Intensive Care Medicine

, Volume 36, Issue 8, pp 1286–1298 | Cite as

The endothelium: physiological functions and role in microcirculatory failure during severe sepsis

  • H. Ait-OufellaEmail author
  • E. Maury
  • S. Lehoux
  • B. Guidet
  • G. Offenstadt


The endothelium is a highly dynamic cell layer that is involved in a multitude of physiological functions, including the control of vascular tone, the movement of cells and nutrients, the maintenance of blood fluidity and the growth of new vessels. During severe sepsis, the endothelium becomes proadhesive, procoagulant, antifibrinolytic and is characterized by alterations of vasomotor regulation. Most of these functions have been discovered using in vitro and animal models, but in vivo exploration of endothelium in patients remains difficult. New tools to analyze endothelial dysfunction at bedside have to be developed.


Endothelium Sepsis Coagulation Cytokines 



Stephanie Lehoux, PhD, is funded by the Canadian Institutes of Health Research (CIHR).


  1. 1.
    Wolinsky H, Katz D, Markle R, Mills J, Brem S, Wassertheil-Smoller S (1980) Hydrolase activities in the rat aorta. IV. Relation between clearance rates of circulating 125I-labeled low-density lipoproteins and levels of tissue hydrolase activity. Circ Res 47:433–442PubMedGoogle Scholar
  2. 2.
    Augustin HG, Kozian DH, Johnson RC (1994) Differentiation of endothelial cells: analysis of the constitutive and activated endothelial cell phenotypes. Bioessays 16:901–906PubMedCrossRefGoogle Scholar
  3. 3.
    Luft JH (1966) Fine structures of capillary and endocapillary layer as revealed by ruthenium red. Fed Proc 25:1773–1783PubMedGoogle Scholar
  4. 4.
    Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG (2007) The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 454:345–359PubMedCrossRefGoogle Scholar
  5. 5.
    Sugahara K, Mikami T, Uyama T, Mizuguchi S, Nomura K, Kitagawa H (2003) Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. Curr Opin Struct Biol 13:612–620PubMedCrossRefGoogle Scholar
  6. 6.
    Henry CB, Duling BR (1999) Permeation of the luminal capillary glycocalyx is determined by hyaluronan. Am J Physiol 277:H508–H514PubMedGoogle Scholar
  7. 7.
    Jacob M, Bruegger D, Rehm M, Welsch U, Conzen P, Becker BF (2006) Contrasting effects of colloid and crystalloid resuscitation fluids on cardiac vascular permeability. Anesthesiology 104:1223–1231PubMedCrossRefGoogle Scholar
  8. 8.
    Constantinescu AA, Vink H, Spaan JA (2003) Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler Thromb Vasc Biol 23:1541–1547PubMedCrossRefGoogle Scholar
  9. 9.
    Davies PF (1995) Flow-mediated endothelial mechanotransduction. Physiol Rev 75:519–560PubMedGoogle Scholar
  10. 10.
    Allaire E, Clowes AW (1997) Endothelial cell injury in cardiovascular surgery: the intimal hyperplastic response. Ann Thorac Surg 63:582–591PubMedCrossRefGoogle Scholar
  11. 11.
    Lehoux S (2006) Redox signalling in vascular responses to shear and stretch. Cardiovasc Res 71:269–279PubMedCrossRefGoogle Scholar
  12. 12.
    Aird WC, Edelberg JM, Weiler-Guettler H, Simmons WW, Smith TW, Rosenberg RD (1997) Vascular bed-specific expression of an endothelial cell gene is programmed by the tissue microenvironment. J Cell Biol 138:1117–1124PubMedCrossRefGoogle Scholar
  13. 13.
    Jalali S, del Pozo MA, Chen K, Miao H, Li Y, Schwartz MA, Shyy JY, Chien S (2001) Integrin-mediated mechanotransduction requires its dynamic interaction with specific extracellular matrix (ECM) ligands. Proc Natl Acad Sci USA 98:1042–1046PubMedCrossRefGoogle Scholar
  14. 14.
    Lacorre DA, Baekkevold ES, Garrido I, Brandtzaeg P, Haraldsen G, Amalric F, Girard JP (2004) Plasticity of endothelial cells: rapid dedifferentiation of freshly isolated high endothelial venule endothelial cells outside the lymphoid tissue microenvironment. Blood 103:4164–4172PubMedCrossRefGoogle Scholar
  15. 15.
    Jackson SP, Mistry N, Yuan Y (2000) Platelets and the injured vessel wall—“rolling into action”: focus on glycoprotein Ib/V/IX and the platelet cytoskeleton. Trends Cardiovasc Med 10:192–197PubMedCrossRefGoogle Scholar
  16. 16.
    Roth GJ (1992) Platelets and blood vessels: the adhesion event. Immunol Today 13:100–105PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenberg RD (1989) Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural anticoagulant mechanism. Am J Med 87:2S–9SPubMedCrossRefGoogle Scholar
  18. 18.
    Rosenberg RD, Rosenberg JS (1984) Natural anticoagulant mechanisms. J Clin Invest 74:1–6PubMedCrossRefGoogle Scholar
  19. 19.
    Tollefsen DM, Pestka CA (1985) Heparin cofactor II activity in patients with disseminated intravascular coagulation and hepatic failure. Blood 66:769–774PubMedGoogle Scholar
  20. 20.
    Broze GJ Jr (1995) Tissue factor pathway inhibitor. Thromb Haemost 74:90–93PubMedGoogle Scholar
  21. 21.
    Esmon CT (2001) Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 29:S48–S51 discussion 51–42PubMedCrossRefGoogle Scholar
  22. 22.
    Fukudome K, Kurosawa S, Stearns-Kurosawa DJ, He X, Rezaie AR, Esmon CT (1996) The endothelial cell protein C receptor. Cell surface expression and direct ligand binding by the soluble receptor. J Biol Chem 271:17491–17498PubMedCrossRefGoogle Scholar
  23. 23.
    Thompson EA, Salem HH (1986) Inhibition by human thrombomodulin of factor Xa-mediated cleavage of prothrombin. J Clin Invest 78:13–17PubMedCrossRefGoogle Scholar
  24. 24.
    Moore KL, Andreoli SP, Esmon NL, Esmon CT, Bang NU (1987) Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 79:124–130PubMedCrossRefGoogle Scholar
  25. 25.
    Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA Jr (1986) Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 83:4533–4537PubMedCrossRefGoogle Scholar
  26. 26.
    Bombeli T, Karsan A, Tait JF, Harlan JM (1997) Apoptotic vascular endothelial cells become procoagulant. Blood 89:2429–2442PubMedGoogle Scholar
  27. 27.
    Combes V, Simon AC, Grau GE, Arnoux D, Camoin L, Sabatier F, Mutin M, Sanmarco M, Sampol J, Dignat-George F (1999) In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest 104:93–102PubMedCrossRefGoogle Scholar
  28. 28.
    Woolkalis MJ, DeMelfi TM Jr, Blanchard N, Hoxie JA, Brass LF (1995) Regulation of thrombin receptors on human umbilical vein endothelial cells. J Biol Chem 270:9868–9875PubMedCrossRefGoogle Scholar
  29. 29.
    Mirza H, Yatsula V, Bahou WF (1996) The proteinase activated receptor-2 (PAR-2) mediates mitogenic responses in human vascular endothelial cells. J Clin Invest 97:1705–1714PubMedCrossRefGoogle Scholar
  30. 30.
    Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW, Timmons C, Tram T, Coughlin SR (1997) Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 386:502–506PubMedCrossRefGoogle Scholar
  31. 31.
    Todd AS (1959) The histological localisation of fibrinolysin activator. J Pathol Bacteriol 78:281–283PubMedCrossRefGoogle Scholar
  32. 32.
    Barnathan ES, Kuo A, Kariko K, Rosenfeld L, Murray SC, Behrendt N, Ronne E, Weiner D, Henkin J, Cines DB (1990) Characterization of human endothelial cell urokinase-type plasminogen activator receptor protein and messenger RNA. Blood 76:1795–1806PubMedGoogle Scholar
  33. 33.
    Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, De Vos R, van den Oord JJ, Collen D, Mulligan RC (1994) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368:419–424PubMedCrossRefGoogle Scholar
  34. 34.
    Yamamoto K, Loskutoff DJ (1996) Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator. J Clin Invest 97:2440–2451PubMedCrossRefGoogle Scholar
  35. 35.
    Wang L, Bastarache JA, Ware LB (2008) The coagulation cascade in sepsis. Curr Pharm Des 14:1860–1869PubMedCrossRefGoogle Scholar
  36. 36.
    Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376PubMedCrossRefGoogle Scholar
  37. 37.
    Stamler JS, Singel DJ, Loscalzo J (1992) Biochemistry of nitric oxide and its redox-activated forms. Science 258:1898–1902PubMedCrossRefGoogle Scholar
  38. 38.
    Loscalzo J, Vita JA (1994) Ischemia, hyperemia, exercise, and nitric oxide. Complex physiology and complex molecular adaptations. Circulation 90:2556–2559PubMedGoogle Scholar
  39. 39.
    Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142PubMedGoogle Scholar
  40. 40.
    Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424PubMedCrossRefGoogle Scholar
  41. 41.
    Levin ER (1995) Endothelins. N Engl J Med 333:356–363PubMedCrossRefGoogle Scholar
  42. 42.
    Imaizumi TA, Stafforini DM, Yamada Y, McIntyre TM, Prescott SM, Zimmerman GA (1995) Platelet-activating factor: a mediator for clinicians. J Intern Med 238:5–20PubMedCrossRefGoogle Scholar
  43. 43.
    Lorant DE, Zimmerman GA, McIntyre TM, Prescott SM (1995) Platelet-activating factor mediates procoagulant activity on the surface of endothelial cells by promoting leukocyte adhesion. Semin Cell Biol 6:295–303PubMedCrossRefGoogle Scholar
  44. 44.
    McEver RP, Moore KL, Cummings RD (1995) Leukocyte trafficking mediated by selectin–carbohydrate interactions. J Biol Chem 270:11025–11028PubMedCrossRefGoogle Scholar
  45. 45.
    Springer TA (1995) Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol 57:827–872PubMedCrossRefGoogle Scholar
  46. 46.
    Languino LR, Plescia J, Duperray A, Brian AA, Plow EF, Geltosky JE, Altieri DC (1993) Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell 73:1423–1434PubMedCrossRefGoogle Scholar
  47. 47.
    Muller WA, Weigl SA (1992) Monocyte-selective transendothelial migration: dissection of the binding and transmigration phases by an in vitro assay. J Exp Med 176:819–828PubMedCrossRefGoogle Scholar
  48. 48.
    Dejana E, Corada M, Lampugnani MG (1995) Endothelial cell-to-cell junctions. FASEB J 9:910–918PubMedGoogle Scholar
  49. 49.
    Pober JS, Orosz CG, Rose ML, Savage CO (1996) Can graft endothelial cells initiate a host anti-graft immune response? Transplantation 61:343–349PubMedCrossRefGoogle Scholar
  50. 50.
    Marelli-Berg FM, Hargreaves RE, Carmichael P, Dorling A, Lombardi G, Lechler RI (1996) Major histocompatibility complex class II-expressing endothelial cells induce allospecific nonresponsiveness in naive T cells. J Exp Med 183:1603–1612PubMedCrossRefGoogle Scholar
  51. 51.
    Ait-Oufella H, Salomon BL, Potteaux S, Robertson AK, Gourdy P, Zoll J, Merval R, Esposito B, Cohen JL, Fisson S, Flavell RA, Hansson GK, Klatzmann D, Tedgui A, Mallat Z (2006) Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 12:178–180PubMedCrossRefGoogle Scholar
  52. 52.
    Murray AG, Khodadoust MM, Pober JS, Bothwell AL (1994) Porcine aortic endothelial cells activate human T cells: direct presentation of MHC antigens and costimulation by ligands for human CD2 and CD28. Immunity 1:57–63PubMedCrossRefGoogle Scholar
  53. 53.
    Cooper ME, Bonnet F, Oldfield M, Jandeleit-Dahm K (2001) Mechanisms of diabetic vasculopathy: an overview. Am J Hypertens 14:475–486PubMedCrossRefGoogle Scholar
  54. 54.
    Bearman SI (2000) Veno-occlusive disease of the liver. Curr Opin Oncol 12:103–109PubMedCrossRefGoogle Scholar
  55. 55.
    Tsai HM (2003) Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 14:1072–1081PubMedCrossRefGoogle Scholar
  56. 56.
    Steinsiepe KF, Weibel ER (1970) Electron microscopic studies on specific organelles of endothelial cells in the frog (Rana temporaria). Z Zellforsch Mikrosk Anat 108:105–126PubMedCrossRefGoogle Scholar
  57. 57.
    Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S, Laszik Z, Esmon CT, Heyderman RS (2001) Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 345:408–416PubMedCrossRefGoogle Scholar
  58. 58.
    Ishii H, Salem HH, Bell CE, Laposata EA, Majerus PW (1986) Thrombomodulin, an endothelial anticoagulant protein, is absent from the human brain. Blood 67:362–365PubMedGoogle Scholar
  59. 59.
    Aird WC (2003) Endothelial cell heterogeneity. Crit Care Med 31:S221–S230PubMedCrossRefGoogle Scholar
  60. 60.
    Reidy MA, Schwartz SM (1983) Endothelial injury and regeneration. IV. Endotoxin: a nondenuding injury to aortic endothelium. Lab Invest 48:25–34PubMedGoogle Scholar
  61. 61.
    Leclerc J, Pu Q, Corseaux D, Haddad E, Decoene C, Bordet R, Six I, Jude B, Vallet B (2000) A single endotoxin injection in the rabbit causes prolonged blood vessel dysfunction and a procoagulant state. Crit Care Med 28:3672–3678PubMedCrossRefGoogle Scholar
  62. 62.
    Lee MM, Schuessler GB, Chien S (1988) Time-dependent effects of endotoxin on the ultrastructure of aortic endothelium. Artery 15:71–89PubMedGoogle Scholar
  63. 63.
    Wang P, Wood TJ, Zhou M, Ba ZF, Chaudry IH (1996) Inhibition of the biologic activity of tumor necrosis factor maintains vascular endothelial cell function during hyperdynamic sepsis. J Trauma 40:694–700PubMedCrossRefGoogle Scholar
  64. 64.
    Mutunga M, Fulton B, Bullock R, Batchelor A, Gascoigne A, Gillespie JI, Baudouin SV (2001) Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 163:195–200PubMedGoogle Scholar
  65. 65.
    Polunovsky VA, Wendt CH, Ingbar DH, Peterson MS, Bitterman PB (1994) Induction of endothelial cell apoptosis by TNF alpha: modulation by inhibitors of protein synthesis. Exp Cell Res 214:584–594PubMedCrossRefGoogle Scholar
  66. 66.
    Messmer UK, Briner VA, Pfeilschifter J (1999) Tumor necrosis factor-alpha and lipopolysaccharide induce apoptotic cell death in bovine glomerular endothelial cells. Kidney Int 55:2322–2337PubMedCrossRefGoogle Scholar
  67. 67.
    Stefanec T (2000) Endothelial apoptosis: could it have a role in the pathogenesis and treatment of disease? Chest 117:841–854PubMedCrossRefGoogle Scholar
  68. 68.
    Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21:157–171PubMedCrossRefGoogle Scholar
  69. 69.
    Soriano AO, Jy W, Chirinos JA, Valdivia MA, Velasquez HS, Jimenez JJ, Horstman LL, Kett DH, Schein RM, Ahn YS (2005) Levels of endothelial and platelet microparticles and their interactions with leukocytes negatively correlate with organ dysfunction and predict mortality in severe sepsis. Crit Care Med 33:2540–2546PubMedCrossRefGoogle Scholar
  70. 70.
    Levi M, Ten Cate H (1999) Disseminated intravascular coagulation. N Engl J Med 341:586–592PubMedCrossRefGoogle Scholar
  71. 71.
    Heckel K, Kiefmann R, Dorger M, Stoeckelhuber M, Goetz AE (2004) Colloidal gold particles as a new in vivo marker of early acute lung injury. Am J Physiol Lung Cell Mol Physiol 287:L867–L878PubMedCrossRefGoogle Scholar
  72. 72.
    Parrillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471–1477PubMedCrossRefGoogle Scholar
  73. 73.
    Shapiro NI, Yano K, Sorasaki M, Fischer C, Shih SC, Aird WC (2009) Skin biopsies demonstrate site-specific endothelial activation in mouse models of sepsis. J Vasc Res 46:495–502PubMedCrossRefGoogle Scholar
  74. 74.
    Nooteboom A, van der Linden CJ, Hendriks T (2004) Modulation of adhesion molecule expression on endothelial cells after induction by lipopolysaccharide-stimulated whole blood. Scand J Immunol 59:440–448PubMedCrossRefGoogle Scholar
  75. 75.
    Sessler CN, Windsor AC, Schwartz M, Watson L, Fisher BJ, Sugerman HJ, Fowler AA 3rd (1995) Circulating ICAM-1 is increased in septic shock. Am J Respir Crit Care Med 151:1420–1427PubMedGoogle Scholar
  76. 76.
    Xu H, Gonzalo JA, St Pierre Y, Williams IR, Kupper TS, Cotran RS, Springer TA, Gutierrez-Ramos JC (1994) Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J Exp Med 180:95–109PubMedCrossRefGoogle Scholar
  77. 77.
    Kuhns DB, Alvord WG, Gallin JI (1995) Increased circulating cytokines, cytokine antagonists, and E-selectin after intravenous administration of endotoxin in humans. J Infect Dis 171:145–152PubMedGoogle Scholar
  78. 78.
    Boldt J, Muller M, Kuhn D, Linke LC, Hempelmann G (1996) Circulating adhesion molecules in the critically ill: a comparison between trauma and sepsis patients. Intensive Care Med 22:122–128PubMedCrossRefGoogle Scholar
  79. 79.
    Kayal S, Jais JP, Aguini N, Chaudiere J, Labrousse J (1998) Elevated circulating E-selectin, intercellular adhesion molecule 1, and von Willebrand factor in patients with severe infection. Am J Respir Crit Care Med 157:776–784PubMedGoogle Scholar
  80. 80.
    Harlan JM, Winn RK (2002) Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit Care Med 30:S214–S219PubMedCrossRefGoogle Scholar
  81. 81.
    Ye X, Ding J, Zhou X, Chen G, Liu SF (2008) Divergent roles of endothelial NF-kappaB in multiple organ injury and bacterial clearance in mouse models of sepsis. J Exp Med 205:1303–1315PubMedCrossRefGoogle Scholar
  82. 82.
    Blanks JE, Moll T, Eytner R, Vestweber D (1998) Stimulation of P-selectin glycoprotein ligand-1 on mouse neutrophils activates beta 2-integrin mediated cell attachment to ICAM-1. Eur J Immunol 28:433–443PubMedCrossRefGoogle Scholar
  83. 83.
    Asaduzzaman M, Lavasani S, Rahman M, Zhang S, Braun OO, Jeppsson B, Thorlacius H (2009) Platelets support pulmonary recruitment of neutrophils in abdominal sepsis. Crit Care Med 37:1389–1396PubMedCrossRefGoogle Scholar
  84. 84.
    Aird WC (2001) Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 29:S28–S34 discussion S34–25PubMedCrossRefGoogle Scholar
  85. 85.
    Franco RF, de Jonge E, Dekkers PE, Timmerman JJ, Spek CA, van Deventer SJ, van Deursen P, van Kerkhoff L, van Gemen B, ten Cate H, van der Poll T, Reitsma PH (2000) The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. Blood 96:554–559PubMedGoogle Scholar
  86. 86.
    Osterud B, Flaegstad T (1983) Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 49:5–7PubMedGoogle Scholar
  87. 87.
    Lupu C, Westmuckett AD, Peer G, Ivanciu L, Zhu H, Taylor FB Jr, Lupu F (2005) Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis. Am J Pathol 167:1161–1172PubMedGoogle Scholar
  88. 88.
    Solovey A, Gui L, Key NS, Hebbel RP (1998) Tissue factor expression by endothelial cells in sickle cell anemia. J Clin Invest 101:1899–1904PubMedCrossRefGoogle Scholar
  89. 89.
    Moore KL, Esmon CT, Esmon NL (1989) Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood 73:159–165PubMedGoogle Scholar
  90. 90.
    Nawroth PP, Stern DM (1986) Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 163:740–745PubMedCrossRefGoogle Scholar
  91. 91.
    Mesters RM, Helterbrand J, Utterback BG, Yan B, Chao YB, Fernandez JA, Griffin JH, Hartman DL (2000) Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med 28:2209–2216PubMedCrossRefGoogle Scholar
  92. 92.
    Taylor FB Jr, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S, Blick KE (1987) Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 79:918–925PubMedCrossRefGoogle Scholar
  93. 93.
    Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709PubMedCrossRefGoogle Scholar
  94. 94.
    Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL (2005) Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353:1332–1341PubMedCrossRefGoogle Scholar
  95. 95.
    Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B (2007) Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 369:836–843PubMedCrossRefGoogle Scholar
  96. 96.
    Ely EW, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, Vincent JL, Macias WL, Bernard GR (2003) Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 31:12–19PubMedCrossRefGoogle Scholar
  97. 97.
    Toussaint S, Gerlach H (2009) Activated protein C for sepsis. N Engl J Med 361:2646–2652PubMedCrossRefGoogle Scholar
  98. 98.
    Sarangi PP, Lee HW, Kim M (2009) Activated protein C action in inflammation. Br J Haematol [Epub ahead of print]Google Scholar
  99. 99.
    Sandset PM, Warn-Cramer BJ, Rao LV, Maki SL, Rapaport SI (1991) Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 88:708–712PubMedCrossRefGoogle Scholar
  100. 100.
    Creasey AA, Chang AC, Feigen L, Wun TC, Taylor FB Jr, Hinshaw LB (1993) Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 91:2850–2860PubMedCrossRefGoogle Scholar
  101. 101.
    Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, Simon S, Light B, Spapen H, Stone J, Seibert A, Peckelsen C, De Deyne C, Postier R, Pettila V, Artigas A, Percell SR, Shu V, Zwingelstein C, Tobias J, Poole L, Stolzenbach JC, Creasey AA (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290:238–247PubMedCrossRefGoogle Scholar
  102. 102.
    Levin EG, Marotti KR, Santell L (1989) Protein kinase C and the stimulation of tissue plasminogen activator release from human endothelial cells. Dependence on the elevation of messenger RNA. J Biol Chem 264:16030–16036PubMedGoogle Scholar
  103. 103.
    Green J, Doughty L, Kaplan SS, Sasser H, Carcillo JA (2002) The tissue factor and plasminogen activator inhibitor type-1 response in pediatric sepsis-induced multiple organ failure. Thromb Haemost 87:218–223PubMedGoogle Scholar
  104. 104.
    Mavrommatis AC, Theodoridis T, Economou M, Kotanidou A, El Ali M, Christopoulou-Kokkinou V, Zakynthinos SG (2001) Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock. Intensive Care Med 27:1853–1859PubMedCrossRefGoogle Scholar
  105. 105.
    Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA (2003) Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol 285:L20–L28PubMedGoogle Scholar
  106. 106.
    Hermans PW, Hazelzet JA (2005) Plasminogen activator inhibitor type 1 gene polymorphism and sepsis. Clin Infect Dis 41(Suppl 7):S453–S458PubMedCrossRefGoogle Scholar
  107. 107.
    Regoeczi E, Brain MC (1969) Organ distribution of fibrin in disseminated intravascular coagulation. Br J Haematol 17:73–81PubMedCrossRefGoogle Scholar
  108. 108.
    Salzman AL, Wang H, Wollert PS, Vandermeer TJ, Compton CC, Denenberg AG, Fink MP (1994) Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis. Am J Physiol 266:G633–G646PubMedGoogle Scholar
  109. 109.
    Wiel E, Pu Q, Corseaux D, Robin E, Bordet R, Lund N, Jude B, Vallet B (2000) Effect of L-arginine on endothelial injury and hemostasis in rabbit endotoxin shock. J Appl Physiol 89:1811–1818PubMedGoogle Scholar
  110. 110.
    Wiel E, Pu Q, Leclerc J, Corseaux D, Bordet R, Lund N, Jude B, Vallet B (2004) Effects of the angiotensin-converting enzyme inhibitor perindopril on endothelial injury and hemostasis in rabbit endotoxic shock. Intensive Care Med 30:1652–1659PubMedCrossRefGoogle Scholar
  111. 111.
    Zhou M, Wang P, Chaudry IH (1997) Endothelial nitric oxide synthase is downregulated during hyperdynamic sepsis. Biochim Biophys Acta 1335:182–190PubMedGoogle Scholar
  112. 112.
    Bhagat K, Collier J, Vallance P (1996) Local venous responses to endotoxin in humans. Circulation 94:490–497PubMedGoogle Scholar
  113. 113.
    Bhagat K, Moss R, Collier J, Vallance P (1996) Endothelial “stunning” following a brief exposure to endotoxin: a mechanism to link infection and infarction? Cardiovasc Res 32:822–829PubMedGoogle Scholar
  114. 114.
    Cobb JP, Natanson C, Quezado ZM, Hoffman WD, Koev CA, Banks S, Correa R, Levi R, Elin RJ, Hosseini JM et al (1995) Differential hemodynamic effects of l-NMMA in endotoxemic and normal dogs. Am J Physiol 268:H1634–H1642PubMedGoogle Scholar
  115. 115.
    Jourdain M, Tournoys A, Leroy X, Mangalaboyi J, Fourrier F, Goudemand J, Gosselin B, Vallet B, Chopin C (1997) Effects of N omega-nitro-L-arginine methyl ester on the endotoxin-induced disseminated intravascular coagulation in porcine septic shock. Crit Care Med 25:452–459PubMedCrossRefGoogle Scholar
  116. 116.
    Walker TA, Curtis SE, King-VanVlack CE, Chapler CK, Vallet B, Cain SM (1995) Effects of nitric oxide synthase inhibition on regional hemodynamics and oxygen transport in endotoxic dogs. Shock 4:415–420PubMedGoogle Scholar
  117. 117.
    Grover R, Zaccardelli D, Colice G, Guntupalli K, Watson D, Vincent JL (1999) An open-label dose escalation study of the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock. Glaxo Wellcome International Septic Shock Study Group. Crit Care Med 27:913–922PubMedCrossRefGoogle Scholar
  118. 118.
    Vincent JL, Zhang H, Szabo C, Preiser JC (2000) Effects of nitric oxide in septic shock. Am J Respir Crit Care Med 161:1781–1785PubMedGoogle Scholar
  119. 119.
    Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, Silverman MS, Takala J, Donaldson J, Arneson C, Grove G, Grossman S, Grover R (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32:21–30PubMedCrossRefGoogle Scholar
  120. 120.
    De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL (2002) Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 166:98–104PubMedCrossRefGoogle Scholar
  121. 121.
    Nieuwdorp M, Meuwese MC, Mooij HL, Ince C, Broekhuizen LN, Kastelein JJ, Stroes ES, Vink H (2008) Measuring endothelial glycocalyx dimensions in humans: a potential novel tool to monitor vascular vulnerability. J Appl Physiol 104:845–852PubMedCrossRefGoogle Scholar
  122. 122.
    Li JM, Shah AM (2004) Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287:R1014–R1030PubMedGoogle Scholar
  123. 123.
    Marechal X, Favory R, Joulin O, Montaigne D, Hassoun S, Decoster B, Zerimech F, Neviere R (2008) Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock 29:572–576PubMedGoogle Scholar
  124. 124.
    Cerwinka WH, Cooper D, Krieglstein CF, Feelisch M, Granger DN (2002) Nitric oxide modulates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules. Am J Physiol Heart Circ Physiol 282:H1111–H1117PubMedGoogle Scholar
  125. 125.
    Cepinskas G, Wilson JX (2008) Inflammatory response in microvascular endothelium in sepsis: role of oxidants. J Clin Biochem Nutr 42:175–184PubMedCrossRefGoogle Scholar
  126. 126.
    Lush CW, Cepinskas G, Kvietys PR (2003) Regulation of intestinal nuclear factor-kappaB activity and E-selectin expression during sepsis: a role for peroxynitrite. Gastroenterology 124:118–128PubMedCrossRefGoogle Scholar
  127. 127.
    Steffel J, Luscher TF, Tanner FC (2006) Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation 113:722–731PubMedCrossRefGoogle Scholar
  128. 128.
    Shen KP, Lo YC, Yang RC, Liu HW, Chen IJ, Wu BN (2005) Antioxidant eugenosedin-A protects against lipopolysaccharide-induced hypotension, hyperglycaemia and cytokine immunoreactivity in rats and mice. J Pharm Pharmacol 57:117–125PubMedCrossRefGoogle Scholar
  129. 129.
    Crimi E, Liguori A, Condorelli M, Cioffi M, Astuto M, Bontempo P, Pignalosa O, Vietri MT, Molinari AM, Sica V, Della Corte F, Napoli C (2004) The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double-blind, placebo-controlled trial. Anesth Analg 99:857–863PubMedCrossRefGoogle Scholar

Copyright information

© Copyright jointly held by Springer and ESICM 2010

Authors and Affiliations

  • H. Ait-Oufella
    • 1
    • 2
    • 6
    Email author
  • E. Maury
    • 2
    • 3
    • 4
  • S. Lehoux
    • 5
  • B. Guidet
    • 2
    • 3
    • 4
  • G. Offenstadt
    • 2
    • 3
    • 4
  1. 1.Inserm U970, PAris Research Cardiovascular Center (PARCC)ParisFrance
  2. 2.Service de Réanimation MédicaleHôpital Saint-Antoine, AP-HPParisFrance
  3. 3.Université Pierre et Marie Curie-Paris 6, UMR S707ParisFrance
  4. 4.Inserm U707ParisFrance
  5. 5.Lady Davis Institute for Medical ResearchMcGill UniversityMontrealCanada
  6. 6.Service de Réanimation MédicaleHôpital Saint-AntoineParis Cedex 12France

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