large-scale observational studies published between 2006 and 2010. BMJ Open 3:e2154. https://doi.org/10.1136/bmjopen-2012-002154

    Article  PubMed  PubMed Central  Google Scholar 

  25. Innerhofer P, Kühbacher G (2002) Mechanisms of immunomodulation after transfusion of allogeneic and autologous red cell concentrate. Anasthesiol Intensivmed Notfallmed Schmerzther 37:681–684. https://doi.org/10.1055/s-2002-35115

    Article  CAS  PubMed  Google Scholar 

  26. Johnson JL, Moore EE, Gonzalez RJ et al (2003) Alteration of the postinjury hyperinflammatory response by means of resuscitation with a red cell substitute. J Trauma 54:133–139. https://doi.org/10.1097/01.TA.0000046321.17688.40 (discussion 139–40)

    Article  PubMed  Google Scholar 

  27. Llewelyn CA, Taylor RS, Todd AAM et al (2004) The effect of universal leukoreduction on postoperative infections and length of hospital stay in elective orthopedic and cardiac surgery. Transfusion 44:489–500. https://doi.org/10.1111/j.1537-2995.2004.03325.x

    Article  PubMed  Google Scholar 

  28. Lorente L, Martín MM, Labarta L et al (2009) Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis. Crit Care 13:R158. https://doi.org/10.1186/cc8115

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lorente L, Martín MM, López P et al (2014) Association between serum tissue inhibitor of matrix metalloproteinase-1 levels and mortality in patients with severe brain trauma injury. PLoS ONE 9:e94370. https://doi.org/10.1371/journal.pone.0094370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Malone DL, Dunne J, Tracy JK et al (2003) Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma 54:898–905. https://doi.org/10.1097/01.TA.0000060261.10597.5C (discussion 905–7)

    Article  PubMed  Google Scholar 

  31. Miñambres E, Cemborain A, Sánchez-Velasco P et al (2003) Correlation between transcranial interleukin-6 gradient and outcome in patients with acute brain injury. Crit Care Med 31:933–938. https://doi.org/10.1097/01.CCM.0000055370.66389.59

    Article  CAS  PubMed  Google Scholar 

  32. Moore FA, Moore EE, Sauaia A (1997) Blood transfusion. An independent risk factor for postinjury multiple organ failure. Arch Surg 132:620–624 (discussion 624–5)

    Article  CAS  Google Scholar 

  33. Mostafa Mtairag E, Chollet-Martin S, Oudghiri M et al (2001) Effects of interleukin-10 on monocyte/endothelial cell adhesion and MMP‑9/TIMP‑1 secretion. Cardiovasc Res 49:882–890

    Article  CAS  Google Scholar 

  34. Nathens AB, Nester TA, Rubenfeld GD et al (2006) The effects of leukoreduced blood transfusion on infection risk following injury: a randomized controlled trial. Shock 26:342–347. https://doi.org/10.1097/01.shk.0000228171.32587.a1

    Article  PubMed  Google Scholar 

  35. Opelz G, Sengar DP, Mickey MR, Terasaki PI (1973) Effect of blood transfusions on subsequent kidney transplants. Transplant Proc 5:253–259

    CAS  PubMed  Google Scholar 

  36. Parks WC, Wilson CL, López-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4:617–629. https://doi.org/10.1038/nri1418

    Article  CAS  PubMed  Google Scholar 

  37. Pavenski K, Saidenberg E, Lavoie M et al (2012) Red blood cell storage lesions and related transfusion issues: a Canadian Blood Services research and development symposium. Transfus Med Rev. https://doi.org/10.1016/j.tmrv.2011.07.003

    Article  PubMed  Google Scholar 

  38. Plurad D, Belzberg H, Schulman I et al (2008) Leukoreduction is associated with a decreased incidence of late onset acute respiratory distress syndrome after injury. Am Surg 74:117–123

    PubMed  Google Scholar 

  39. Ramos-Fernandez M, Bellolio MF, Stead LG (2011) Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review. J Stroke Cerebrovasc Dis 20:47–54. https://doi.org/10.1016/j.jstrokecerebrovasdis.2009.10.008

    Article  PubMed  Google Scholar 

  40. Ricou B, Nicod L, Lacraz S et al (1996) Matrix metalloproteinases and TIMP in acute respiratory distress syndrome. Am J Respir Crit Care Med 154:346–352. https://doi.org/10.1164/ajrccm.154.2.8756805

    Article  CAS  PubMed  Google Scholar 

  41. Sauaia A, Moore FA, Moore EE (2017) Postinjury inflammation and organ dysfunction. Crit Care Clin 33:167–191. https://doi.org/10.1016/j.ccc.2016.08.006

    Article  PubMed  PubMed Central  Google Scholar 

  42. Simon D, Evaldt J, Nabinger DD et al (2017) Plasma matrix metalloproteinase-9 levels predict intensive care unit mortality early after severe traumatic brain injury. Brain Inj 31:390–395. https://doi.org/10.1080/02699052.2016.1259501

    Article  PubMed  Google Scholar 

  43. Suofu Y, Clark JF, Broderick JP et al (2012) Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience 212:180–189. https://doi.org/10.1016/j.neuroscience.2012.03.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. van de Watering LM, Hermans J, Houbiers JG et al (1998) Beneficial effects of leukocyte depletion of transfused blood on postoperative complications in patients undergoing cardiac surgery: a randomized clinical trial. Circulation 97:562–568

    Article  Google Scholar 

  45. Vilalta A, Sahuquillo J, Rosell A et al (2008) Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med 34:1384–1392. https://doi.org/10.1007/s00134-008-1056-1

    Article  CAS  PubMed  Google Scholar 

  46. Wang X, Jung J, Asahi M et al (2000) Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci 20:7037–7042

    Article  CAS  Google Scholar 

  47. Watkins TR, Rubenfeld GD, Martin TR et al (2008) Effects of leukoreduced blood on acute lung injury after trauma: a randomized controlled trial. Crit Care Med 36:1493–1499. https://doi.org/10.1097/CCM.0b013e318170a9ce

    Article  PubMed  Google Scholar 

  48. Zubair AC (2010) Clinical impact of blood storage lesions. Am J Hematol 85:117–122. https://doi.org/10.1002/ajh.21599

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Klinik für Allgemeine, Unfall- und Wiederherstellungschirurgie, Klinikum der Universität München, LMU München, Nußbaumstr. 20, 80336, München, Deutschland

    M. Braunstein, T. Kusmenkov, W. Böcker & V. Bogner-Flatz

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Correspondence to M. Braunstein.

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Interessenkonflikt

M. Braunstein, T. Kusmenkov, W. Böcker und V. Bogner-Flatz geben an, dass kein Interessenkonflikt besteht.

Alle im vorliegenden Manuskript beschriebenen Untersuchungen am Menschen wurden mit Zustimmung der zuständigen Ethik-Kommission, im Einklang mit nationalem Recht sowie gemäß der Deklaration von Helsinki von 1975 (in der aktuellen, überarbeiteten Fassung) durchgeführt. Von allen beteiligten Patienten liegt eine Einverständniserklärung vor.

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Braunstein, M., Kusmenkov, T., Böcker, W. et al. Der Einfluss von Massentransfusion und Schädel-Hirn-Trauma auf die Seruminflammationsmarker TIMP‑1 und MMP‑9 bei polytraumatisierten Patienten. Unfallchirurg 122, 967–976 (2019). https://doi.org/10.1007/s00113-019-0623-y

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