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Lymphocyte Apoptosis in Sepsis and Potential Anti-apoptotic Strategies

  • S. Weber
  • B. Baessler
  • S. Schroeder

Abstract

Sepsis is a leading cause of death in many intensive care units [1]. The pathophysiology of sepsis is characterized by a dysregulation of the immune system in response to infection or secondary to trauma. Initial hyperinflammation often results in septic shock. Simultaneously, part of the immune system is deactivated leading to a emporary but often deadly immunosuppression. In attempting to arrive at a more detailed understanding of immunophysiological processes during sepsis over the last few years, apoptosis has been recognized as one of the key factors in the pathophysiology of sepsis [2]. As shown in several animal models, accelerated apoptosis seems to be induced in leukocytes and many immunocompetent cells during sepsis [3, 4]. Similar processes are involved in humans [5].

Keywords

Systemic Inflammatory Response Syndrome Septic Patient Lymphocyte Apoptosis Polymicrobial Sepsis Apoptotic Protease Activate Factor 
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.
    Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348: 138–150CrossRefPubMedGoogle Scholar
  2. 2.
    Hotchkiss RS, Nicholson DW (2006) Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 6: 813–822CrossRefPubMedGoogle Scholar
  3. 3.
    Ayala A, Herdon CD, Lehman DL, Ayala CA, Chaudry IH (1996) Differential induction of capoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators. Blood 87: 4261–4275PubMedGoogle Scholar
  4. 4.
    Wang SD, Huang KJ, Lin YS, Lei HY (1994) Sepsis-induced apoptosis of the thymocytes in mice. J Immunol 152: 5014–5021PubMedGoogle Scholar
  5. 5.
    Hotchkiss RS, Swanson PE, Freeman BD, et al (1999) Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 27: 1230–1251CrossRefPubMedGoogle Scholar
  6. 6.
    Wheeler AP, Bernard GR (1999) Treating patients with severe sepsis. N Engl J Med 340: 207–214CrossRefPubMedGoogle Scholar
  7. 7.
    Kox WJ, Volk T, Kox SN, Volk HD (2000) Immunomodulatory therapies in sepsis. Intensive Care Med 26 (Suppl 1): S124–S128CrossRefPubMedGoogle Scholar
  8. 8.
    Hotchkiss RS, Chang KC, Swanson PE, et al (2000) Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 1: 496–501CrossRefPubMedGoogle Scholar
  9. 9.
    Fisher CJ, Jr., Agosti JM, Opal SM, et al (1996) Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 334: 1697–1702CrossRefPubMedGoogle Scholar
  10. 10.
    Weber SU, Brummer-Smith S, Schroeder S (2008) Apoptosis in sepsis. In: Fenton RH, Burnside CB (eds) Cell Apoptosis Research Progress, 1st edn. Nova Science Publishers Inc, Hauppauge, pp 113–134Google Scholar
  11. 11.
    Hengartner MO (2000) The biochemistry of apoptosis. Nature 407: 770–776CrossRefPubMedGoogle Scholar
  12. 12.
    Perl M, Chung CS, Ayala A (2005) Apoptosis. Crit Care Med 33: S526–S529CrossRefPubMedGoogle Scholar
  13. 13.
    Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305: 626–629CrossRefPubMedGoogle Scholar
  14. 14.
    Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11: 381–389CrossRefPubMedGoogle Scholar
  15. 15.
    Krammer PH (2000) CD95’s deadly mission in the immune system. Nature 407: 789–795CrossRefPubMedGoogle Scholar
  16. 16.
    Weber SU, Schewe JC, Putensen C, Stüber F, Schröder S (2004) [Apoptosis as a pathomechanism in sepsis]. Anaesthesist 53: 59–65CrossRefPubMedGoogle Scholar
  17. 17.
    Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol 2: 67–71CrossRefPubMedGoogle Scholar
  18. 18.
    Braun JS, Novak R, Herzog KH, Bodner SM, Cleveland JL, Tuomanen EI (1999) Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat Med 5: 298–302CrossRefPubMedGoogle Scholar
  19. 19.
    Hotchkiss RS, Tinsley KW, Swanson PE, et al (1999) Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci USA 96: 14541–14546CrossRefPubMedGoogle Scholar
  20. 20.
    Neviere R, Fauvel H, Chopin C, Formstecher P, Marchetti P (2001) Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis. Am J Respir Crit Care Med 163: 218–225PubMedGoogle Scholar
  21. 21.
    Hotchkiss RS, Coopersmith CM, Karl IE (2005) Prevention of lymphocyte apoptosis-a potential treatment of sepsis?. Clin Infect Dis 41 (Suppl 7): S465–S469CrossRefPubMedGoogle Scholar
  22. 22.
    Rouquet N, Pages JC, Molina T, Briand P, Joulin V (1996) ICE inhibitor YVADcmk is a potent therapeutic agent against in vivo liver apoptosis. Curr Biol 6: 1192–1195CrossRefPubMedGoogle Scholar
  23. 23.
    Wesche-Soldato DE, Swan RZ, Chung CS, Ayala A (2007) The apoptotic pathway as a therapeutic target in sepsis. Curr Drug Targets 8: 493–500CrossRefPubMedGoogle Scholar
  24. 24.
    Kang SJ, Wang S, Kuida K, Yuan J (2002) Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic shock response. Cell Death Differ 9: 1115–1125CrossRefPubMedGoogle Scholar
  25. 25.
    Wesche-Soldato DE, Chung CS, Lomas-Neira J, Doughty LA, Gregory SH, Ayala A (2005) In vivo delivery of caspase-8 or Fas siRNA improves the survival of septic mice. Blood 106: 2295–2301CrossRefPubMedGoogle Scholar
  26. 26.
    Saleh M, Vaillancourt JP, Graham RK, et al (2004) Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429: 75–79CrossRefPubMedGoogle Scholar
  27. 27.
    Ayala A, Chung CS, Xu YX, Evans TA, Redmond KM, Chaudry IH (1999) Increased inducible apoptosis in CD4+ T lymphocytes during polymicrobial sepsis is mediated by Fas ligand and not endotoxin. Immunology 97: 45–55CrossRefPubMedGoogle Scholar
  28. 28.
    Chung CS, Yang S, Song GY, et al (2001) Inhibition of Fas signaling prevents hepatic injury and improves organ blood flow during sepsis. Surgery 130: 339–345CrossRefPubMedGoogle Scholar
  29. 29.
    Hotchkiss RS, Swanson PE, Knudson CM, et al (1999) Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol 162: 4148–4156PubMedGoogle Scholar
  30. 30.
    Hotchkiss RS, McConnell KW, Bullok K, et al (2006) TAT-BH4 and TAT-Bcl-xL peptides protect against sepsis-induced lymphocyte apoptosis in vivo. J Immunol 176: 5471–5477PubMedGoogle Scholar
  31. 31.
    Bommhardt U, Chang KC, Swanson PE, et al (2004) Akt decreases lymphocyte apoptosis and improves survival in sepsis. J Immunol 172: 7583–7591PubMedGoogle Scholar
  32. 32.
    Zeerleder S, Zwart B, Wuillemin WA, et al (2003) Elevated nucleosome levels in systemic inflammation and sepsis. Crit Care Med 31: 1947–1951CrossRefPubMedGoogle Scholar
  33. 33.
    Bilbault P, Lavaux T, Lahlou A, et al (2004) Transient Bcl-2 gene down-expression in circulating mononuclear cells of severe sepsis patients who died despite appropriate intensive care. Intensive Care Med 30: 408–415CrossRefPubMedGoogle Scholar
  34. 34.
    Hotchkiss RS, Tinsley KW, Swanson PE, et al (2001) Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol. 166: 6952–6963PubMedGoogle Scholar
  35. 35.
    Hotchkiss RS, Tinsley KW, Swanson PE, et al (2002) Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol. 168: 2493–2500PubMedGoogle Scholar
  36. 36.
    Schroeder S, Lindemann C, Decker D, et al (2001) Increased susceptibility to apoptosis in circulating lymphocytes of critically ill patients. Langenbecks Arch Surg. 386: 42–46CrossRefPubMedGoogle Scholar
  37. 37.
    Roth G, Moser B, Krenn C, et al (2003) Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance. Biochem Biophys Res Commun 308: 840–846CrossRefPubMedGoogle Scholar
  38. 38.
    Adrie C, Bachelet M, Vayssier-Taussat M, et al (2001) Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis. Am J Respir Crit Care Med 164: 389–395PubMedGoogle Scholar
  39. 39.
    Doughty L, Clark RS, Kaplan SS, Sasser H, Carcillo J (2002) sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome. Pediatr Res 52: 922–927PubMedGoogle Scholar
  40. 40.
    Papathanassoglou ED, Moynihan JA, Vermillion DL, McDermott MP, Ackerman MH (2000) Soluble fas levels correlate with multiple organ dysfunction severity, survival and nitrate levels, but not with cellular apoptotic markers in critically ill patients. Shock 14: 107–112CrossRefPubMedGoogle Scholar
  41. 41.
    Torre D, Tambini R, Manfredi M, et al (2003) Circulating levels of FAS/APO-1 in patients with the sytemic inflammatory response syndrome. Diagn Microbiol Infect Dis 45: 233–236CrossRefPubMedGoogle Scholar
  42. 42.
    De Freitas I, Fernandez-Somoza M, Essenfeld-Sekler E, Cardier JE (2004) Serum levels of the apoptosis-associated molecules, tumor necrosis factor-alpha/tumor necrosis factor type-I receptor and Fas/FasL, in sepsis. Chest 125: 2238–2246CrossRefPubMedGoogle Scholar
  43. 43.
    Marsik C, Halama T, Cardona F, et al (2003) Regulation of Fas (APO-1, CD95) and Fas ligand expression in leukocytes during systemic inflammation in humans. Shock 20: 493–496CrossRefPubMedGoogle Scholar
  44. 44.
    Papathanassoglou ED, Moynihan JA, McDermott MP, Ackerman MH (2001) Expression of Fas (CD95) and Fas ligand on peripheral blood mononuclear cells in critical illness and association with multiorgan dysfunction severity and survival. Crit Care Med 29: 709–718CrossRefPubMedGoogle Scholar
  45. 45.
    Perfettini JL, Kroemer G (2003) Caspase activation is not death. Nat Immunol 4: 308–310CrossRefPubMedGoogle Scholar
  46. 46.
    Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P (2003) Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2 Nat Immunol 4: 387–393CrossRefPubMedGoogle Scholar
  47. 47.
    Kroemer G, Martin SJ (2005) Caspase-independent cell death Nat Med 11: 725–730CrossRefPubMedGoogle Scholar
  48. 48.
    Weaver JG, Rouse MS, Steckelberg JM, Badley AD (2004) Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis. Faseb J 18: 1185–1191CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • S. Weber
    • 1
  • B. Baessler
    • 1
  • S. Schroeder
    • 2
  1. 1.Department of Anesthesiology and Intensive CareUniversity of BonnBonnGermany
  2. 2.Department of Anesthesiology and Intensive CareWestküstenklinikum HeideHeideGermany

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