Scientific and clinical challenges in sepsis

Current Pharmaceutical Design

Volumn 15, Issue 16, 2009, Pages 1918-1935

  Ulloa, Luis ^a   Brunner, Michael ^a   Ramos, Laura ^a   Deitch, Edwin A ^a  

^a RUTGERS NEW JERSEY MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATED PROTEIN C; ADVANCED GLYCATION END PRODUCT RECEPTOR; ANTIINFLAMMATORY AGENT; CASPASE 12; CASPASE 3; CASPASE INHIBITOR; DEXAMETHASONE; DROTRECOGIN; FLUDROCORTISONE; GAMMA INTERFERON; GLUCOCORTICOID; GLUCOCORTICOID RECEPTOR; HEPARIN; HIGH MOBILITY GROUP B1 PROTEIN; HIGH MOBILITY GROUP B1 PROTEIN ANTIBODY; HYDROCORTISONE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LYSOPHOSPHATIDYLCHOLINE; MACROPHAGE MIGRATION INHIBITION FACTOR; NICOTINE; NICOTINIC RECEPTOR; PLACEBO; PYRUVIC ACID ETHYL ESTER; RECOMBINANT ANTITHROMBIN III; RECOMBINANT TISSUE FACTOR PATHWAY INHIBITOR; STAT3 PROTEIN; THROMBIN; TUMOR NECROSIS FACTOR; TUMOR NECROSIS FACTOR INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ADAPTIVE IMMUNITY; ADRENAL INSUFFICIENCY; ADULT RESPIRATORY DISTRESS SYNDROME; ANTICOAGULANT THERAPY; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; BACTEREMIA; BLEEDING; BLOOD CLOTTING; CHOLINERGIC SYSTEM; CLINICAL TRIAL; CORTICOSTEROID THERAPY; CYTOKINE PRODUCTION; DIABETES MELLITUS; DIAGNOSTIC TEST; DISSEMINATED INTRAVASCULAR CLOTTING; DRUG MEGADOSE; DRUG SAFETY; ENDOTHELIUM CELL; ENDOTOXEMIA; EXPERIMENTAL MODEL; GENE ACTIVITY; GENETIC POLYMORPHISM; GLAUCOMA; HUMAN; HYPERTENSION; IMMUNE DEFICIENCY; IMMUNOMODULATION; INNATE IMMUNITY; LOW DRUG DOSE; LYMPHOCYTE; MACROPHAGE; MORTALITY; NEUTROPHIL; NONHUMAN; OSTEOPOROSIS; PERITONITIS; PNEUMONIA; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN SECRETION; REVIEW; SEPSIS; SEPTIC SHOCK; SIGNAL TRANSDUCTION; SKIN ATROPHY; SUPERINFECTION; SURVIVAL RATE; T LYMPHOCYTE; THROMBOCYTE ACTIVATION; TRANSACTIVATION; TREATMENT DURATION; VAGUS NERVE STIMULATION; WOUND HEALING IMPAIRMENT;

ANIMALS; ANTICOAGULANTS; CASPASES; CLINICAL TRIALS AS TOPIC; GLUCOCORTICOIDS; HMGB1 PROTEIN; HUMANS; LYSOPHOSPHATIDYLCHOLINES; MACROPHAGE MIGRATION-INHIBITORY FACTORS; NICOTINIC AGONISTS; SEPSIS;

EID: 68449089525     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161209788453248     Document Type: Review

References (204)

1. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 2005; 4: 673-84.
2. Ulloa L, Tracey KJ. The "cytokine profile": A code for sepsis. Trends Mol Med 2005; 11: 56-63.
3. Ulloa L, Messmer D. High-mobility group box 1 (HMGB1) protein: Friend and foe. Cytokine Growth Factor Rev 2006; 17: 189-201.
4. Deitch EA, Dayal SD. Intensive care unit management of the trauma patient. Crit Care Med 2006; 34: 2294-301.
5. Mantell LL, Parrish WR, Ulloa L. Hmgb-1 as a therapeutic target for infectious and inflammatory disorders. Shock 2006; 25: 4-11.
6. Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5: 331-42.
7. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1303-10.
8. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348: 1546-54.
9. Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med 2003; 9: 517-24.
10. Abraham E, Matthay MA, Dinarello CA, Vincent JL, Cohen J, Opal SM, et al. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: Time for a reevaluation. Crit Care Med 2000; 28: 232-5.
11. Riedemann NC, Guo R-F, Ward PA. The enigma of sepsis. J Clin Invest 2003; 112: 460-7.
12. Fisher CJJ, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994; 271: 1836-43.
13. Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 1998; 351: 929-33.
14. Abraham E, Laterre PF, Garbino J, Pingleton S, Butler T, Dugernier T, et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: A randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med 2001; 29: 503-10.
15. Smoak KA, Cidlowski JA. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev 2004; 125: 697-706.
16. Yeager MP, Guyre PM, Munck AU. Glucocorticoid regulation of the inflammatory response to injury. Acta Anaesthesiol Scand 2004; 48: 799-813.
17. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004; 10: 1216-21.
18. Czura CJ, Tracey KJ. Autonomic neural regulation of immunity. J Intern Med 2005; 257: 156-66.
19. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003; 421: 384-8.
20. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
21. Esmon CT. The protein C pathway. Chest 2003; 124: 26S-32S.
22. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-64.
23. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276: 11199-203.
24. Bernard GR. Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003; 31: S85-93.
25. Bertolini G, Rossi C, Anghileri A, Livigni S, Addis A, Poole D. Use of Drotrecogin alfa (activated) in Italian intensive care units: The results of a nationwide survey. Intens Care Med 2007; 33: 426-34.
26. Kanji S, Perreault MM, Chant C, Williamson D, Burry L. Evaluating the use of Drotrecogin alfa (activated) in adult severe sepsis: A Canadian multicenter observational study. Intensive Care Med 2007; 33: 517-23
27. Williams G. Recently published papers: Therapies failed, disputed, and beneficent. Crit Care 2007; 11: 143.
28. Eichacker PQ, Natanson C. Increasing evidence that the risks of rhAPC may outweigh its benefits. Intensive Care Med 2007; 33: 396-9.
29. Finfer S, Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, et al. Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock. Intensive Care Med 2008; 34: 2319.
30. Kerschen EJ, Fernandez JA, Cooley BC, Yang XV, Sood R, Mosnier LO, et al. Endotoxemia and sepsis mortality reduction by nonanticoagulant activated protein C. J Exp Med 2007; 204: 2439-48.
31. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: A randomized controlled trial. JAMA 2001; 286: 1869-78.
32. Creasey AA, Chang AC, Feigen L, Wun TC, Taylor FB, Jr., Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850-60.
33. Carr C, Bild GS, Chang AC, Peer GT, Palmier MO, Frazier RB, et al. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circ Shock 1994; 44: 126-37.
34. Camerota AJ, Creasey AA, Patla V, Larkin VA, Fink MP. Delayed treatment with recombinant human tissue factor pathway inhibitor improves survival in rabbits with gram-negative peritonitis. J Infect Dis 1998; 177: 668-76.
35. de Jonge E, Dekkers PE, Creasey AA, Hack CE, Paulson SK, Karim A, et al. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 2000; 95: 1124-9.
36. de Jonge E, Dekkers PE, Creasey AA, Hack CE, Paulson SK, Karim A, et al. Tissue factor pathway inhibitor does not influence inflammatory pathways during human endotoxemia. J Infect Dis 2001; 183: 1815-8.
37. Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: A randomized controlled trial. JAMA 2003; 290: 238-47.
38. Angus DC, Crowther MA. Unraveling severe sepsis: Why did OPTIMIST fail and what's next? JAMA 2003; 290: 256-8.
39. Munck A, Naray-Fejes-Toth A. Glucocorticoids and stress: Permissive and suppressive actions. Ann NY Acad Sci 1994; 746: 115-30.
40. Perlstein R, Whitnall M, Abrams J, Mougey E, Neta R. Synergistic roles of interleukin-6, interleukin-1, and tumor necrosis factor in the adrenocorticotropin response to bacterial lipopolysaccharide in vivo. Endocrinology 1993; 132: 946-52.
41. Almawi WY, Melemedjian OK. Molecular mechanisms of glucocorticoid antiproliferative effects: Antagonism of transcription factor activity by glucocorticoid receptor. J Leukoc Biol 2002; 71: 9-15.
42. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: A new look at an old problem. Chest 2002; 122: 1784-96.
43. Yang J, DeFranco DB. Assessment of glucocorticoid receptor-heat shock protein 90 interactions in vivo during nucleocytoplasmic trafficking. Mol Endocrinol 1996; 10: 3-13.
44. Schmidt C, Hocherl K, Kurt B, Bucher M. Role of nuclear factorkappaB-dependent induction of cytokines in the regulation of vasopressin V1A-receptors during cecal ligation and puncture-induced circulatory failure. Crit Care Med 2008; 36: 2363-72.
45. Gottlicher M, Heck S, Herrlich P. Transcriptional cross-talk, the second mode of steroid hormone receptor action. J Mol Med 1998; 76: 480-9.
46. Hawiger J. Innate Immunity and Inflammation: A Transcriptional Paradigm. Immunol Res 2001; 23: 99-110.
47. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002; 2: 725-34.
48. Reichardt HM, Tuckermann JP, Gottlicher M, Vujic M, Weih F, Angel P, et al. Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J 2001; 20: 7168-73.
49. Heck S, Kullmann M, Gast A, Ponta H, Rahmsdorf HJ, Herrlich P, et al. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1. EMBO J 1994; 13: 4087-95.
50. Heck S, Bender K, Kullmann M, Gottlicher M, Herrlich P, Cato AC. I kappaB alpha-independent downregulation of NF-kappaB activity by glucocorticoid receptor. EMBO J 1997; 16: 4698-707.
51. Reichardt HM, Kaestner KH, Wessely O, Gass P, Schmid W, Schutz G. Analysis of glucocorticoid signalling by gene targeting. J Steroid Biochem Mol Biol 1998; 65: 111-5.
52. Hinshaw LB, Archer LT, Beller-Todd BK, Coalson JJ, Flournoy DJ, Passey R, et al. Survival of primates in LD100 septic shock following steroid/antibiotic therapy. J Surg Res 1980; 28: 151-70.
53. Fabian TC, Patterson R. Steroid therapy in septic shock. Survival studies in a laboratory model. Am Surg 1982; 48: 614-7.
54. Beller BK, Archer LT, Passey RB, Flournoy DJ, Hinshaw LB. Effectiveness of modified steroid-antibiotic therapies for lethal sepsis in the dog. Arch Surg 1983; 118: 1293-9.
55. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984; 311: 1137-43.
56. Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: A meta-analysis. Crit Care Med 1995; 23: 1294-303.
57. Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, et al. Corticosteroid treatment for sepsis: A critical appraisal and meta-analysis of the literature. Crit Care Med 1995; 23: 1430-9.
58. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: A reassessment. Crit Care Med 1997; 25: 1095-100.
59. Bone RC, Fisher CJ, Jr., Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317: 653-8.
60. Klastersky J, Cappel R, Debusscher L. Effectiveness of beta-methasone in management of severe infections. A double-blind study. N Engl J Med 1971; 284: 1248-50.
61. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med 2003; 31: 141-5.
62. Zaloga GP. Sepsis-induced adrenal deficiency syndrome. Crit Care Med 2001; 29: 688-90.
63. Soni A, Pepper GM, Wyrwinski PM, Ramirez NE, Simon R, Pina T, et al. Adrenal insufficiency occurring during septic shock: Incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 1995; 98: 266-71.
64. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008; 36: 1937-49.
65. Jaattela M, Carpen O, Stenman UH, Saksela E. Regulation of ACTH-induced steroidogenesis in human fetal adrenals by rTNFalpha. Mol Cell Endocrinol 1990; 68: R31-6.
66. Jaattela M, Ilvesmaki V, Voutilainen R, Stenman UH, Saksela E. Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells. Endocrinology 1991; 128: 623-9.
67. Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med 2001; 163: 1520-3.
68. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004; 141: 47-56.
69. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71.
70. Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002; 96: 23-43.
71. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358: 111-24.
72. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36: 296-327.
73. Song IH, Gold R, Straub RH, Burmester GR, Buttgereit F. New glucocorticoids on the horizon: Repress, don't activate. J Rheumatol 2005; 32: 1199-207.
74. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27: 1230-51.
75. Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998; 281: 1312-6.
76. Hotchkiss RS, Tinsley KW, Swanson PE, Chang KC, Cobb JP, Buchman TG, et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. PNAS 1999; 96: 14541-6.
77. Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, Klender P, et al. Caspase inhibitors improve survival in sepsis: A critical role of the lymphocyte. Nat Immunol 2000; 1: 496-501.
78. Badami CD, Senthil M, Caputo FJ, Rupani BJ, Doucet D, Pisarenko V, et al. Mesenteric lymph duct ligation improves survival in a lethal shock model. Shock 2008; 30: 680-5.
79. Barlos D, Deitch EA, Watkins AC, Caputo FJ, Lu Q, Abungu B, et al. Trauma hemorrhagic shock-induced pulmonary epithelial and endothelial cell injury utilizes different programmed cell death signaling pathways. Am J Physiol Lung Cell Mol Physiol 2009; 296(3): L404-17.
80. Xu DZ, Zaets SB, Chen R, Lu Q, Rajan H, Yang X, et al. Elimination of C5ar Prevents Intestinal Mucosal Damage and attenuates neutrophil infiltration in local and remote organs. Shock 2008; [Epub ahead of print].
81. Martinon F, Tschopp J. Inflammatory caspases: Linking an intracellular innate immune system to autoinflammatory diseases. Cell 2004; 117: 561-74.
82. Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene 1999; 18: 6910-24.
83. Ravi R, Bedi A, Fuchs EJ, Bedi A. CD95 (Fas)-induced caspase-mediated proteolysis of NF-kappaB. Cancer Res 1998; 58: 882-6.
84. Reuther JY, Baldwin AS, Jr. Apoptosis promotes a caspaseinduced amino-terminal truncation of Ikappa Balpha that functions as a stable inhibitor of NF-kappa B. J Biol Chem 1999; 274: 20664-70.
85. Nicholson DW. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 1999; 6: 1028-42.
86. Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 2004; 429: 35-7.
87. Texereau J, Pene F, Chiche JD, Rousseau C, Mira JP. Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis. Crit Care Med 2004; 32: S313-9.
88. Villar J, Maca-Meyer N, Perez-Mendez L, Flores C. Bench-tobedside review: Understanding genetic predisposition to sepsis. Crit Care 2004; 8: 180-9.
89. Bucala R. MIF rediscovered: Cytokine, pituitary hormone, and glucocorticoid- induced regulator of the immune response. FASEB J 1996; 10: 1607-13.
90. Calandra T, Roger T. Macrophage migration inhibitory factor: A regulator of innate immunity. Nat Rev Immunol 2003; 3: 791-800.
91. Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 1994; 179: 1895-902.
92. Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bachner M, Donnelly T, et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 1995; 377: 68-71.
93. Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, Hultner L, et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000; 6: 164-70.
94. Tohyama S, Onodera S, Tohyama H, Yasuda K, Nishihira J, Mizue Y, et al. A novel DNA vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis. Gene Ther 2008.
95. Lubetsky JB, Dios A, Han J, Aljabari B, Ruzsicska B, Mitchell R, et al. The Tautomerase Active Site of Macrophage Migration Inhibitory Factor Is a Potential Target for Discovery of Novel Anti-inflammatory Agents. J Biol Chem 2002; 277: 24976-82.
96. Lubetsky JB, Swope M, Dealwis C, Blake P, Lolis E. Pro-1 of macrophage migration inhibitory factor functions as a catalytic base in the phenylpyruvate tautomerase activity. Biochemistry 1999; 38: 7346-54
97. Drobnik W, Liebisch G, Audebert F-X, Frohlich D, Gluck T, Vogel P, et al. Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J Lipid Res 2003; 44: 754-61.
98. Chen G, Li J, Qiang X, Czura CJ, Ochani M, Ochani K, et al. Suppression of HMGB1 release by stearoyl lysophosphatidylcholine: An additional mechanism for its therapeutic effects in experimental sepsis. J Lipid Res 2005; 46: 623-7.
99. Yan JJ, Jung JS, Lee JE, Lee J, Huh SO, Kim HS, et al. Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nat Med 2004; 10: 161-7.
100. Czermak BJ, Sarma V, Pierson CL, Warner RL, Huber-Lang M, Bless NM, et al. Protective effects of C5a blockade in sepsis. Nat Med 1999; 5: 788-92.
101. Muller Kobold AC, Tulleken JE, Zijlstra JG, Sluiter W, Hermans J, Kallenberg CG, et al. Leukocyte activation in sepsis; correlations with disease state and mortality. Intens Care Med 2000; 26: 883-92.
102. Huber-Lang MS, Younkin EM, Sarma JV, McGuire SR, Lu KT, Guo RF, et al. Complement-induced impairment of innate immunity during sepsis. J Immunol 2002; 169: 3223-31.
103. Coutant F, Perrin-Cocon L, Agaugue S, Delair T, Andre P, Lotteau V. Mature dendritic cell generation promoted by lysophosphatidylcholine. J Immunol 2002; 169: 1688-95.
104. Coutant F, Agaugue S, Perrin-Cocon L, Andre P, Lotteau V. Sensing environmental lipids by dendritic cell modulates its function J Immunol 2004; 172: 54-60.
105. Engelmann B, Zieseniss S, Brand K, Page S, Lentschat A, Ulmer AJ, et al. Tissue factor expression of human monocytes is suppressed by lysophosphatidylcholine. Arterioscler Thromb Vasc Biol 1999; 19: 47-53.
106. Kume H, Ito S, Ito Y, Yamaki K. Role of lysophosphatidylcholine in the desensitization of beta -adrenergic receptors by Ca2+ sensitization in tracheal smooth muscle. Am J Respir Cell Mol Biol 2001; 25: 291-8.
107. Legradi A, Chitu V, Szukacsov V, Fajka-Boja R, Szekely Szucs K, Monostori E. Lysophosphatidylcholine is a regulator of tyrosine kinase activity and intracellular Ca(2+) level in Jurkat T cell line. Immunol Lett 2004; 91: 17-21.
108. Murugesan G, Sandhya Rani MR, Gerber CE, Mukhopadhyay C, Ransohoff RM, Chisolm GM, et al. Lysophosphatidylcholine regulates human microvascular endothelial cell expression of chemokines. J Mol Cell Cardiol 2003; 35: 1375-84.
109. Takabe W, Kanai Y, Chairoungdua A, Shibata N, Toi S, Kobayashi M, et al. Lysophosphatidylcholine enhances cytokine production of endothelial cells via induction of L-type amino acid transporter 1 and cell surface antigen 4F2. Arterioscler Thromb Vasc Biol 2004; 24: 1640-5.
110. Xu Y. Sphingosylphosphorylcholine and lysophosphatidylcholine: G protein-coupled receptors and receptor-mediated signal transduction. Biochim Biophys Acta 2002; 1582: 81-8.
111. Kabarowski JH, Xu Y, Witte ON. Lysophosphatidylcholine as a ligand for immunoregulation. Biochem Pharmacol 2002; 64: 161-7.
112. Le LQ, Kabarowski JH, Weng Z, Satterthwaite AB, Harvill ET, Jensen ER, et al. Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 2001; 14: 561-71
113. Radu CG, Yang LV, Riedinger M, Au M, Witte ON. T cell chemotaxis to lysophosphatidylcholine through the G2A receptor. PNAS 2004; 101: 245-50.
114. Hourton D, Stengel D, Chapman MJ, Ninio E. Oxidized low density lipoproteins downregulate LPS-induced platelet-activating fac tor receptor expression in human monocyte-derived macrophages: Implications for LPS-induced nuclear factor-{kappa}B binding activity. Eur J Biochem 2001; 268: 4489-96.
115. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330: 662-4.
116. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285: 248-51.
117. Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A 2002; 99: 12351-6
118. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 2000; 192: 565-70.
119. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 2003; 22: 5551-60.
120. Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X, et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med 2003; 9: 37-45.
121. Bustin M. At the crossroads of necrosis and apoptosis: Signaling to multiple cellular targets by HMGB1. Sci STKE 2002; 2002: PE39.
122. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, et al. Reversing established sepsis with antagonists of endogenous highmobility group box 1. Proc Natl Acad Sci USA 2004; 101: 296-301.
123. Tracey KJ, Cerami A. Tumor necrosis factor: A pleiotropic cytokine and therapuetic target. Ann Rev Med 1994; 45: 491-503.
124. Ulloa L, Fink MP, Tracey KJ. Ethyl pyruvate protects against lethal systemic inflammation by preventing HMGB1 release. Ann NY Acad Sci 2003; 987: 319-21.
125. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285: 248-51.
126. Degryse B, Bonaldi T, Scaffidi P, Muller S, Resnati M, Sanvito F, et al. The High Mobility Group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol 2001; 152: 1197-206.
127. Sappington PL, Yang R, Yang H, Tracey KJ, Delude RL, Fink MP. HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology 2002; 123: 790-802.
128. Li J, Wang H, Mason JM, Levine J, Yu M, Ulloa L, et al. Recombinant HMGB1 with cytokine-stimulating activity. J Immunol Methods 2004 289: 211-23.
129. Parrish W, Ulloa L. High-mobility group box-1 isoforms as potential therapeutic targets in sepsis. Methods Mol Biol 2007; 361: 145-62.
130. Tsung A, Kaizu T, Nakao A, Shao L, Bucher B, Fink MP, et al. Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis. Transplantation 2005; 79: 196-204.
131. Mallet RT, Sun J, Knott M, Sharma AB, Olivencia-Yurvati AH. Metabolic cardioprotection by pyruvate: Recent progress. Exp Biol Med 2005; 230: 435-43.
132. Fink MP. Ethyl pyruvate: A novel anti-inflammatory agent. Crit Care Med 2003; 31: S51-6.
133. Toyosawa T, Suzuki M, Kodama K, Araki S. Highly purified vitamin B2 presents a promising therapeutic strategy for sepsis and septic shock. Infect Immun 2004; 72: 1820-3.
134. Montgomery CM, Fairhurst AS, Webb JL. Metabolic studies on heart mitochondria. III. THE action of parapyruvate on agrketoglutaric oxidase. J Biol Chem 1956; 221: 369-76.
135. Montgomery CM, Webb JL. Metabolic studies on heart mitochondria. II. The inhibitory action of parapyruvate on the tricarboxylic acid cycle. J Biol Chem 1956; 221: 359-68.
136. Fink MP. Ethyl pyruvate: A novel treatment for sepsis and shock. Minerva Anestesiol 2004; 70: 365-71.
137. Tawadrous ZS, Delude RL, Fink MP. Resuscitation from hemorrhagic shock with Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats. Shock 2002; 17: 473-7
138. Yang R, Gallo DJ, Baust JJ, Uchiyama T, Watkins SK, Delude RL, et al. Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 2002; 283: G212-21.
139. Sims CA, Wattanasirichaigoon S, Menconi MJ, Ajami AM, Fink MP. Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats. Crit Care Med 2001; 29: 1513-8.
140. Uchiyama T, Delude RL, Fink MP. Dose-dependent effects of ethyl pyruvate in mice subjected to mesenteric ischemia and reperfusion. Intensive Care Med 2003; 29: 2050-8.
141. Yang R, Uchiyama T, Alber SM, Han X, Watkins SK, Delude RL, et al. Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizing pancreatitis. Crit Care Med 2004; 32: 1453-9.
142. Cheng BQ, Liu CT, Li WJ, Fan W, Zhong N, Zhang Y, et al. Ethyl pyruvate improves survival and ameliorates distant organ injury in rats with severe acute pancreatitis. Pancreas 2007; 35: 256-61.
143. Venkataraman R, Kellum JA, Song M, Fink MP. Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharide-induced shock. Shock 2002; 18: 507-12.
144. Miyaji T, Hu X, Yuen PS, Muramatsu Y, Iyer S, Hewitt SM, et al. Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. Kidney Int 2003; 64: 1620-31.
145. Su J, Li X, Cui X, Li Y, Fitz Y, Hsu L, et al. Ethyl pyruvate decreased early nuclear factor-kappaB levels but worsened survival in lipopolysaccharide-challenged mice. Crit Care Med 2008; 36: 1059-67
146. Tenhunen JJ. Bull's eye missed by the magic bullet: Preclinical investigations, publication bias, and promising new interventions. Crit Care Med 2008; 36: 1361-3.
147. Fink MP. Ethyl pyruvate. Curr Opin Anaesthesiol 2008; 21: 160-7.
148. Sappington PL, Fink ME, Yang R, Delude RL, Fink MP. Ethyl pyruvate provides durable protection against inflammation-induced intestinal epithelial barrier dysfunction. Shock 2003; 20: 521-8.
149. Droge W, Mihm S, Bockstette M, Roth S. Effect of reactive oxygen intermediates and antioxidants on proliferation and function of T lymphocytes. Methods Enzymol 1994; 234: 135-51.
150. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82: 47-95.
151. Pineda-Molina E, Klatt P, Vazquez J, Marina A, Garcia de Lacoba M, Perez-Sala D, et al. Glutathionylation of the p50 subunit of NFkappaB: A mechanism for redox-induced inhibition of DNA binding. Biochemistry 2001; 40: 14134-42.
152. Han Y, Englert JA, Yang R, Delude RL, Fink MP. Ethyl Pyruvate Inhibits Nuclear Factor-{kappa}B-Dependent Signaling by Directly Targeting p65. J Pharmacol Exp Ther 2005; 312: 1097-105.
153. Berkowitz B, Huang DB, Chen-Park FE, Sigler PB, Ghosh G. The x-ray crystal structure of the NF-kappa B p50.p65 heterodimer bound to the interferon beta -kappa B site. J Biol Chem 2002; 277: 24694-700.
154. Fong CH, Bebien M, Didierlaurent A, Nebauer R, Hussell T, Broide D, et al. An antiinflammatory role for IKKbeta through the inhibition of "classical" macrophage activation. J Exp Med 2008; 205: 1269-76.
155. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 1995; 270: 25752-61.
156. Huttunen HJ, Rauvala H. Amphoterin as an extracellular regulator of cell motility: From discovery to disease. J Intern Med 2004; 255: 351-66
157. Kokkola R, Andersson A, Mullins G, Ostberg T, Treutiger CJ, Arnold B, et al. RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand J Immunol 2005; 61: 1-9.
158. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279: 7370-7
159. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418: 191-5.
160. Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 2002; 3: 995-1001.
161. Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR, Ferguson TA. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 2008; 29: 21-32.
162. Tracey KJ. The inflammatory reflex. Nature 2002; 420: 853-9.
163. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405: 4458-62.
164. Matthay MA, Ware LB. Can nicotine treat sepsis? Nat Med 2004; 10: 1161-2.
165. Saeed RW, Varma S, Peng-Nemeroff T, Sherry B, Balakhaneh D, Huston J, et al. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J Exp Med 2005; 201: 1113-23.
166. Ravikumar R, Flora G, Geddes JW, Hennig B, Toborek M. Nicotine attenuates oxidative stress, activation of redox-regulated transcription factors and induction of proinflammatory genes in compressive spinal cord trauma. Brain Res Mol Brain Res 2004; 124: 188-98.
167. Shaw S, Bencherif M, Marrero MB. Janus Kinase 2, an Early Target of alpha 7 Nicotinic Acetylcholine Receptor-mediated Neuroprotection against Abeta -(1-42) Amyloid. J Biol Chem 2002; 277: 44920-4.
168. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 2005; 6: 844-51.
169. Metz CN, Gregersen PK, Malhotra AK. Metabolism and biochemical effects of nicotine for primary care providers. Med Clin North Am 2004; 88: 1399-413, ix.
170. Meyer EM, Tay ET, Papke RL, Meyers C, Huang GL, de Fiebre CM. 3-[2,4-Dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat alpha7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner. Brain Res 1997; 768: 49-56.
171. Marrero MB, Papke RL, Bhatti BS, Shaw S, Bencherif M. The neuroprotective effect of 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel {alpha}7 ligand, is prevented through angiotensin II activation of a tyrosine phosphatase. J Pharmacol Exp Ther 2004; 309: 16-27.
172. Nanri M, Kasahara N, Yamamoto J, Miyake H, Watanabe H. A comparative study on the effects of nicotine and GTS-21, a new nicotinic agonist, on the locomotor activity and brain monoamine level. Jpn J Pharmacol 1998; 78: 385-9.
173. Kitagawa H, Takenouchi T, Azuma R, Wesnes KA, Kramer WG, Clody DE, et al. Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 2003; 28: 542-51.
174. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: A trend analysis from 1993 to 2003. Crit Care Med 2007; 35: 1244-50.
175. Poli-de-Figueiredo LF, Garrido AG, Nakagawa N, Sannomiya P. Experimental models of sepsis and their clinical relevance. Shock 2008; 30(Suppl 1): 53-9.
176. Rittirsch D, Hoesel LM, Ward PA. The disconnect between animal models of
177. Piper RD, Cook DJ, Bone RC, Sibbald WJ. Introducing Critical Appraisal to studies of animal models investigating novel therapies in sepsis. Crit Care Med 1996; 24: 2059-70.
178. Mathiak G, Szewczyk D, Abdullah F, Ovadia P, Feuerstein G, Rabinovici R. An improved clinically relevant sepsis model in the conscious rat. Crit Care Med 2000; 28: 1947-52.
179. Brackett DJ, Schaefer CF, Tompkins P, Fagraeus L, Peters LJ, Wilson MF. Evaluation of cardiac output, total peripheral vascular resistance, and plasma concentrations of vasopressin in the conscious, unrestrained rat during endotoxemia. Circ Shock 1985; 17: 273-84.
180. Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J Surg Res 1990; 49: 186-96.
181. Singleton KD, Wischmeyer PE. Distance of cecum ligated influences mortality, tumor necrosis factor-alpha and interleukin-6 expression following cecal ligation and puncture in the rat. Eur Surg Res 2003; 35: 486-91.
182. Leon C, Alvarez-Lerma F, Ruiz-Santana S, Leon MA, Nolla J, Jorda R, et al. Fungal colonization and/or infection in non-neutropenic critically ill patients: Results of the EPCAN observational study. Eur J Clin Microbiol Infect Dis 2009; 28(3): 233-42.
183. Yin QQ, Zhang YT, Fang Q. [Study on the morbidity and pathogens of patients with candidemia at the intensive care unit]. Zhonghua Liu Xing Bing Xue Za Zhi 2008; 29: 464-8.
184. Opal SM, Cohen J. Clinical gram-positive sepsis: Does it fundamentally differ from gram-negative bacterial sepsis? Crit Care Med 1999; 27: 1608-16.
185. Fink MP, MacVittie TJ, Casey LC. Inhibition of prostaglandin synthesis restores normal hemodynamics in canine hyperdynamic sepsis. Ann Surg 1984; 200: 619-26.
186. Natanson C, Fink MP, Ballantyne HK, MacVittie TJ, Conklin JJ, Parrillo JE. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock. J Clin Invest 1986; 78: 259-70.
187. Taylor FB, Jr. Staging of the pathophysiologic responses of the primate microvasculature to Escherichia coli and endotoxin: Examination of the elements of the compensated response and their links to the corresponding uncompensated lethal variants. Crit Care Med 2001; 29: S78-89.
188. Espat NJ, Cendan JC, Beierle EA, Auffenberg TA, Rosenberg J, Russell D, et al. PEG-BP-30 monotherapy attenuates the cytokinemediated inflammatory cascade in baboon Escherichia coli septic shock. J Surg Res 1995; 59: 153-8.
189. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006; 440: 1217-21.
190. Beutler B, Rehli M. Evolution of the TIR, tolls and TLRs: Functional inferences from computational biology. Curr Top Microbiol Immunol 2002; 270: 1-21.
191. Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ. HMG-1 as a mediator of acute lung inflammation. J Immunol 2000; 165: 2950-4.
192. Lin X, Yang H, Sakuragi T, Hu M, Mantell LL, Hayashi S, et al. Alpha-chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis. Am J Physiol Lung Cell Mol Physiol 2005; 289: L583-90.
193. Nieuwenhuijzen GA, Haskel Y, Lu Q, Berg RD, van Rooijen N, Goris RJ, et al. Macrophage elimination increases bacterial translocation and gut-origin septicemia but attenuates symptoms and mortality rate in a model of systemic inflammation. Ann Surg 1993; 218: 791-9.
194. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the Lps gene product. J Immunol 1999; 162: 3749-52.
195. Myhre AE, Aasen AO, Thiemermann C, Wang JE. Peptidoglycan - an endotoxin in its own right? Shock 2006; 25: 227-35.
196. Sugawara I, Yamada H, Li C, Mizuno S, Takeuchi O, Akira S. Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiol Immunol 2003; 47: 327-36.
197. Takeuchi O, Kawai T, Sanjo H, Copeland NG, Gilbert DJ, Jenkins NA, et al. TLR6: A novel member of an expanding toll-like receptor family. Gene 1999; 231: 59-65.
198. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8: 776-87.
199. Dehring DJ, Crocker SH, Wismar BL, Steinberg SM, Lowery BD, Cloutier CT. Comparison of live bacteria infusions in a porcine model of acute respiratory failure. J Surg Res 1983; 34: 151-8.
200. Sligl W, Taylor G, Gibney RN, Rennie R, Chui L. Methicillin-resistant Staphylococcus aureus in a Canadian intensive care unit: Delays in initiating effective therapy due to the low prevalence of infection. Can J Infect Dis Med Microbiol 2007; 18: 139-43.
201. Stamme C, Bundschuh DS, Hartung T, Gebert U, Wollin L, Nusing R, et al. Temporal sequence of pulmonary and systemic inflammatory responses to graded polymicrobial peritonitis in mice. Infect Immun 1999; 67: 5642-50.
202. Parker SJ, Watkins PE. Experimental models of gram-negative sepsis. Br J Surg 2001; 88: 22-30.
203. Martich GD, Danner RL, Ceska M, Suffredini AF. Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: The effect of antiinflammatory agents. J Exp Med 1991; 173: 1021-4.
204. Michie HR, Manogue KR, Spriggs DR, Revhaug A, O'Dwyer S, Dinarello CA, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318: 1481-6.