Advertisement

Hemorrhagic shock induces renal complement activation

  • Christian EhrnthallerEmail author
  • Anke Schultze
  • Gamal Wakileh
  • Thomas Neff
  • Sebastian Hafner
  • Peter Radermacher
  • Markus Huber-Lang
Original Article
  • 28 Downloads

Abstract

Purpose

Complement is activated in hemorrhagic shock and protective effects by specific complement inhibition were shown. However, it remains unclear if complement activation contributes to the local tissue damage and organ failure. Zonulin is known to activate complement and affect organ failure. Therefore, local and systemic complement activation during hemorrhagic shock and its consequences on zonulin were examined.

Methods

Porcine hemorrhagic shock (n = 9) was initiated with mean arterial blood pressure maintained constant for 4 h before retransfusion. Before, 4 h after hemorrhage and 12 and 22 h after resuscitation, central and renal blood samples were drawn. Analysis included HMGB-1, C3a, and zonulin (blood and kidney homogenisates) as well as terminal complement complex (TCC) and CH50 (blood). Organ samples were taken for histological and immunohistochemical analyses (C3c).

Results

HMGB-1 was significantly elevated in plasma 4 h after hemorrhagic shock and in homogenized kidneys. TCC after 12 h was significantly elevated centrally, while renal levels were not altered. In contrast, CH50 showed diminished renal values, while normal central levels were observed. Local complement activation was observed with enhanced C3c deposition in kidneys. Zonulin showed significantly diminished levels at 12 and 22 h after hemorrhagic shock (central and renal) and significantly correlated with levels of CH50 and neutrophil gelatinase-associated lipocalin (NGAL).

Conclusion

The more pronounced complement activation centrally might indicate consumption of complement products in kidney tissue, which is underlined by C3c staining. Together with diminished levels of zonulin in both systemic and local samples, results could indicate the involvement of complement as well as zonulin in acute kidney failure.

Keywords

Complement Hemorrhagic shock Tight junction Acute kidney failure Zonulin 

Notes

Acknowledgements

This work is supported by grants from the German Research Foundation (DFG) to MH-L and P-R (SFB1149 A01, B03, Z02).

Compliance with ethical standards

Conflict of interest

All authors report no conflict of interests.

References

  1. 1.
    Ehrnthaller C, et al. New insights of an old defense system: structure, function, and clinical relevance of the complement system. Mol Med. 2011;17(3–4):317–29.PubMedGoogle Scholar
  2. 2.
    Huber-Lang M, Ignatius A, Brenner RE. Role of complement on broken surfaces after trauma. Adv Exp Med Biol. 2015;865:43–55.PubMedGoogle Scholar
  3. 3.
    Arumugam TV, et al. Complement mediators in ischemia-reperfusion injury. Clin Chim Acta. 2006;374(1–2):33–45.PubMedGoogle Scholar
  4. 4.
    Tschoeke SK, Ertel W. Immunoparalysis after multiple trauma. Injury. 2007;38(12):1346–57.PubMedGoogle Scholar
  5. 5.
    Huber-Lang MS, et al. Complement-induced impairment of innate immunity during sepsis. J Immunol. 2002;169(6):3223–31.PubMedGoogle Scholar
  6. 6.
    Ward PA. Sepsis, apoptosis and complement. Biochem Pharmacol. 2008;76(11):1383–8.PubMedGoogle Scholar
  7. 7.
    Huber-Lang MS, et al. Protection of innate immunity by C5aR antagonist in septic mice. FASEB J. 2002;16(12):1567–74.PubMedGoogle Scholar
  8. 8.
    Arumugam TV, et al. A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats. Kidney Int. 2003;63(1):134–42.PubMedGoogle Scholar
  9. 9.
    Ehrnthaller C, et al. Alteration of complement hemolytic activity in different trauma and sepsis models. J Inflamm Res. 2012;5:59–66.PubMedGoogle Scholar
  10. 10.
    Chen D, et al. Inhibition of complement C3 might rescue vascular hyporeactivity in a conscious hemorrhagic shock rat model. Microvasc Res. 2016;105:23–9.PubMedGoogle Scholar
  11. 11.
    Goering J, Pope MR, Fleming SD. TLR2 regulates complement-mediated inflammation induced by blood loss during hemorrhage. Shock. 2016;45(1):33–9.PubMedGoogle Scholar
  12. 12.
    Cunningham PN, et al. Complement is activated in kidney by endotoxin but does not cause the ensuing acute renal failure. Kidney Int. 2000;58(4):1580–7.PubMedGoogle Scholar
  13. 13.
    Dalle Lucca JJ, et al. Effects of C1 inhibitor on tissue damage in a porcine model of controlled hemorrhage. Shock. 2012;38(1):82–91.PubMedGoogle Scholar
  14. 14.
    Dalle Lucca JJ, et al. Decay-accelerating factor limits hemorrhage-instigated tissue injury and improves resuscitation clinical parameters. J Surg Res. 2013;179(1):153–67.PubMedGoogle Scholar
  15. 15.
    Rittirsch D, et al. Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system. Am J Physiol Lung Cell Mol Physiol. 2013;304(12):L863–72.PubMedGoogle Scholar
  16. 16.
    Klaus DA, et al. Increased plasma zonulin in patients with sepsis. Biochem Med (Zagreb). 2013;23(1):107–11.Google Scholar
  17. 17.
    Knoller E, et al. Effects of hyperoxia and mild therapeutic hypothermia during resuscitation from porcine hemorrhagic shock. Crit Care Med. 2016;44(5):e264–77.PubMedGoogle Scholar
  18. 18.
    van Vuuren BJ, et al. Electroluminescent TCC, C3dg and fB/Bb epitope assays for profiling complement cascade activation in vitro using an activated complement serum calibration standard. J Immunol Methods. 2014;402(1–2):50–6.PubMedGoogle Scholar
  19. 19.
    Venereau E, et al. HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol. 2013;55(1):76–82.PubMedGoogle Scholar
  20. 20.
    Cohen MJ, et al. Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion. Crit Care. 2009;13(6):R174.PubMedGoogle Scholar
  21. 21.
    Yang H, et al. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013;93(6):865–73.PubMedGoogle Scholar
  22. 22.
    Ganter MT, et al. Role of the alternative pathway in the early complement activation following major trauma. Shock. 2007;28(1):29–34.PubMedGoogle Scholar
  23. 23.
    Frey A, et al. Complement C3c as a biomarker in heart failure. Mediators Inflamm. 2013;2013:716902.PubMedGoogle Scholar
  24. 24.
    Ficek J, et al. Relationship between plasma levels of zonulin, bacterial lipopolysaccharides, D-lactate and markers of inflammation in haemodialysis patients. Int Urol Nephrol. 2017;49(4):717–25.PubMedGoogle Scholar
  25. 25.
    Dschietzig TB, et al. Plasma Zonulin and its association with kidney function, severity of heart failure, and metabolic inflammation. Clin Lab. 2016;62(12):2443–7.PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of SurgeryUniversity of UlmUlmGermany
  2. 2.Department of General, Trauma and Reconstructive SurgeryMunich University Hospital LMUMunichGermany
  3. 3.Institute of Clinical and Experimental TraumaimmunologyUniversity of UlmUlmGermany
  4. 4.Department of Anesthesiology and Intensive Care MedicineCantonal Hospital of MuensterlingenMuensterlingenSwitzerland
  5. 5.Anesthesiological Pathophysiology and Process DevelopmentUniversity of UlmUlmGermany

Personalised recommendations