Protective effects of activated protein C in sepsis

Summary

Sepsis remains a complex syndrome associated with significant morbidity and mortality. It is now widely accepted that the pathways of inflammation, coagulation, apoptosis, and endothelial permeability are intimately linked in sepsis pathophysiology. The clinical success of activated protein C (APC), a natural anticoagulant, in reducing mortality in patients with severe sepsis has fuelled basic and preclinical research on the protective effects of this molecule. Over the past 15 years, impressive research advances have provided novel insights into the multifunctional activities of APC. APC is now viewed not only as an anticoagulant, but also as a cell signaling molecule that dampens the excessive or insufficiently controlled host response during sepsis. This review attempts to summarize the pleiotropic activities of APC with focus on its ability to inhibit coagulation, inflammation, apoptosis, and endothelial barrier breakdown. A comprehensive PUBMED literature review up to May 2008 was conducted.

Keywords

Protein C/S pathway - sepsis - acquired coagulation disorders

• References

• 1 Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999; 340: 207-214.
• 2 Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N EnglJ Med 2003; 348: 138-150.
• 3 Angus DC. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1303-1310.
• 4 Aird W. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101: 3765-3777.
• 5 Aird W. Sepsis and coagulation. Crit Care Clin 2005; 21: 417-431.
• 6 Cavaillon JM, Adib-Conquy M. Monocytes/macro-phages and sepsis. Crit Care Med 2005; 33: S506-S509.
• 7 Prydz H. et al. In vitro stimulation of tissue thromboplastin (factor III) activity in human monocytes by immune complexes and lectins. Thromb Res 1979; 15: 465-474.
• 8 Schwartz BS. et al. Plasma lipoprotein induction and suppression of the generation of cellular procoagulant activity in vitro: two procoagulant activities are produced by peripheral blood mononuclear cells. J Clin Invest 1981; 67: 1650-1658.
• 9 Broze Jr GJ. Binding of human factor VII andVIIa to monocytes. J Clin Invest 1982; 70: 526-535.
• 10 Esmon C. The protein C pathway. Crit Care Med 2000; 28: S44-S48.
• 11 Grinnell BW, Joyce D. Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis. Crit Care Med 2001; 29: S53-S60.
• 12 Stefanec T. Endothelial apoptosis: could it have a role in the pathogenesis and treatment of disease?. Chest 2000; 117: 841-854.
• 13 Mavrommatis AC. et al. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 2000; 28: 451-457.
• 14 Kinasewitz GT. et al. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative microorganism. Crit Care 2004; 08: R82-R90.
• 15 Vanderschueren S. et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med 2000; 28: 1871-1876.
• 16 Baughman RP. et al. Thrombocytopenia in the intensive care unit. Chest 1993; 104: 1243-1247.
• 17 Nesheim ME. et al. The contribution of bovine Factor V and Factor Va to the activity of prothrombinase. J Biol Chem 1979; 254: 10952-10962.
• 18 Stief TW. et al. Analysis of hemostasis alterations in sepsis. Blood Coagul Fibrinolysis 2007; 18: 179-186.
• 19 Gando S. et al. Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock. Crit Care Med 1998; 26: 2005-2009.
• 20 Taylor Jr FB. et al. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-134.
• 21 Levi M. et al. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93: 114-120.
• 22 Biemond BJ. et al. Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VII/ VIIa. Thromb Haemost 1995; 73: 223-230.
• 23 Grignani G, Maiolo A. Cytokines and hemostasis. Haematologica 2000; 85: 967-972.
• 24 Pradier O. et al. Interleukin-10 inhibits the induction of monocyte procoagulant activity by bacterial lipopolysaccharide. Eur J Immunol 1993; 23: 2700-2703.
• 25 Collins PW. et al. Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. Br J Haematol 2006; 135: 220-227.
• 26 Nieuwland R. et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95: 930-935.
• 27 Soriano AO. et al. 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 2005; 33: 2540-2546.
• 28 Ogura H. et al. Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma andsepsis. JTrauma 2001; 50: 801-809.
• 29 Osmanovic N. et al. Soluble selectins in sepsis: microparticle-associated, but only to a minor degree. Thromb Haemost 2000; 84: 731-732.
• 30 Celi A. et al. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci USA 1994; 91: 8767-8771.
• 31 del Conde I. et al. Effect of P-selectin on phosphatidylserine exposure and surface-dependent thrombin generation on monocytes. Arterioscler Thromb Vasc Biol 2005; 25: 1065-1070.
• 32 Mesters RM. et al. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 1996; 88: 881-886.
• 33 Fourrier F. et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101: 816-823.
• 34 Mavrommatis AC. et al. Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock. Intensive Care Med 2001; 27: 1853-1859.
• 35 Leitner JM. et al. Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia. Clin Pharmacol Ther 2006; 79: 23-34.
• 36 de Jonge E. et al. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 2000; 95: 1124-1129.
• 37 Gando S. et al. Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis. Crit Care Med 2002; 30: 1729-1734.
• 38 Ravindranath TM. et al. Plasma thrombin activatable fibrinolysis inhibitor and tissue factor pathway inhibitor changes following sepsis. Clin Appl Thromb Hemost 2007; 13: 362-368.
• 39 Mesters RM. et al. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med 2000; 28: 2209-2216.
• 40 Yan SB. et al. Low levels of protein C are associated with poor outcome in severe sepsis. Chest 2001; 120: 915-922.
• 41 Liaw PC. et al. Patients with severe sepsis vary markedly in their ability to generate activated protein C. Blood 2004; 104: 3958-3964.
• 42 Vary TC, Kimball SR. Regulation of hepatic protein synthesis in chronic inflammation and sepsis. Am J Physiol 1992; 262: C445-C452.
• 43 Eckle I. et al. Protein S degradation in vitro by neutrophil elastase. Scand J Clin Lab Invest 1993; 53: 281-288.
• 44 Eckle I. et al. Protein C degradation in vitro by neutrophil elastase. Biol Chem Hoppe Seyler 1991; 372: 1007-1013.
• 45 Faust SN. et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345: 408-416.
• 46 Conway EM, Rosenberg RD. Tu mor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 1988; 08: 5588-5592.
• 47 Fukudome K, Esmon CT. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 1994; 269: 26486-26491.
• 48 Moore KL. et al. Tu mor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture. Blood 1989; 73: 159-165.
• 49 Xu J. et al. Metalloproteolytic release of endothelial cell protein C receptor. J Biol Chem 2000; 275: 6038-6044.
• 50 Takano S. et al. Plasma thrombomodulin in health and diseases. Blood 1990; 76: 2024-2029.
• 51 Boehme MW. et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies. Immunology 1996; 87: 134-140.
• 52 Borgel D. et al. A comparative study of the protein C pathway in septic and nonseptic patients with organ failure. Am J Respir Crit Care Med 2007; 176: 878-885.
• 53 Fukudome K. et al. The endothelial cell protein C receptor. Cell surface expression and direct ligand binding by the soluble receptor. J Biol Chem 1996; 271: 17491-17498.
• 54 Kurosawa S. et al. Identification of functional endothelial protein C receptor in human plasma. J Clin Invest 1997; 100: 411-418.
• 55 Liaw PC. Endogenous protein C activation in patients with severe sepsis. Crit Care Med 2004; 32: S214-S218.
• 56 Voss R. et al. Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit. Br J Haematol 1990; 75: 99-105.
• 57 Lorente JA. et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 1993; 103: 1536-1542.
• 58 Lopez-Aguirre Y, Paramo JA. Endothelial cell and hemostatic activation in relation to cytokines in patients with sepsis. Thromb Res 1999; 94: 95-101.
• 59 Cavaillon JM. et al. Cytokine cascade in sepsis. Scand J Infect Dis 2003; 35: 535-544.
• 60 Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 1996; 24: 1125-1128.
• 61 Nystrom PO. The systemic inflammatory response syndrome: definitions and aetiology. J Antimicrob Chemother 1998; 41 (Suppl A): 1-7.
• 62 Gando S. et al. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost 1996; 75: 224-228.
• 63 Hartemink KJ. et al. Immunoparalysis as a cause for invasive aspergillosis?. Intensive Care Med 2003; 29: 2068-2071.
• 64 Hotchkiss RS. et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27: 1230-1251.
• 65 Adrie C. et al. Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis. Am J Respir Crit Care Med 2001; 164: 389-395.
• 66 Keel M. et al. Interleukin-10 counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis. Blood 1997; 90: 3356-3363.
• 67 Hotchkiss RS. et al. Endothelial cell apoptosis in sepsis. Crit Care Med 2002; 30: S225-S228.
• 68 Bombeli T. et al. Apoptotic vascular endothelial cells become procoagulant. Blood 1997; 89: 2429-2442.
• 69 Riedemann NC. et al. Novel strategies for the treatment of sepsis. Nat Med 2003; 09: 517-524.
• 70 Abraham E. et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. J Am Med Assoc 2003; 290: 238-247.
• 71 Warren BL. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. J Am Med Assoc 2001; 286: 1869-1878.
• 72 Bernard GR. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
• 73 Ely EW. et al. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003; 31: 12-19.
• 74 Abraham E. et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005; 353: 1332-1341.
• 75 Vincent JL. et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med 2005; 33: 2266-2277.
• 76 Bernard GR. et al. Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 2004; 125: 2206-2216.
• 77 Lay AJ. et al. Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency. Blood 2007; 109: 1984-1991.
• 78 Ganopolsky JG, Castellino FJ. A protein C deficiency exacerbates inflammatory and hypotensive responses in mice during polymicrobial sepsis in a cecal ligation and puncture model. Am J Pathol 2004; 165: 1433-1446.
• 79 Levi M. et al. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice. Blood 2003; 101: 4823-4827.
• 80 Lay AJ. et al. Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities. J Clin Invest 2005; 115: 1552-1561.
• 81 Zheng X. et al. Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice. Blood 2007; 109: 1003-1009.
• 82 Aiach M. et al. Complex association of protein C gene promoter polymorphism with circulating protein C levels and thrombotic risk. Arterioscler Thromb Va sc Biol 1999; 19: 1573-1576.
• 83 Spek CA. et al. Genotypic variation in thepromoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. Arterioscler Thromb Vasc Biol 1995; 15: 214-218.
• 84 Walley KR, Russell JA. Protein C -1641 AA is associated with decreased survival and more organ dysfunction in severe sepsis. Crit Care Med 2007; 35: 12-17.
• 85 Chen QX. et al. Protein C -1641A/-1654C haplotype is associated with organ dysfunction and the fatal outcome of severe sepsis in Chinese Han population. Hum Genet 2008; 123: 281-287.
• 86 Esmon CT. The protein C pathway. Chest 2003; 124: 26S-32S.
• 87 Shu F. et al. Activated protein C suppresses tissue factor expression on U937 cells in the endothelial protein C receptor-dependent manner. FEBS Lett 2000; 477: 208-212.
• 88 Toltl LJ. et al. Activated protein C upregulates interleukin-10 and inhibits tissue factor in blood monocytes. J Immunol. 2008 in press.
• 89 Pralong G. et al. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989; 61: 459-462.
• 90 Gando S. et al. Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome. Crit Care Med 1995; 23: 1835-1842.
• 91 Mesters RM. et al. Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis. Thromb Haemost 1996; 75: 902-907.
• 92 Raaphorst J. et al. Early inhibition of activated fibrinolysis predicts microbial infection, shock and mortality in febrile medical patients. Thromb Haemost 2001; 86: 543-549.
• 93 Sakata Y. et al. Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 1986; 68: 1218-1223.
• 94 de Fouw NJ. et al. The interaction of activated protein C and thrombin with the plasminogen activator inhibitor released from human endothelial cells. Thromb Haemost 1987; 57: 176-182.
• 95 Bajzar L. et al. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFIdependent. Blood 1996; 88: 2093-2100.
• 96 Yuksel M. et al. Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes. Thromb Haemost 2002; 88: 267-273.
• 97 White B. et al. Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br J Haematol 2000; 110: 130-134.
• 98 Brueckmann M. et al. Activated protein C inhibits the release of macrophage inflammatory protein1-alpha from THP-1 cells and from human monocytes. Cytokine 2004; 26: 106-113.
• 99 Brueckmann M. et al. Drotrecogin alfa (activated) inhibits NF-kappa B activation and MIP-1-alpha release from isolated mononuclear cells of patients with severe sepsis. Inflamm Res 2004; 53: 528-533.
• 100 Pereira C. et al. Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the antiinflammatory action of activated protein C and interleukin-10. Arterioscler Thromb Vasc Biol 2008; 28: 504-510.
• 101 Joyce DE. et al. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276: 11199-11203.
• 102 Grinnell BW. et al. Human protein C inhibits selectin-mediated cell adhesion: role of unique fucosylated oligosaccharide. Glycobiology 1994; 04: 221-225.
• 103 Hooper WC. et al. The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C. J Immunol 1998; 161: 2567-2573.
• 104 Hooper WC. et al. Activated protein C induction of MCP-1 in human endothelial cells: a possible role for endothelial cell nitric oxide synthase. Thromb Res 2001; 103: 209-219.
• 105 Brueckmann M. et al. Stabilization of monocyte chemoattractant protein-1-mRNA by activated protein C. Thromb Haemost 2003; 89: 149-160.
• 106 Brueckmann M. et al. 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 2005; 93: 743-750.
• 107 Moncada S. Biology and therapeutic potential of prostacyclin. Stroke 1983; 14: 157-168.
• 108 Sturn DH. et al. Expression and function of the endothelial protein C receptor in human neutrophils. Blood 2003; 102: 1499-1505.
• 109 Feistritzer C. et al. Endothelial protein C receptor-dependent inhibition of migration of human lymphocytes by protein C involves epidermal growth factor receptor. J Immunol 2006; 176: 1019-1025.
• 110 Feistritzer C. et al. Endothelial protein C receptor-dependent inhibition of human eosinophil chemotaxis by protein C. J Allergy Clin Immunol 2003; 112: 375-381.
• 111 Taylor Jr FB. et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-925.
• 112 Lehmann C. et al. Activated protein C improves intestinal microcirculation in experimental endotoxaemia in the rat. Crit Care 2006; 10: R157.
• 113 Nick JA. et al. Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 2004; 104: 3878-3885.
• 114 Chung CS. et al. Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity. J Leukoc Biol 2003; 74: 344-351.
• 115 Chung CS. et al. Inhibition of Fas signaling prevents hepatic injury and improves organ blood flow during sepsis. Surgery 2001; 130: 339-345.
• 116 Riewald M. et al. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-1882.
• 117 Stephenson DA. et al. Modulation of monocyte function by activated protein C, a natural anticoagulant. J Immunol 2006; 177: 2115-2122.
• 118 Mosnier LO, Griffin JH. 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 2003; 373: 65-70.
• 119 Cheng T. et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 2003; 09: 338-342.
• 120 Sakar A. et al. Effect of recombinant human activated protein C on apoptosis-related proteins. Eur J Histochem 2007; 51: 103-109.
• 121 Guo H. et al. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 2004; 41: 563-572.
• 122 O’Brien LA. et al. Activated protein C decreases tumor necrosis factor related apoptosis-inducing ligand by an EPCR independent mechanism involving Egr-1/Erk-1/2 activation. Arterioscler Thromb Va sc Biol 2007; 27: 2634-2641.
• 123 Zeng W. et al. Effect of drotrecogin alfa (activated) on human endothelial cell permeability and Rho kinase signaling. Crit Care Med 2004; 32: S302-S308.
• 124 McVerry BJ, Garcia JG. Endothelial cell barrier regulation by sphingosine 1-phosphate. J Cell Biochem 2004; 92: 1075-1085.
• 125 Singleton PA. et al. Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and alpha-actinin. FA SEB J 2005; 19: 1646-1656.
• 126 Hoffmann JN. et al. A chronic model for intravital microscopic study of microcirculatory disorders and leukocyte/endothelial cell interaction during normotensive endotoxemia. Shock 1999; 12: 355-364.
• 127 Hoffmann JN. et al. Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia. Crit Care Med 2004; 32: 1011-1017.
• 128 Bartolome S. et al. Activated protein C attenuates microvascular injury during systemic hypoxia. Shock 2008; 29: 384-387.
• 129 Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PA R1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 2005; 105: 3178-3184.
• 130 Finigan JH. et al. Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation. J Biol Chem 2005; 280: 17286-17293.
• 131 Mosnier LO. et al. The cytoprotective protein C pathway. Blood 2007; 109: 3161-3172.
• 132 Galligan L. et al. Characterization of protein C receptor expression in monocytes. Br J Haematol 2001; 115: 408-414.
• 133 Domotor E. et al. Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1. Blood 2003; 101: 4797-4801.
• 134 Schmidlin F, Bunnett NW. Protease-activated receptors: how proteases signal to cells. Curr Opin Pharmacol 2001; 01: 575-582.
• 135 Ludeman MJ. et al. PA R1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem 2005; 280: 13122-13128.
• 136 Riewald M, Ruf W. Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling. J Biol Chem 2005; 280: 19808-19814.
• 137 Cheng T. et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med 2006; 12: 1278-1285.
• 138 Feistritzer C. et al. Protective signaling by activated protein C is mechanistically linked to protein C activation on endothelial cells. J Biol Chem 2006; 281: 20077-20084.
• 139 Bae JS. et al. Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells. Proc Natl Acad Sci USA 2007; 104: 2867-2872.
• 140 Bae JS. et al. The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 2007; 110: 3909-3916.
• 141 Bae JS. et al. Lipid raft localization regulates the cleavage specificity of protease activated receptor 1 in endothelial cells. J Thromb Haemost 2008; 06: 954-961.
• 142 Schuepbach RA. et al. Activated protein C-cleaved protease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin. Blood 2007; 111: 2667-2673.
• 143 Kaneider NC. et al. ‘Role reversal’ for the receptor PA R1 in sepsis-induced vascular damage. Nat Immunol 2007; 08: 1303-1312.
• 144 Pawlinski R. et al. Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood 2004; 103: 1342-1347.
• 145 Camerer E. et al. Roles of protease-activated receptors in a mouse model of endotoxemia. Blood 2006; 107: 3912-3921.
• 146 Zheng X. et al. Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 2007; 05: 1394-1400.
• 147 Hancock WW. et al. Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte-dependent proliferative responses. Transplantation 1995; 60: 1525-1532.
• 148 Kerschen EJ. et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med 2007; 204: 2439-2448.
• 149 Bae JS. et al. Engineering a disulfide bond to stabilize the calcium-binding loop of activated protein C eliminates its anticoagulant but not its protective signaling properties. J Biol Chem 2007; 282: 9251-9259.
• 150 Uchiba M. et al. Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ Res 2004; 95: 34-41.
• 151 Perez-Casal M. et al. Activated protein C induces the release of microparticle-associated endothelial protein C receptor. Blood 2005; 105: 1515-1522.
• 152 Nold MF. et al. Activated protein C downregulates p38 mitogen-activated protein kinase and improves clinical parameters in an in-vivo model of septic shock. Thromb Haemost 2007; 98: 1118-1126.
• 153 Isermann B. et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med 2007; 13: 1349-1358.
• 154 Brueckmann M. et al. Recombinant human activated protein C upregulates the release of soluble fract-alkine from human endothelial cells. Br J Haematol 2006; 133: 550-557.
• 155 Franscini N. et al. Gene expression profiling of inflamed human endothelial cells and influence of activated protein C. Circulation 2004; 110: 2903-2909.
• 156 Grey ST. et al. Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-gamma, or phorol ester. J Immunol 1994; 153: 3664.
• 157 Xue M. et al. Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: relevance to inflammation in rheumatoid arthritis. Arthritis Rheum 2007; 56: 2864-2874.
• 158 Bilbault P. et al. Influence of drotrecogin alpha (activated) infusion on the variation of Bax/Bcl-2 and Bax/ Bcl-xl ratios in circulating mononuclear cells: a cohort study in septic shock patients. Crit Care Med 2007; 35: 69-75.
• 159 Baltch AL. et al. Effect of recombinant human activated protein C on the bactericidal activity of human monocytes and modulation of pro-inflammatory cyto kines in the presence of antimicrobial agents. J Anti microb Chemother 2007; 59: 1177-1181.
• 160 Gupta A. et al. Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2. Am J Physiol Renal Phy siol 2007; 293: F245-F254.
• 161 Xue M. et al. Activated protein C stimulates proliferation, migration and wound closure, inhibits apopto sis and upregulates MMP-2 activity in cultured human keratinocytes. Exp Cell Res 2004; 299: 119-127.
• 162 Xue M. et al. Endothelial protein C receptor and protease-activated receptor-1 mediate induction of a wound-healing phenotype in human keratinocytes by activated protein C. J Invest Dermatol 2005; 125: 1279-1285.
• 163 Jackson CJ. et al. Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing. Wo und Repair Regen 2005; 13: 284-294.
• 164 Menschikowski M. et al. On interaction of activated protein C with human aortic smooth muscle cells attenuating the secretory group IIA phospholipase A(2) expression. Thromb Res 2008; 122: 69-76.
• 165 Bretschneider E. et al. Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res 2007; 100: 255-262.
• 166 Nakamura M. et al. Anti-inflammatory effect of activated protein C in gastric epithelial cells. J Thromb Haemost 2005; 03: 2721-2729.