El sistema de la proteína C activada en el cuadro séptico
The effects of activated protein C on the sepsis syndrome
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Escobar Soto, C. H. (2011). El sistema de la proteína C activada en el cuadro séptico. Revista Repertorio De Medicina Y Cirugía, 20(1), 12–17. https://doi.org/10.31260/RepertMedCir.v20.n1.2011.667
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Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial-CompartirIgual 4.0.
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Durante los últimos años y con el advenimiento del conocimiento y las técnicas de biología molecular, las concepciones fisiopatológicas del cuadro séptico han cambiado en forma dramática. Prueba de ello es la aprobación del empleo de formas recombinantes de la proteína C activada por parte de la Administración Federal de Alimentos y Medicamentos de Estados Unidos (FDA). Con la presente revisión se pretende hacer un análisis del estado general del conocimiento respecto al papel que la proteína C activada y su sistema de respuesta cumplen en el contexto del cuadro séptico.
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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.
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.
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