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⇱ Protective effects of C5a blockade in sepsis | Nature Medicine

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Abstract

Sepsis in humans is a difficult condition to treat and is often associated with a high mortality rate. In this study, we induced sepsis in rats using cecal ligation and puncture (CLP). In rats depleted of the complement factor C3, CLP led to very short survival times (about 4 days). Of the rats that underwent CLP ('CLP rats') that were C3-intact and treated with preimmune IgG, most (92%) were dead by 7 days. Blood neutrophils from these rats contained on their surfaces the powerful complement activation product C5a. This group had high levels of bacteremia, and their blood neutrophils when stimulated in vitro had greatly reduced production of H2O2, which is known to be essential for the bactericidal function of neutrophils. In contrast, when companion CLP rats were treated with IgG antibody against C5a, survival rates were significantly improved, levels of bacteremia were considerably reduced, and the H2O2 response of blood neutrophils was preserved. Bacterial colony-forming units in spleen and liver were very high in CLP rats treated with preimmune IgG and very low in CLP rats treated with IgG antibody against C5a, similar to values obtained in rats that underwent 'sham' operations (without CLP). These data indicate that sepsis causes an excessive production of C5a, which compromises the bactericidal function of neutrophils. Thus, C5a may be a useful target for the treatment of sepsis.

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Figure 1: Rates of survival in rats after cecal ligation and puncture (CLP).
The alternative text for this image may have been generated using AI.
Figure 2: Bacterial colony-forming units (CFU) in blood.
The alternative text for this image may have been generated using AI.
Figure 3: Bacterial colony-forming units (CFU) in spleen and liver.
The alternative text for this image may have been generated using AI.
Figure 4: H2O2 production by blood neutrophils.
The alternative text for this image may have been generated using AI.

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References

  1. Bone, R.C. Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit. Care Med. 24, 163–172 (1996).

    Article  CAS  Google Scholar 

  2. Nichols, R. et al. Risk of infection after penetrating abdominal trauma. N. Engl. J. Med. 311, 1065–1070 (1984).

    Article  CAS  Google Scholar 

  3. Border, J.R. et al. The gut origin sepsis state in blunt multiple trauma (ISS=40) in the ICU. Ann. Surg. 206, 427–448 (1987).

    Article  CAS  Google Scholar 

  4. Dinarello, C.A., Gelfand, J.A. & Wolff, S.M. Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. J. Am. Med. Assoc. 269, 1829–1835 (1993).

    Article  CAS  Google Scholar 

  5. Deitch, E.A. Animal models of sepsis and shock: a review and lessons learned. Shock 9, 1–11 (1997).

    Article  Google Scholar 

  6. Wichtermann, K.A., Bauer, A.E. & Chaudry, I.H. Sepsis and shock – a review of laboratory models and a proposal. J. Surg. Res. 29, 189–201 (1980).

    Article  Google Scholar 

  7. Nakae, H., Endo, S., Inada, K. & Yoshida, M. Chronological changes in the complement system in sepsis. Jpn. J. Surg. 26, 225–229 (1996).

    CAS  Google Scholar 

  8. Quezado, Z.M. et al. The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ failure. J. Exp. Med. 179, 569–578 (1994).

    Article  CAS  Google Scholar 

  9. Kubens, B.S. & Opferkuch, W. in The Complement System (eds. Rother, K. & Till, G.O.) 469–487 (Springer-Verlag, Berlin, 1988).

    Google Scholar 

  10. Koehl, J. & Bitter-Suermann, D. in Anaphylatoxins. Complement in Health and Disease (eds. Whaley, K., Loos, M. & Weiler, J.M.) 299–324 (Kluwer Academic, London, 1993).

    Book  Google Scholar 

  11. Klebanoff, S.J. Antimicrobial mechanisms in neutrophilic polymorphonuclear leukocytes. Semin. Hematol. 12, 117–142 (1975).

    CAS  PubMed  Google Scholar 

  12. Elsbach, P. & Weiss, J. Oxygen-dependent and oxygen-independent mechanisms of microbicidal activity of neutrophils. Immunol. Lett. 11, 159–163 (1983).

    Article  Google Scholar 

  13. Wessels, M.R. Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity. Proc. Natl. Acad. Sci. USA 92, 11490–11494 (1995).

    Article  CAS  Google Scholar 

  14. Fischer, M.B. et al. Increased susceptibility to endotoxin shock in complement C3- and C4-deficient mice is corrected by C1 inhibitor replacement. J. Immunol. 159, 976–982 (1997).

    CAS  PubMed  Google Scholar 

  15. May, J.E., Kane, M.A. & Frank, M.M. Host defense against bacterial endotoxemia–contribution of the early and late components of complement to detoxification. J. Immunol. 109, 893–895 (1972).

    CAS  PubMed  Google Scholar 

  16. Schumacher, W.A., Fantone, J.C., Kunkel, S.E., Webb, R.C. & Lucchesi, B.R. The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculature in vitro and in vivo. Agents Actions 34, 345–349 (1991).

    Article  CAS  Google Scholar 

  17. Ward, P.A. & Becker, E.L. The deactivation of rabbit neutrophils by chemotactic factor and the nature of activatable esterase. J. Exp. Med. 127, 693–709 (1968).

    Article  CAS  Google Scholar 

  18. Solomkin, J.S., Jenkins, M.K., Nelson, R.D., Chenoweth, D. & Simmons, R.L. Neutrophil dysfunction in sepsis. II. Evidence for the role of complement activation products in cellular deactivation. Surgery 90, 319–327 (1981).

    CAS  PubMed  Google Scholar 

  19. Mulligan, M.S. et al. Requirement and role of C5a in acute inflammatory lung injury in rats. J. Clin. Invest. 98, 503–512 (1996).

    Article  CAS  Google Scholar 

  20. Hill, J.H. & Ward, P.A. The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J. Exp. Med. 133, 885–900 (1971).

    Article  CAS  Google Scholar 

  21. Alexander, J.W. et al. A comparison of immunologic profiles and their influence on bacteremia in surgical patients with a high risk of infection. Surgery 86, 84–104 (1979).

    Google Scholar 

  22. Mohr M et al. Effects of anti-C5a monoclonal antibodies on oxygen use in a porcine model of severe sepsis. Eur. J. Clin. Invest. 28, 227–234 (1998).

    Article  CAS  Google Scholar 

  23. Stevens, J.H. et al. Effects of anti-C5a antibodies on the adult respiratory distress syndrome in septic primates. J. Clin. Invest. 77, 1812–1816 (1986).

    Article  CAS  Google Scholar 

  24. Johnson, K.J. & Ward, P.A. Protective function of C6 in rabbits treated with bacterial endotoxin. J. Immunol. 106, 1125–1127 (1971).

    CAS  PubMed  Google Scholar 

  25. HΓΆpken, U.E., Lu, B., Gerard, N.P. & Gerard, C. The C5a chemoattractant receptor mediates mucosal defense to infection. Nature 383, 86–89 (1996).

    Article  Google Scholar 

  26. Naik, N., Giannini, E., Brouchon, L. & Boulay, F. Internalization and recycling of the C5a anaphylatoxin receptor: evidence that the agonist-mediated internalization is modulated by phosphorylation of the C-terminal domain. J. Cell Science. 110, 2381–2390 (1997).

    CAS  PubMed  Google Scholar 

  27. Giannini, E. & Boulay, F. Phosphorylation, dephosphorylation, and recycling of the C5a receptor in differentiated HL60 cells. J. Immunol. 154, 4055–4064 (1995).

    CAS  PubMed  Google Scholar 

  28. Bock, D. et al. The C terminus of the human C5a receptor (CD88) is required for normal ligand-dependent receptor internalization. Eur. J. Immunol. 27, 1522–1529 (1997).

    Article  CAS  Google Scholar 

  29. Van Epps, D.E., Simpson, S., Bender, J.G. & Chenoweth, D.E. Regulation of C5a and formyl peptide receptor expression on human polymorphonuclear leukocytes. J Immunol 144, 1062–1068 (1990).

    CAS  PubMed  Google Scholar 

  30. Van Epps, D.E., Simpson, S.J. & Johnson, R. Relationship of C5a receptor modulation to the functional responsiveness of human polymorphonuclear leukocytes to C5a. J. Immunol. 150, 246–252 (1993).

    CAS  PubMed  Google Scholar 

  31. Czermak, B.J. et al. Mechanisms of enhanced lung injury during sepsis. Am J Path 154, 1057–1065 (1999).

    Article  CAS  Google Scholar 

  32. Olson, L.M., Moss, G.S., Baukus, O. & Das Gupta, T.K. The role of C5 in septic lung injury. Ann. Surg. 202, 771–776 (1985).

    Article  CAS  Google Scholar 

  33. Rothermel, E., Rolf, O., GΓΆtze, O. & Zwirner, J. Nucleotide and corrected amino acid sequence of the functional recombinant rat anaphylatoxin C5a. Biochim. Biophys. Acta 1351, 9–12 (1997).

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Trauma Surgery, University of Freiburg Medical School, Freiburg/Breisgau, Germany, D-79106

    Boris J. Czermak, Markus Huber-Lang, Nicolas M. Bless, Hagen Schmal & Hans Peter Friedl

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, 48109, Michigan

    Boris J. Czermak, Vidya Sarma, Carl L. Pierson, Roscoe L. Warner, Markus Huber-Lang & Peter A. Ward

Authors
  1. Boris J. Czermak
  2. Vidya Sarma
  3. Carl L. Pierson
  4. Roscoe L. Warner
  5. Markus Huber-Lang
  6. Nicolas M. Bless
  7. Hagen Schmal
  8. Hans Peter Friedl
  9. Peter A. Ward

Corresponding author

Correspondence to Peter A. Ward.

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Czermak, B., Sarma, V., Pierson, C. et al. Protective effects of C5a blockade in sepsis. Nat Med 5, 788–792 (1999). https://doi.org/10.1038/10512

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  • DOI: https://doi.org/10.1038/10512

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