The effects of activated protein C on the sepsis syndrome

El sistema de la proteína C activada en el cuadro séptico

The concepts on the pathophysiology of the clinical manifestations of sepsis have changed dramatically during recent years due to the development ofknowledge and techniques in molecular biology. Aproof of this is the approval by the US Food and Drug Administration (FDA) of the use of recombinant forms of activated protein C. This review attempts to analyze the overall state ofknowledge regarding the role activated protein C and its response system play on the sepsis syndrome.

1. Angus D, Linde-Zwirble, Lidicker J, Clemont G, Carcillo J, Pinsky M. Epidemiology ofsevere sepsis in the United States: analysis ofincidence, outcome, and associated costs ofcare. Crit Care Med. 2001; 29: 1303-1 O.
2. Martín G, ManninoD, Eaton S, Moss M. Tbe epidemiology ofsepsis in the United States from 1979 through 2000. N Eng!J Med. 2003; 348: 1546-54.
3. Riedemann N, Guo R, Ward P. The enigma ofsepsis. J Clin Invest. 2003; 112:460--67.
4. Hotchkiss RS, Karl IE. Toe pathophysiology and treatment of sepsis. N Engl J Med. 2003; 348:138 50.
5. Riedemann NC, Guo R, Ward PA. Novel strategies for the treatrnent of sepsis. Nat Med. 2003; 9:517-24.
6. Hattori Y, Takano K, Teramae H, Yamamoto S, Yokoo H, Matsuda N. Insight into sepsis therapeutic design based on the apoptotic death pathway. J Pharmacol Sci. [serie en Internet]. 2010 [citado 2011 Feb 1]; 114 (4):[aprox. 12 p.]. Disponible en: http://www.jstage.jst.go.jp/article/jphs/advpub/O/ advpub_l0l1100472/_article
7. Yan S, BrandtT, CorrellN, Um S, BourdageJ. Evaluation ofanti-activated protein C antibody development in patients with severe sepsis form four clinical studies with drotrecogin alpha (activated).J Thromb Haemost. 2009 Nov;7(11):1787-94.
Tang B, McLean A, Dawes I, et al. Gene-expression profiling of gram­ positive and gram-negative sepsis in critically ill patients. Crit Care Med. 2008; 36 (4): 1125 28.
9. Fitting C, Dhawan S, Cavaillon J. Compartmentalisation ofendotoxin tolerance. JinfectDis 2004; 189: 1295-1303.
10. Bemard G, Margolis B, Shaines H, Ely E, Wheeler A, Levy H, et al. Extended evaluation ofrecombinan! human activated protein C United States trial (ENHANCE US): a single arm, phase 3B, multicenter study ofdrotrecogin alfa (Activated) in severe sepsis. CHEST. 2004; 125 (4): 2206- 16.
11. Martín G, Brunkhorst FM, Janes JM, et al. The intemational PROGRESS registry ofpatients with severe sepsis: drotrecogin alfa (activated) use and patient outcomes. Crit Care 2009; 13: RI03.
12. Zeni F, FreemanB, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med. 1997; 25: 1095-11OO.
13. Natanson C, Esposito CJ, Banks SM. The sirens' songs of confirmatory sepsis trials: selection bias and sampling error. Crit Care Med. 1998; 26: 1927-31.
14. Marshall JC. Clinical trials ofmediator-directed therapy in sepsis: what have we leamed?. Intensive Care Med. 2000;26 Suppl 1:S75-83.
15. Mosnier L, Zlokovic B and Griffm J. The cytoprotective protein c pathway.
Blood. 2006; 109 (8): 3161 72.
16. Griffin J, FemándezA, Gale A and Mosnier L. Activated protein C. JThromb Haemost. 2007; 5 (Suppl Í): 73-80.
17. Esmon C. The endothelial cell protein C receptor. Thromb Haemost. 2000; 83: 639-43.
18. Liaw P, Mather T, Oganesyan N, Ferrell G, Esmon C. Identification ofthe protein C/activated protein C binding sites on the endothelial cell protein C receptor. lmplications for a novel mode of ligand recognition by a major histocompatibility complex class 1- type receptor. JBiol Chem 2001; 276: 8364-70.
19. Ni Ainle F, O'Donnell J, Johnson J, Brown L, Gleeson E, Smith O, et al. Activated protein C N-Linked glycans modulate cytoprotective signaling function on endothelial cells. J Biol. Chem. 2011 Jan 14; 286(2):1323-30.
20. Mosnier L, Yang X, Griffin J. Activated protein C mutan! with minimal antiocoagulant activity, normal cytoprotective activity, and preservation of thrombinactivablefibrinolysis inhibitor-dependent cytoprotective functions. J Biol Chem. 2007; 282 (45): 33022-33.
21. Bae J, YangL, Manithody Ch, et al. Engineering a disulfide bond to stabilize the calcium-binding loop ofactivated protein C eliminates its anticoagulant but not its protective signaling properties. J Biol Chem. 2007; 282 (12): 9251-59.
22. MosnierL, Zampolli A, Kerschen E, Schuepbach R, Benerjee Y, Femández J, et al. Hyperantithrombotic, noncytoprotective Glul 49Ala-activated c mutant. Blood. 2009; 113 (23): 5970-78.
23. Kerschen E, Femandez J, CooleyB, et al. Endotoxemia and sepsismortality reduction by non-anticoagulant-activated protein C. J Exp Med. 2004; 1O: 2439-48.
24. Douglas A, Rafferty H, Hodgkins P, Nagra A, Foulds N, Morgan M, et al. Persistent fetal vasculature and severe protein C deficiency. Mol Syndromol. 201O; 1 (2): 82-6.
25. Allaart C, P oort S, Rosendaal F, Reitsma P, Bertina R, Briet E. Increased risk ofvenous thrombosis in carriers ofhereditary protein C deficiency defect. Lancet. 1993; 341: 134-38.
26. Millar D, JohansenB, Bemtorp E, Minford A, Bolton-Maggs P, Wensley R, et al. Molecular genetic analysis ofsevere protein C deficiency. Hum. Genet. 2000; 106: 646-53.
27. Lay A, Liang Z, Rosen E, Castellino F. Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities. J Clin Invest. 2005; 115: 1552-61.
28. Weiler, H. Regulation ofinflammation by the protein C system. Crit Care Med. 2010; 38 (2): S18-S25.
29. Mosnier L and Griffin J. Protein C anticoagulant activity in relation to anti­ inflammatory and antiapoptotic activities. FrontBiosci. 2006; 11: 2381- 99.
30. MosnierL, ZlokovicB and Griffin J. The cytoprotective protein C pathway. Blood. 2006; 109 (8): 3161-72.
31. Seeley S, Covic L, Jacques S, et al. Structural basis for thrombin activation ofa protease-activated receptor: inhibition ofa intramolecular liganding. 2003; 10: 1033-1041.
32. Hartmut W. Regulation ofinflammation by the protein C system. Crit Care Med. 201O, 38 (2): S18-S25.
33. Seeley S, Covic L, Jacques S, et al. Structural basis for thrombin activation ofa protease-activated receptor: lnhibition ofa intramolecular liganding. 2003; 10: 1033-41.
34. Coughlin S. Thrombin signaling and protease activated receptors. Nature. 2000; 407: 258-64.
35. Griffin C, Srinivasan Y, Zheng Y, Huang, W and Cougblin S. A role for thrombin receptor signaling in endotelial cells during embryonic development. Science. 2001; 293: 1666-70.
36. Even-Ram S, Uziely B, Cohen P, et al. Thrombin receptor over expression in malignan! and physiological invasion processes. Nat. Med. 1998; 4: 909-14.
37. Zain J, Huang Y, FengX,Nierodzik M, Li J and Karpat-kin S. Concentration­ dependent dual effect ofthrombin on impaired growth/apoptosis or rnitogenesis in tumor cells. Blood 2000; 95: 3133-38.
38. Boire A, Covic L, Agarwal A, et al. PAR! is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005; 120: 303-13.
39. Ludeman M, Kataoka H, Srinivasan Y, et al. PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem. 2005; 280: 13122-28.
40. Coughlin SR, Camerer E. PARticipation in inflammation. J Clin Invest. 2003; 111: 25-27.
41. Ludeman M, Kataoka H, Srinivasan Y, et al. PAR! cleavage and signaling in response to activated protein C and thrombin. J Biol Chem. 2005; 280:13122-28.
42. Riewald M, Ruf W. Protease-activated receptor-! signaling by activated protein C in cytokine perturbed endothelial cells is distinct from thrombin signaling. J Biol Chem. 2005; 280: 19808-14.
43. Franscini N, Bachli E, Blau N, et al. Gene expression profiling ofinflamed human endotbelial cells and influence ofactivated protein C. Circulation. 2004; 110: 2903-09.
44. Pereira C,Bacbil E, Schaer D, Schoedon G. Transcriptome analysis revelaled unique genes as targets for the anti-inflamatory action ofactivated protein e in human macrophages. PLoS One. 2010; 5 (10): el 5352.
45. Joyce D, Gelbert L, Ciaccia A, DeHoffB and Grinnell B. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem. 2001; 276: 11199-203.
46. Murakami K, Okajima K, Uchiba M, et al. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood. 1996; 87: 642-47.
47. Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PARl-dependent sphingosine 1-phosphate receptor-] crossactivation. Blood. 2005; 105: 3178-84.
48. NickJ,ColdrenC, Geraci M, Poch K, Fouty B, O'Brien J, et al. Recombinan! human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition ofneutrophil chemotaxis. Blood. 2004; 104: 3878-85.
49. Niessen F, Furlan-Freguia C, Fernández J, Mosnier L, Castellino F, Weiler H, et al. Endogenous EPCR/aPC-PAR-1 signalling prevents inflammation­ induced vascular leakage and lethaly. Blood. 2009; 113 (12): 2859-66.
50. Cheng T, Liu D, GriffinJH, et al. ActivatedproteinC blocks p53-mediated apoptosis in ischemic human brainendothelium and is neuroprotective. Nat Med. 2003; 9: 338-42.
51. Stephenson D, Toltl L, Beaudin S and Liaw P. Modulation ofmonocyte function by activated protein C, a natural anticoagulant.J Immunol. 2006; 177: 2115-22.
52. Hotchkiss R, Chang K, Swanson P, Tinsley K, Hui J, Klender P, et al. Caspase inhibitors improve survival in sepsis: a critica! role offte lymphocyte. Nat Immunol. 2000; 1: 496-501.
53. McVerry B, GarcíaJ. Endothelial cell barrier regulation by sphingosine 1- phosphate. J Cell Biocbem. Mosnier L and GriflinJ 2004; 92: 1075-85.
54. Burridge K, Wennerberg K. Rho and Rae take center stage. Cell. 2004; 116: 167-79.
55. Singleton P, Dudek S,Chiang E and GarcíaJ. Regulation ofspbingosine 1- phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by SI PI receptor, PI3 kinase, Tiam 1 /Rac1, and alpha-actinin. FASEB J. 2005; 19: 1646-56.