The Effects of Activated Protein C on the Septic Endothelium

  • S. E. Orfanos
  • N. A. Maniatis
  • A. Kotanidou
Conference paper


Sepsis is a serious disorder with high morbidity and mortality worldwide and an increasing incidence [1]. Sepsis is the result of an overwhelming and maladaptive response of the host organism to the invasion of pathogenic microorganisms, which generates an uncontrolled and auto-destructive inflammatory process [2]. The septic syndrome carries various degrees of severity, and critically ill patients often develop sepsis-induced acute organ dysfunction (i.e., severe sepsis) and fluid-refractory hypotension (i.e., septic shock). Extensive research performed during the past two decades has greatly improved our understanding of the mechanisms underlying sepsis pathophysiology: Widespread devastating inflammation and microvascular coagulation are common denominators in severe sepsis, while endothelial cell dysfunction appears to be a key determinant in the development of the syndrome [3, 4].


Severe Sepsis Acute Lung Injury Drotrecogin Alfa Cytoprotective Protein Endothelial Cell Protein 
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  1. 1.
    Martin GS, Mannini DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348: 1546–1554PubMedCrossRefGoogle Scholar
  2. 2.
    Cinel I, Dellinger RP (2007) Advances in pathogenesis and management of sepsis. Curr Opin Infect Dis 20: 345–352PubMedCrossRefGoogle Scholar
  3. 3.
    Abraham E, Singer M (2007) Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 35: 2408–2416PubMedCrossRefGoogle Scholar
  4. 4.
    Aird WC (2004) Endothelium as an organ system. Crit Care Med 32: S271–S279PubMedCrossRefGoogle Scholar
  5. 5.
    Aird WC (2007) Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res 100: 174–190PubMedCrossRefGoogle Scholar
  6. 6.
    Orfanos SE, Mavrommati I, Korovesi I, Roussos C (2004) Pulmonary endothelium in acute lung injury: from basic science to the critically ill. Intensive Care Med 30: 1702–1714PubMedCrossRefGoogle Scholar
  7. 7.
    Mosnier LO, Zlokovic BV, Griffin JH (2007) The cytoprotective protein C pathway. Blood 109: 3161–3172PubMedCrossRefGoogle Scholar
  8. 8.
    Looney MR, Matthay MA (2006) Bench-to-bedside review: The role of activated protein C in maintaining endothelial tight junction function and its relationship to organ injury. Crit Care 10: 239PubMedCrossRefGoogle Scholar
  9. 9.
    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: 699–709PubMedCrossRefGoogle Scholar
  10. 10.
    Esmon CT (2004) Structure and functions of the endothelial cell protein C receptor. Crit Care Med 32 (suppl): S298–S301PubMedCrossRefGoogle Scholar
  11. 11.
    Thiyagarajan M, Cheng T, Zlokovic BV (2007) Endothelial cell protein C receptor. Role beyond endothelium? Circ Res 100: 155–157PubMedCrossRefGoogle Scholar
  12. 12.
    Bretschneider E, Uzonyi B, Weber AA, et al (2007) Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res 100: 255–262PubMedCrossRefGoogle Scholar
  13. 13.
    Zheng X, Li W, Song Y, et al (2007) Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 5: 1394–1400PubMedCrossRefGoogle Scholar
  14. 14.
    Bastarache JA, Ware LB, Bernard GR (2006) The role of the coagulation cascade in the continuum of sepsis and acute lung injury and acute respiratory distress syndrome. Semin Respir Crit Care Med 27: 365–376PubMedCrossRefGoogle Scholar
  15. 15.
    Villegas-Mendez A, Montes R, Ambrose LR, Warrens AN, Laffan M, Lane DA (2007) Proteolysis of the endothelial cell protein C receptor by neutrophil proteinase 3. J Thromb Haemost 5: 980–988PubMedCrossRefGoogle Scholar
  16. 16.
    Weijer S, Wieland CW, Florquin S, Van der Poll T (2007) A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis. Blood 106: 2761–2768CrossRefGoogle Scholar
  17. 17.
    Scaldaferri F, Sans M, Vetrano S, et al (2007) Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 117: 1951–1960PubMedCrossRefGoogle Scholar
  18. 18.
    Griffin JH, Fernandez JA, Gale AJ, Mosnier LO (2007) Activated protein C. J Thromb Haemost 5(suppl l):73–80PubMedCrossRefGoogle Scholar
  19. 19.
    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: 1880–1882PubMedCrossRefGoogle Scholar
  20. 20.
    Coughlin SR, Camerer E (2003) Participation in inflammation. J Clin Invest 111: 25–27PubMedGoogle Scholar
  21. 21.
    Ruf W (2005) Is APC activation of endothelial cell PAR1 important in severe sepsis?: Yes. J Thromb Haemost 3: 1912–1914PubMedCrossRefGoogle Scholar
  22. 22.
    Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW (2001) Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 276: 11199–11203PubMedCrossRefGoogle Scholar
  23. 23.
    Joyce DE, Grinnell BW (2002) Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-KB. Crit Care Med 30 (suppl): S288–S293PubMedCrossRefGoogle Scholar
  24. 24.
    Brueckmann M, Horn S, Lang S, et al (2005) Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell protein C receptor and activation of protease-activated receptor-1. Thromb Haemost 93: 743–750PubMedGoogle Scholar
  25. 25.
    Isobe H, Okajima K, Uchiba M, et al (2001) Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation 104: 1171–1175PubMedCrossRefGoogle Scholar
  26. 26.
    Mosnier LO, Griffin JH (2003) Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor. Biochem J 373: 65–70PubMedCrossRefGoogle Scholar
  27. 27.
    Cheng T, Liu D, Griffin JH (2003) Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 9: 338–342PubMedCrossRefGoogle Scholar
  28. 28.
    Zeng W, Matter WF, Yan SB, Urn SL, Vlachos CJ, Liu L (2004) Effect of drotrecogin alfa (activated) on human endothelial cell permeability and Rho kinase signaling. Crit Care Med 32 (suppl): S302–S308PubMedCrossRefGoogle Scholar
  29. 29.
    Finigan JH, Dudek SM, Singleton PA, et al (2005) Activated protein C mediates novel lung endothelial barrier enhancement. Role of sphingosine 1-phopshate receptor transactivation. J Biol Chem 280: 17286–17293PubMedCrossRefGoogle Scholar
  30. 30.
    Feistritzer C, Riewald M (2005) Endothelial barrier protection by activated protein C through PAR-1-dependent sphingosine 1-phopshate receptor-1 crossactivation. Blood 105: 3178–3184PubMedCrossRefGoogle Scholar
  31. 31.
    Matthay MA, Zimmerman GA, Esmon C, et al (2003) Future research directions in acute lung injury. Summary of a National Heart, Lung and Blood Institute working group. Am J Respir Crit Care Med 167: 1027–1035PubMedCrossRefGoogle Scholar
  32. 32.
    Murakami K, Okajima K, Uchiba M, et al (1996) Activated protein C attenuates endotoxininduced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 87: 642–647PubMedGoogle Scholar
  33. 33.
    Nick JA, Coldren CD, Geraci MW, et al (2004) Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 104: 3878–3885PubMedCrossRefGoogle Scholar
  34. 34.
    Van der Poll T, Levi M, Nick JA, Abraham E (2005) Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans. Am J Respir Crit Care Med 171: 1125–1128PubMedCrossRefGoogle Scholar
  35. 35.
    Kotanidou K, Loutrari H, Papadomichelakis E, et al (2006) Inhaled activated protein C attenuates lung injury induced by aerosolized endotoxin in mice. Vascul Pharmacol 45: 134–140PubMedCrossRefGoogle Scholar
  36. 36.
    Slofstra SH, Groot AP, Maris NA, et al (2006) Inhalation of activated protein C inhibits endotoxin-induced pulmonary inflammation in mice independent of neutrophil recruitment. Br J Pharmacol 149: 740–746PubMedCrossRefGoogle Scholar
  37. 37.
    Kerschen EJ, Fernandez JA, Cooley BC, et al (2007) Endotoxemia and sepsis mortality reduction by non-anticoagulant-activated protein C. J Exp Med 204: 2439–2448PubMedCrossRefGoogle Scholar
  38. 38.
    Regnault V, Levy B (2007) Commentary. Recombinant activated protein C in sepsis: endothelium protection or endothelium therapy? Crit Care 11: 103PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2008

Authors and Affiliations

  • S. E. Orfanos
    • 1
  • N. A. Maniatis
    • 2
  • A. Kotanidou
    • 3
  1. 1.2nd Department of Critical Care MedicineAttikon HospitalHaidariGreece
  2. 2.M. Simou LaboratoryUniversity of Athens Medical School Evangelismos General HospitalAthensGreece
  3. 3.1st Department of Critical CareUniversity of Athens Medical School Evangelismos General HospitalAthensGreece

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