Innate immunity in sepsis pathogenesis and its modulation: New immunomodulatory targets revealed

Journal of Chemotherapy

Volumn 20, Issue 6, 2008, Pages 672-683

  Kumar, Vijay ^a   Sharma, A ^b  

^a PANJAB UNIVERSITY   (India)

^b DR Y S PARMAR UNIVERSITY OF HORTICULTURE AND FORESTRY   (India)

Author keywords

Immunomodulation; Innate immunity; Sepsis; Systemic inflammatory immune response (SIRS)

Indexed keywords

2 (2,4 DICHLOROPHENYL) 3 (1 METHYL 3 INDOLYL)MALEIMIDE; 2 (3 CHLORO 4 HYDROXYANILINO) 3 (2 NITROPHENYL)MALEIMIDE; 6 [N (2 CHLORO 4 FLUOROPHENYL)SULFAMOYL] 1 CYCLOHEXENE 1 CARBOXYLIC ACID ETHYL ESTER; ANTIBIOTIC AGENT; ANTIINFLAMMATORY AGENT; BACTERIUM LIPOPOLYSACCHARIDE; BRADYKININ ANTAGONIST; CASPASE RECRUITMENT DOMAIN PROTEIN 15; CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; CD14 ANTIGEN; CD18 ANTIGEN; CHEMOKINE RECEPTOR CCR4; CHEMOKINE RECEPTOR CXCR4; COMPLEMENT COMPONENT C5A; CYTOKINE; DROTRECOGIN; ERITORAN; GAMMA INTERFERON; GRANULOCYTE COLONY STIMULATING FACTOR; HIGH MOBILITY GROUP B1 PROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMMUNOMODULATING AGENT; METHYLPREDNISOLONE; MIGRATION INHIBITION FACTOR; PYRROLIDINE DITHIOCARBAMATE; RECOMBINANT BACTERICIDAL PERMEABILITY INCREASING PROTEIN; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; THROMBOCYTE ACTIVATING FACTOR ANTAGONIST; TOLL LIKE RECEPTOR 2; UNINDEXED DRUG;

ANTIMICROBIAL ACTIVITY; CAUSE OF DEATH; CLINICAL TRIAL; COMPLEMENT SYSTEM; DRUG PROTEIN BINDING; DRUG TARGETING; GRAM NEGATIVE BACTERIUM; GRAM NEGATIVE SEPSIS; GRAM POSITIVE BACTERIUM; HUMAN; IMMUNOMODULATION; IMMUNOPATHOGENESIS; IMMUNOREGULATION; IMMUNOSTIMULATION; INNATE IMMUNITY; INTENSIVE CARE UNIT; MORTALITY; NONHUMAN; REVIEW; SEPSIS; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME;

EID: 59349121715     PISSN: 1120009X     EISSN: None     Source Type: Journal    
DOI: 10.1179/joc.2008.20.6.672     Document Type: Review

References (144)

1. Ulloa L, Tracy KJ. The 'cytokine profile': a code for sepsis. Trends Mol Med 2005; 11: 56-63.
2. Chen G, Li J, Qiang X, Czura CJ, Ochani M, Ochani K et al. Suppression of HMGB1 release by stearoyl lysophosphatidylchine: an additional mechanism for its therapeutic effects in experimental sepsis. J Lipid Res 2005; 46: 623-627.
3. 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: 1546-1554.
4. Cohen J. The immunopathogenesis of sepsis. Nature 2002; 420: 885-891.
5. Netea MG, Van der Meer JWM, Deuren MV, Kullberg BJ. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of good thing? Trends Immunol 2003; 24: 254-259.
6. 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: a reevaluation. Crit Care Med 2000; 28: 232-235.
7. Matot I, Sprung CL. Definitions of sepsis. Intensive Care Med 2001; 27: 83-89.
8. 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: 1303-1310.
9. Alexopoulou L, Holt AC, Medzhitov R, Havell RA. Recognition of double-stranded RNA and activation of NF-kappa B by Toll-like receptor 3. Nature 2001; 413: 732-738.
10. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990; 24: 1431-1433.
11. Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med. 1999; 189(11):1777-1782.
12. Akashi S, Shimazu R, Ogata H, Nagai Y, Takeda K, Kimoto M, Miyake K. Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J Immunol 2000; 164(7): 3471-3475.
13. Lynn WA, Liu Y, Golenbock DT. Neither CD14 nor serum is absolutely necessary for activation of mononuclear phagocytes by bacterial lipopolysaccharide. Infect Immun 1993; 61: 4452-4461.
14. Triantafilou M, Triantafilou K, Fernandez N. Rough and smooth forms of fluorescein-labelled bacterial endotoxin exhibit CD14/LPB dependent and independent binding that is influenced endotoxin concentration. Eur J Biochem 2000: 267: 2218-2226.
15. Gessani S, Testa U, Varano B, Di Marzio P, Borghi P, Conti L et al. Enhanced production of LPS-induced cytokines during differentiation of human monocytes to macrophages. Role of LPS receptors. J Immunol. 1993; 151(7): 3758-3766.
16. Gobert V, Gottar M, Matskevich AA, Rutschmann S, Royet J, Belvin M et al. Dual activation of the Drosophila toll pathway by two pattern recognition receptors. Science. 2003; 302(5653): 2126-2130.
17. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Gosh S. A toll-like receptor that prevents infection by uropathogenic bacteria. Science 2004; 303:1522-1526.
18. Arbour NC, Lorenz E, SchutteBC, Zabner J, Kline JN, Jones M et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000; 25: 187-191.
19. Lorenz E, Frees KL, Schwartz DA. Determination of the TLR4 genotype using allele-specific PCR. Biotechniques 2001; 31: 22-24.
20. Schwartz DA. TLR4 and LPS hyporesponsiveness in humans. Int J Hyg Environ Health 2002; 205: 221-227.
21. O'Neill L. The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defense. Biochem Soc Trans. 2000; 28: 557-563.
22. Suzuki N, Suzuki S, Duncan GS, Millar DG, Wada T, Mirtsos C et al. Severe impairment of interleukin-1 and Toll-like receptor signaling in mice lacking IRAK-4. Nature. 2002; 416: 750-756.
23. Zhang FX, Kirschning CJ, Mancinelli R, Xu XP, Xin Y, Faure E et al. Bacterial lipopolysaccharide activates nuclear factor-_B through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 1999; 274: 7611-7614.
24. Lomaga MA, Ych WC, Sarosi I, Duncan GS, Furlonger C, Ho A et al. TRAF6 deficiency results in osteoporosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 1999; 13: 1015-1024.
25. Lee J, Mira-Arbibe L, Ulevitch RJ. TAK1 regulates multiple protein kinase cascades activated by bacterial lipopolysaccharides. J Leukoc Biol 2000; 68: 909-915.
26. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 2003; 301: 640-643.
27. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO et al. Identification of LPS as a key transducer of MyD88-independent TIR signaling. Nature 2003; 424: 743-748.
28. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003; 4: 1144-1150.
29. Werts C, Tapping Ri, Mathison JC, Chuang TH, Kravchenko V, Girons IS et al. Leptospiral lipopolysaccharide activates cells through a TLR2 dependent mechanism. Nat Immunol 2001; 2 (4): 346-352.
30. Werner T, Liu G, Kang D, Ekengren S, Steiner H, Hultmark D. A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster. Proc Natl Acad Sci USA 2000; 97: 13772-13777.
31. Liu C, Xu Z, Gupta D, Dziarski R. Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules. J Biol Chem 2001; 276: 34686-34694.
32. Bouchan A, Dietrich J, Colonna M. Cutting edge: Inflammatory response can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 2000; 164:4991-4995.
33. Bouchan A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 2001; 410: 1103-1107.
34. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jéhanno M, Viala J et al. Nodl detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003; 300 (5625): 1584-1587.
35. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003; 278(11): 8869-8872.
36. Inohara N, Ogura Y, Chen FF, Muto A, Nuñez G. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem. 2001; 276(4): 2551-2554.
37. Tschopp J, Martinon F, Burns K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 2003; 4(2): 95-104.
38. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 2003; 4(7): 702-707.
39. Bertin J, Nir WJ, Fischer CM, Tayber OV, Errada PR, Grant JR et al. Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB. J Biol Chem 1999; 274(19): 12955-12958.
40. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/ Apaf-1 family member that is restricted to monocytes and activates NF-kappa B. J Biol Chem 2001; 276(7): 4812-4818.
41. Cartwright N, Murch O, McMaster KS, Paul-Clark MJ, Heel DAV, Ryffel B et al. Selective NOD1 agonists cause shock and organ injury/dysfunction in vivo. Am J Respir Crit Care Med 2007; 175: 595-603.
42. Fritz JH, Girardin SE, Fitting C, Werts C, Mengin-Lecreulx D, Caroff M, et al. Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2- activating agonists. Eur J Immunol 2005; 35: 2459-2470.
43. Uehara A, Yang S, Fujimoto Y, Fukase K, Kusumoto S, Shibata K, et al. Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2- and NOD1-dependent manner, respectively, in human monocytic cells in culture. Cell Microbiol 2005; 7: 53-61.
44. Tada H, Aiba S, Shibata K, Ohteki T, Takada H. Synergistic effect of Nod1 and Nod2 agonists with Toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun 2005; 73: 7967-7976.
45. Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 2007; 7: 179-190.
46. Watanabe T, Kitani A, Murray PJ, Strober W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 2004; 5: 800-808.
47. de Boer JP, Creasey AA, Chang A, Roem D, Eerenberg Ad, Hack CE, Taylor FB Jr. Activation of the complement system in baboons challenged with live Escherichia coli: correlation with mortality and evidence for a biphasic activation pattern. Infect Immun 1993; 61: 4293-4301.
48. Bengtson A, Heideman M. Anaphylatoxin formation in sepsis. Arch Surg 1988; 123: 645-649.
49. Nakae H, Endo S, Inada K, Takakuwa T, Kasai T, Yoshida M. Serum complement levels and severity of sepsis. Res Commun Chem Pathol Pharmacol 1994; 84: 189-195.
50. Fierl MA, Schreiber H, Huber-Lang MS. The role of complement, C5a, and its receptors in sepsis and multiorgan dysfunction syndrome. J Invest Surg 2006; 19: 255-265.
51. Muller-Eberhard HJ. Molecular organization and function of the complement system. Annu Rev Biochem 1988; 57: 321-347.
52. Reid KB, Porter RR. The proteolytic activation systems of complement. Ann Rev Biochem 1981; 50: 433-464.
53. Fujita T. Evolution of the lectin-complement pathway and its role in innate immunity. Nat Rev Immunol 2002; 2: 346-353.
54. Zhao L, Ohtaki Y, Yamaguchi K, Matsushita M, Fujita T, Yokochi T, et al. LPS-induced platelet response and rapid shock in mice: contribution of O antigen region of LPS and involvement of the lectin pathway of the complement system. Blood 2002; 100: 3233-3239.
55. Gerard C. Complement C5a in the sepsis syndrome - Too much of a good thing? N Engl J Med 2003; 348: 167-169.
56. Ward PA. The dark side of C5a in sepsis. Nat Rev Immunol 2004; 4: 133-142.
57. Smedegard G, Cui LX, Hugli TE: Endotoxin-induced shock in the rat. A role for C5a. Am J Pathol 1989; 135: 489-497.
58. Bengtson A, Heideman M: Anaphylatoxin formation in sepsis. Arch Surg 1988; 123: 645-649.
59. Nakae H, Endo S, Inada K, Takakuwa T, Kasai T, Yoshida M: Serum complement levels and severity of sepsis. Res Commun Chem Pathol Pharmacol 1994, 84: 189-195.
60. de Boer JP, Creasey AA, Chang A, Roem D, Eerenberg AJ, Hack CE, Taylor Jr FB. Activation of the complement system in baboons challenged with live Escherichia coli: correlation with mortality and evidence for a biphasic activation pattern. Infect Immun 1993; 61: 4293-4301.
61. Huber-Lang M, Sarma VJ, Lu KT, McGuire SR, Padgaonkar VA, Guo RF et al. Role of C5a in multiorgan failure during sepsis. J Immunol 2001; 166: 1193-1199.
62. Huber-Lang M, Younkin EM, Sarma JV, Riedemann N, McGuire SR, Lu KT et al. Generation of C5a by phagocytic cells. Am J Pathol 2002; 161: 1849-1859.
63. Sacks T, Moldow CF, Craddock PR, Bowers TK, Jacob HS. Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage. J Clin Invest 1978; 61: 1161-1167.
64. Shin HS, Snyderman R, Friedman E, Mellors A, Mayer MM. Chemotactic and anaphylatoxic fragment cleaved from the fifth component of guinea pig complement. Science 1968; 162: 361-363.
65. Goldstein IM, Weissmann G. Generation of C5-derived lysosoma enzyme-releasing activity (C5a) by lysates of leukocyte lysosomes. J Immunol 1974; 113: 1583-1588.
66. Ward PA. Role of the complement in experimental sepsis. J Leukoc Biol 2008; 83: 1-4.
67. Hoesel LM, Niederbichler AD, Ward PA. Complement-related molecular events in sepsis leading to heart failure. Mol Immunol 2007; 44: 95-102.
68. Chen NJ et al. C5L2 is critical for the biological activities of the anaphlatoxins C5a and C3a. Nature 2007; 446; 203-207.
69. Rittrisch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR et al. Functional role for C5a receptors in sepsis. Nat Med 2008;
70. Schumacher WA, Fantone JC, Kunkel SE, Webb RC, Luchesi BR. The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculature in vitro and in vivo. Agents Actions 1991; 34: 345-349.
71. Strieter RM, Kasahara K, Allen RM, Standiford TJ, Rolfe MW, Becker FS, et al. Cytokine induced neutrophil-derived interleukin-8. Am J Pathol 1992; 141: 397-407.
72. Hopken U, Mohr M, Struber A, Montz H, Burchardi H, Gotze O, et al. Inhibition of interleukin-6 synthesis in an animal model of septic shock by anti-C5a monoclonal antibodies. Eur J Immunol 1996; 26: 1103-1109.
73. Guo RF, Riedeman NC, Ward PA. Role of C5a-C5aR interaction in sepsis. Shock 2004; 21(1): 1-7.
74. Ikeda K, Nagasawa K, Horiuchi T, Tsuru T, Nishizaka H, Niho Y. C5a induces tissue factor activity on endothelial cells. Thromb Haemost 997; 77: 394-398.
75. Muhlfelder TW, Niemetz J, Kreutzer D, Beebe D, Ward PA, Rosenfeld SI. C5 chemotactic fragment induces leukocyte production of tissue factor activity: a link between complement and coagulation. J Clin Invest 1979; 63: 147-150.
76. Carson SD, Johnson DR. Consecutive enzyme cascades: complement activation at the cell surface triggers increased tissue factor activity. Blood 1990; 76: 361-367.
77. Laudes IJ, Chu JC, Sikranth S, Huber-Lang M, Guo RF, Riedemann N, et al. Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. Am J Pathol 2002; 160: 1867-1875.
78. Guo RF, Ward PA. C5a, a therapeutic target in sepsis. Rec Pat Anti-infect Drug Discov 2006; 1
79. Van der Poll T, Lowry SF. Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense? Shock 1995; 3: 1-12.
80. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348: 138-150.
81. Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med 1994; 45: 491-503.
82. Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol 1993; 9: 317-343.
83. Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS): molecular pathophysiology and gene therapy. J Pharmacol Sci 2006; 101: 189-198.
84. Wang H, Bloom O, Zhang M, Vishnubhakat MJ, Ombrellino M, Che J et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285 (5425): 248-251.
85. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl. Acad. Sci. USA 2001; 101: 296-301.
86. Czura CJ, Yang H, Tracey KJ. High mobility group box-1 as a therapeutic target downstream of tumor necrosis factor. J Infect Dis 2003; 187 Suppl 2: S391-S396.
87. Ombrellino M, Wang H, Ajemian MS, Talhouk A, Scher LA, Friedman SG, Tracey KJ. Increased serum concentrations of high-mobility-group protein 1 in haemorrhagic shock. Lancet 1999; 354(9188): 1446-1447.
88. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418: 191-195.
89. 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(10): 995-1001.
90. Rendon-Mitchell B, Ochani M, Li J, Han J, Wang H, Yang H. IFN-? Induces High Mobility Group Box 1 Protein Release partly through a TNF-dependent mechanism J Immunol 2003; 170: 3890-3897.
91. Erlandsson HH, Andersson U. Mini-review: The nuclear protein HMGBI as proinflammatory mediator. Eur J Immunol 2004; 34: 1503-1512.
92. Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T et al. The pattern recognition receptor (RAGE) is a counter receptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 2003; 198(10): 1507-15.
93. Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S et al. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Invest. 2004; 113(11): 1641-1650.
94. Bozza M, Satoskar AR, Lin G, Lu B, Humbles AA, Gerard C, et al. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 1999; 189(2): 341-346.
95. Calandra T, Spiegel LA, Metz CN, Bucala R. Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. Proc Natl Acad Sci USA 1998; 95: 11383-11388.
96. Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med. 1995; 23: 1294-1303.
97. Cohen J. Adjunctive therapy in sepsis: a critical analysis of the clinical trial programme. Br Med Bull 1999; 55: 212-225.
98. Reinhart K, Karzai W. Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned. Crit Care Med. 2001; 29: S121-S125.
99. Ohlsson K, Bjork P, Bergenfeldt M, Hageman R, Thompson RC. Interleulin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 1990; 348: 550-552.
100. Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 1997 1; 25(7): 1115-1124.
101. Vincent JL, Sun Q, Dubois MJ. Clinical trials of immunomodulatory therapies in sepsis and septic shock. Clin Infect Dis 2001; 34: 1084-1093.
102. Reidmann NC, Guo, RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med 2003; 9: 517-524.
103. Hancock REW, Sahl HG. Antimicrobial and host defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 2006; 24: 1551-1557.
104. Gough M, Hancock RE, Kelly NM. Antiendotoxin activity of cationic peptide antimicrobial agents Infect Immun 1996; 64: 4922-4927.
105. Marra MN, Wilde CG, Griffith JE, Snable JL, Scott RW. Bactericidal/ permeability-increasing protein has endotoxin neutralizing activity. J Immunol 1990; 144: 662-666.
106. + expression of TNF-_by blocking the binding of LPS to CD14 cells. J Immunol 2001; 167: 3329-3338.
107. Weiss J, Muello K, Victor M, Elsbach P. The role of lipopolysaccharides in the action of the bactericidal/permeability increasing neutrophil protein on the bacterial envelope. J Immunol 1984; 132: 3109-3115.
108. Marra MN, Wilde CG, Griffith JE, Snable JL, Scott RW. Bactericidal/ permeability-increasing protein has endotoxin-neutralizing activity. J Immunol 1990; 144: 662-666.
109. Jiang J, Zhu P, Wang Z, He Y, Liu D, Tian K, et al. Protective effect of bactericidal/permeability-increasing protein in mice with E. coli sepsis. Chin J Traumatol 1998; 1(1): 21-24.
110. Jiang J, Xie G, Liu D, Zhu P, Wang Z, He Y et al. Effect of bactericidal/ permeability-increasing protein on sepsis induced by intra-abdominal infection in rats. Chin J Traumatol 1999; 2(2): 84-86.
111. Bowdish DME, Hancock REW. Anti-endotoxin properties of cationic host defense peptides and proteins. J Endo Res 2005; 11 (4): 230-236.
112. Levin M, Quint PA, Goldstein B, Barton P, Bradley JS, Shemie SD et al. Recombinant bactericidal/permeability-increasing protein (rBP121) as adjunctive treatment for children with severe meningococcal sepsis: a randomized trial. rBP121 Meningococcal Sepsis Study Group. Lancet. 2000; 356(9234): 961-967.
113. Lynn M, Rossignol DP, Wheeler JL, Kao RJ, Perdomo CA, Noveck R et al. Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J Infect Dis 2003; 187(4): 631-9.
114. Savov JD, Brass DM, Lawson BL, McElvania-Tekippe E, Walker JK, Schwartz DA. Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide. Am J Physiol Lung Cell Mol Physiol 2005; 289(2): L329-L337.
115. Cristofaro P, Opal SM. Role of Toll-like receptors in infection and immunity. Drugs 2006; 66 (1): 15-29.
116. Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Tsukasa S. A Novel cyclohexene derivative, ethyl (6r)6-[n-(2-chloro-4-fluorophenyl)sulfamoyllcyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits Toll-Like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol 2006; 69:1288-1295.
117. Methe H, Kim JO, Kofler S, Nabauer M, Weis M, Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arterioscler Thromb Vasc Biol 2005; 25(7): 1439-45.
118. Pahan K, Sheikh FG, Namboodiri AM, Singh D. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglial cells and macrophages. J Clin Invest 1997; 100: 2671-1679.
119. Greenwood J, Steinman L, Zamvil SC. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 2006; 6: 358-370.
120. Li SF, Ye X, Malik AB. Inhibition of NF-_B activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation 1999; 100: 1330-1337.
121. Demarchi F, Bertoli C, Sandy P, Schneider C. Glycogen synthase kinase-3 beta regulates NF-kappa B1/p105 stability. J Biol Chem 2003; 278(41):39583-90.
122. Takada Y, Fang X, Jamaluddin MS, Boyd DD, Aggarwal BB. Genetic deletion of glycogen synthase kinase-3beta abrogates activation of ikappabalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. J Biol Chem 2004; 279(38): 39541-39554.
123. Dugo L, Collin M, Allen DA, Patel NS, Bauer I, Mervaala EM et al. GSK-3beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat. Crit Care Med. 2005; 33(9): 1903-1912.
124. Ulloa L, Ochani M, Yang H, TanovicM, HalperinD, Yang R. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci USA 2002; 99: 12351-12356.
125. 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: 1216-1221.
126. 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: 161-167.
127. 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(2): 164-70.
128. Roger T, David J, Glauser MP, Calandra T. MIF regulates innate immune response through modulation of Toll-like receptor 4. Nature 2001; 414: 920-924.
129. Lomas-Neira J, Ayala A. Pepducins: an effective means to inhibit GPCR signaling by neutrophils. Trends Immunol. 2005; 26(12): 619-621.
130. Brown KA,Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher SF. Neutrophils in development of multiorgan failure in sepsis. Lancet 2006; 368: 157-169.
131. Reutershan J, Morris MA, Burcin TL, Smith DF, Chang D, Saprito MS, Ley K. Critical role of endothelial CXCR2 in LPS induced neutrophil migration into the lung. J Clin Invest 2006; 116: 695-702.
132. Kaneider NC, Agarwal A, Leger AJ, Kuliopulos A. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nat Med 2005; 11: 661-665.
133. Abraham, E. Laterre PF, Garbino J, Pingleton S, Butler T, Dugemier 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: 503-510.
134. Fisher, CJ Jr, Dhainaut JFA, Opal SM, Pribble JP, Slotman GJ et al. Recombinant human interleukin 1receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. J Am Med Assoc 1994; 271: 1836-1843.
135. Hornef MW, Normark BH, Vandewalle A, Normark S. Intracellular recognition of lipopolysaccharide by toll-like receptor 4 in intestinal epithelial cells. J Exp Med. 2003; 198: 1225-1435.
136. McCurdy JD, Olynych TJ, Maher LH, Marshall JS. Cutting edge: distinct toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. J Immunol 2003; 170: 1625-1629.
137. Komai-Koma M, Jones L, Ogg GS, Xu D, Liew FY. TLR2 is expressed on activated T cells as costimulatory receptor. Proc. Natl Acad Sci USA 2004; 101: 3029-3034.
138. Wright SD, Jong MT. Adhesion promoting receptors on human macrophages recognize Escherichia coli by binding to lipopolysaccharide. J Exp Med. 1986; 164: 1876-1888.
139. Heine H, Lentschat A, Hamann L. Decay-accelerating factor (DAF/CD55) is a functional active element of the LPS receptor complex. J Endotoxin Res. 2001; 7: 227-231.
140. Nathan C, Ding A. TREM-1: a new regulator of innate immune system in sepsis syndrome. Nat Med 2001; 7: 530-532.
141. Ogata H, Su I, Miyake K, Nagai Y, Akashi S, Mecklenbräuker I, et al. The toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. J Exp Med 2000; 192; 23-29.
142. Triantafilou K, Triantafilou M, Dedrick RL. A CD14-independent LPS receptor cluster. Nat Immunol. 2001; 2: 338-345.
143. Giardin SE, Boneca IG, Carneiro LA, Antignac A, Jéhanno M, Viala J, et al. Nod1 detects a unique muropeptide from gram negative bacterial peptidoglycan. Science 2003; 300: 1584-1587.
144. Giardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003; 278: 8869-8872.