Skip to main content
SpringerLink
Log in

Hemorrhagic shock induces renal complement activation

  • Original Article
  • Published:
European Journal of Trauma and Emergency Surgery Aims and scope Submit manuscript

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.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  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.

    Article  CAS  Google Scholar 

  2. Huber-Lang M, Ignatius A, Brenner RE. Role of complement on broken surfaces after trauma. Adv Exp Med Biol. 2015;865:43–55.

    Article  CAS  Google Scholar 

  3. Arumugam TV, et al. Complement mediators in ischemia-reperfusion injury. Clin Chim Acta. 2006;374(1–2):33–45.

    Article  CAS  Google Scholar 

  4. Tschoeke SK, Ertel W. Immunoparalysis after multiple trauma. Injury. 2007;38(12):1346–57.

    Article  Google Scholar 

  5. Huber-Lang MS, et al. Complement-induced impairment of innate immunity during sepsis. J Immunol. 2002;169(6):3223–31.

    Article  CAS  Google Scholar 

  6. Ward PA. Sepsis, apoptosis and complement. Biochem Pharmacol. 2008;76(11):1383–8.

    Article  CAS  Google Scholar 

  7. Huber-Lang MS, et al. Protection of innate immunity by C5aR antagonist in septic mice. FASEB J. 2002;16(12):1567–74.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  9. Ehrnthaller C, et al. Alteration of complement hemolytic activity in different trauma and sepsis models. J Inflamm Res. 2012;5:59–66.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  11. Goering J, Pope MR, Fleming SD. TLR2 regulates complement-mediated inflammation induced by blood loss during hemorrhage. Shock. 2016;45(1):33–9.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  16. Klaus DA, et al. Increased plasma zonulin in patients with sepsis. Biochem Med (Zagreb). 2013;23(1):107–11.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  19. Venereau E, et al. HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol. 2013;55(1):76–82.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  22. Ganter MT, et al. Role of the alternative pathway in the early complement activation following major trauma. Shock. 2007;28(1):29–34.

    Article  CAS  Google Scholar 

  23. Frey A, et al. Complement C3c as a biomarker in heart failure. Mediators Inflamm. 2013;2013:716902.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany

    Christian Ehrnthaller & Gamal Wakileh

  2. Department of General, Trauma and Reconstructive Surgery, Munich University Hospital LMU, Campus Großhadern, Marchioninistr. 15, 81377, Munich, Germany

    Christian Ehrnthaller

  3. Institute of Clinical and Experimental Traumaimmunology, University of Ulm, Ulm, Germany

    Christian Ehrnthaller, Anke Schultze, Gamal Wakileh & Markus Huber-Lang

  4. Department of Anesthesiology and Intensive Care Medicine, Cantonal Hospital of Muensterlingen, Muensterlingen, Switzerland

    Thomas Neff

  5. Anesthesiological Pathophysiology and Process Development, University of Ulm, Ulm, Germany

    Sebastian Hafner & Peter Radermacher

Authors
  1. Christian Ehrnthaller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anke Schultze
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gamal Wakileh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Neff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sebastian Hafner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Radermacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Markus Huber-Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Ehrnthaller.

Ethics declarations

Conflict of interest

All authors report no conflict of interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ehrnthaller, C., Schultze, A., Wakileh, G. et al. Hemorrhagic shock induces renal complement activation. Eur J Trauma Emerg Surg 47, 373–380 (2021). https://doi.org/10.1007/s00068-019-01187-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00068-019-01187-1

Keywords

Search

Navigation