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The Host Response to Sepsis

  • T. J. Hommes
  • W. J. Wiersinga
  • T. van der Poll

Abstract

Sir William Osler, probably the most influential physician in the English-speaking world at the turn of the century more than a hundred years ago, wrote the following about sepsis in his famous text book, The Evolution of Modern Medicine (1904): “Except on few occasions, the patient appears to die from the body’s response to infection rather than from it”. The assumption that sepsis is the consequence of an overwhelming inflammatory reaction of the patient to microorganisms was widely accepted for many years. Current knowledge indicates that this paradigm is oversimplified and only partially true. The original theory that sepsis mortality is caused by an overstimulated immune system was based on studies in animals that were infused with large doses of bacteria or bacterial products, in particular lipopolysaccharide (LPS), the toxic component of the Gram-negative bacterial cell wall. Such infusions result in a brisk systemic release of an array of pro-inflammatory mediators of which many have been found to be directly responsible for the death of the host. In a hallmark manuscript published in 1985, Beutler and colleagues reported that elimination of the early activity of the pro-inflammatory cytokine, tumor necrosis factor (TNF)-α, after intravenous injection of LPS prevented death in mice [1]. Two years later, these results were confirmed by Tracey and colleagues, who showed that a monoclonal anti-TNF-α antibody protected baboons against lethal Gram-negative sepsis [2].

Keywords

Severe Sepsis Tissue Factor Migration Inhibitory Factor Tissue Factor Pathway Inhibitor Cecal Ligation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Beutler B, Milsark IW, Cerami AC (1985) Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229: 869–871CrossRefPubMedGoogle Scholar
  2. 2.
    Tracey KJ, Fong Y, Hesse DG, et al (1987) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330: 662–664CrossRefPubMedGoogle Scholar
  3. 3.
    Lorente JA, Marshall JC (2005) Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock 24 (Suppl 1): 107–119CrossRefPubMedGoogle Scholar
  4. 4.
    Ohlsson K, Bjork P, Bergenfeldt M, Hageman R, Thompson RC (1990) Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 348: 550–552CrossRefPubMedGoogle Scholar
  5. 5.
    Fischer E, Marano MA, Van Zee KJ, et al (1992) Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest 89: 1551–1557CrossRefPubMedGoogle Scholar
  6. 6.
    Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348: 1546–1554CrossRefPubMedGoogle Scholar
  7. 7.
    Arcaroli J, Fessler MB, Abraham E (2005) Genetic polymorphisms and sepsis. Shock 24: 300–312CrossRefPubMedGoogle Scholar
  8. 8.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124: 783–801CrossRefPubMedGoogle Scholar
  9. 9.
    Netea MG, Gow NA, Munro CA, et al (2006) Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 116: 1642–1650CrossRefPubMedGoogle Scholar
  10. 10.
    Liew FY, Xu D, Brint EK, O’Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5: 446–458CrossRefPubMedGoogle Scholar
  11. 11.
    Beutler B, Rietschel ET (2003) Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol 3: 169–176CrossRefPubMedGoogle Scholar
  12. 12.
    Meng G, Rutz M, Schiemann M, et al (2004) Antagonistic antibody prevents toll-like receptor 2-driven lethal shock-like syndromes. J Clin Invest 113: 1473–1481PubMedGoogle Scholar
  13. 13.
    Takeuchi O, Hoshino K, Akira S (2000) Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 165: 5392–5396PubMedGoogle Scholar
  14. 14.
    Klesney-Tait J, Turnbull IR, Colonna M (2006) The TREM receptor family and signal integration. Nat Immunol 7: 1266–1273CrossRefPubMedGoogle Scholar
  15. 15.
    Ogura Y, Sutterwala FS, Flavell RA (2006) The inflammasome: first line of the immune response to cell stress. Cell 126: 659–662CrossRefPubMedGoogle Scholar
  16. 16.
    Schouten M, Wiersinga WJ, Levi M, van der Poll T (2008) Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 83: 536–545CrossRefPubMedGoogle Scholar
  17. 17.
    Dhainaut JF, Shorr AF, Macias WL, et al (2005) Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med 33: 341–348CrossRefPubMedGoogle Scholar
  18. 18.
    Pawlinski R, Pedersen B, Schabbauer G, et al (2004) Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood 103: 1342–1347CrossRefPubMedGoogle Scholar
  19. 19.
    Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344: 699–709CrossRefPubMedGoogle Scholar
  20. 20.
    Warren BL, Eid A, Singer P, et al (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286: 1869–1878CrossRefPubMedGoogle Scholar
  21. 21.
    Abraham E, Reinhart K, Opal S, et al (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290: 238–247CrossRefPubMedGoogle Scholar
  22. 22.
    Abraham E, Laterre PF, Garg R, et al (2005) Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353: 1332–1341CrossRefPubMedGoogle Scholar
  23. 23.
    Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407: 258–264CrossRefPubMedGoogle Scholar
  24. 24.
    Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W (2002) Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296: 1880–1882CrossRefPubMedGoogle Scholar
  25. 25.
    Kaneider NC, Leger AJ, Agarwal A, et al (2007) ‘Role reversal’ for the receptor PAR1 in sepsis-induced vascular damage. Nat Immunol 8: 1303–1312CrossRefPubMedGoogle Scholar
  26. 26.
    Niessen F, Schaffner F, Furlan-Freguia C, et al (2008) Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 452: 654–658CrossRefPubMedGoogle Scholar
  27. 27.
    van der Poll T, Opal SM (2008) Host-pathogen interactions in sepsis. Lancet Infect Dis 8: 32–43CrossRefPubMedGoogle Scholar
  28. 28.
    Munford RS, Pugin J (2001) Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 163: 316–321PubMedGoogle Scholar
  29. 29.
    Hotchkiss RS, Nicholson DW (2006) Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 6: 813–822CrossRefPubMedGoogle Scholar
  30. 30.
    Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5: 331–342CrossRefPubMedGoogle Scholar
  31. 31.
    Wang H, Bloom O, Zhang M, et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248–251CrossRefPubMedGoogle Scholar
  32. 32.
    Yang H, Ochani M, Li J, et al (2004) Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 101: 296–301CrossRefPubMedGoogle Scholar
  33. 33.
    van Zoelen MA, Yang H, Florquin S, et al (2008) Role of Toll-like receptors 2 and 4, and the receptor for advanced glycation end products (RAGE) in HMGB1 induced inflammation in vivo. Shock (in press)Google Scholar
  34. 34.
    van Zoelen MA, van der Poll T (2008) Targeting RAGE in sepsis. Crit Care 12: 103CrossRefPubMedGoogle Scholar
  35. 35.
    Liliensiek B, Weigand MA, Bierhaus A, et al (2004) Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Invest 113: 1641–1650PubMedGoogle Scholar
  36. 36.
    Lutterloh EC, Opal SM, Pittman DD, et al (2007) Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit Care 11: R122CrossRefPubMedGoogle Scholar
  37. 37.
    Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 117: 289–296CrossRefPubMedGoogle Scholar
  38. 38.
    Pavlov VA, Ochani M, Gallowitsch-Puerta M, et al (2006) Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci USA 103: 5219–5223CrossRefPubMedGoogle Scholar
  39. 39.
    Huston JM, Ochani M, Rosas-Ballina M, et al (2006) Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 203: 1623–1628CrossRefPubMedGoogle Scholar
  40. 40.
    Calandra T, Echtenacher B, Roy DL, et al (2000). Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6: 164–170CrossRefPubMedGoogle Scholar
  41. 41.
    Roger T, David J, Glauser MP, Calandra T (2001) MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414: 920–924CrossRefPubMedGoogle Scholar
  42. 42.
    Al-Abed Y, Dabideen D, Aljabari B, et al (2005) ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis. J Biol Chem 280: 36541–36544CrossRefPubMedGoogle Scholar
  43. 43.
    Guo RF, Ward PA (2005) Role of C5a in inflammatory responses. Annu Rev Immunol 23: 821–852CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • T. J. Hommes
    • 1
  • W. J. Wiersinga
    • 1
  • T. van der Poll
    • 1
  1. 1.Academic Medical CenterUniversity of AmsterdamAmsterdamNetherlands

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