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  • Review Article
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Therapeutic approaches to innate immunity: severe sepsis and septic shock

Nature Reviews Drug Discovery volume 2, pages 635–645 (2003)Cite this article

Key Points

  • After two decades of clinical trials to find therapeutic treatments for sepsis and its related conditions, activated protein C was recently approved for the treatment of severe sepsis. During these years, much has been learned about how innate immunity functions to control microbial infection, and the pathological consequences that ensue when this response fails.

  • Glucocorticoids are used routinely in a pharmacological capacity because of their potent, broad-spectrum anti-inflammatory action, and they are a mainstay of therapy for many different inflammatory and autoimmune diseases. Many believe that these high doses of glucocorticosteroids suppress innate immune responses and compromise the ability of the host to eliminate the ongoing infection.

  • Immunoneutralization of C5/C5a has been successfully applied in clinical settings of cardiac ischaemia/reperfusion, which portends benefit in severe sepsis, a situation in which hypoperfusion and ischaemia contribute to multi-organ damage.

  • The cytokine macrophage migration inhibitory factor (MIF) is an upstream activator of monocytes/macrophages, and MIF immunoneutralization or genetic deletion in mice results in lower concentrations of tumour-necrosis factor-α, interleukin-1 and prostaglandin E2. Anti-MIF also protects mice from toxic-shock syndrome toxin-1-induced lethality, and MIF knockout mice are resistant to a lethal injection of staphylococcal enterotoxin B. MIF is a promising target.

  • High-mobility group B-1 (HMGB-1) is a nuclear binding protein that circulates at high concentrations relatively late (8–32 hours) after lipopolysaccharide administration to mice. This protein might be an appropriate target for sepsis. A candidate small molecule that improves survival in a preclinical model of sepsis was recently reported to be associated with reduced HMGB-1 production in vivo.

  • Our increased understanding of the complex, interconnected networks involving the inflammatory response, the complement and coagulation pathways, and host metabolic responses might lead to new therapeutics for sepsis.

Abstract

Severe sepsis leading to shock is the principal cause of death in non-cardiac intensive care units. This condition develops because of a dysregulation in host responses, such that the mechanisms initially recruited to fight infection produce life-threatening tissue damage and death. Recent advances in our understanding of innate immunity, and the interaction between the inflammatory and the haemostatic cascades, are affording new opportunities for therapeutic development. This article discusses selected pathophysiological mechanisms that might yield to therapeutic intervention, considers rationales for the resurrection of previously failed drugs, and highlights new targets that have shown promise in preclinical studies.

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Figure 1: Structural features of the cell wall that distinguishes the Gram-positive from the Gram-negative bacteria, which are two principal classes of pathogenic bacteria.
Figure 2: The main pathways for the activation of complement.
Figure 3: Impact of sepsis on the physiological network regulating thrombosis.
Figure 4: Scheme for main effector pathways activated by sepsis that contribute to end-organ dysfunction.
Figure 5: Proposed scheme for the therapeutic action of activated protein C in severe sepsis.
Figure 6: Small-molecule inhibitors of MIF targeted to its catalytic pocket.

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Notes

  1. *For additional discussion see Refs 48,54.

References

  1. Martin, G. S., Mannimo, D. M., Eaton, S. & Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546–1554 (2003).

    PubMed  Google Scholar 

  2. Quartin, A. A., Schein, R. M., Kett, D. H. & Peduzzi, P. N. for the Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. Magnitude and duration of the effect of sepsis on survival. JAMA 277, 1058–1063 (1997).

    CAS  PubMed  Google Scholar 

  3. Pert, T. M., Dvorak, L., Hwang, T. & Wenzel, R. P. Long-term survival and function after suspected gram-negative sepsis. JAMA 274, 338–345 (1995).

    Google Scholar 

  4. Bone, R. C. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101, 1644–1655 (1992).

    CAS  PubMed  Google Scholar 

  5. Rangel-Frausto, M. S. et al. The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. JAMA 273, 117–123 (1995).

    CAS  PubMed  Google Scholar 

  6. Cohen, J. The immunopathogenesis of sepsis. Nature 420, 885–891 (2003).

    Google Scholar 

  7. Young, L. S. in Principles and Practice of Infectious Diseases (eds Mandell, G. L., Bennett, J. E. & Dolin, R.) 806–820 (Churchill Livingstone, New York, 2000).

    Google Scholar 

  8. Angus, D. C. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310 (2001).

    CAS  PubMed  Google Scholar 

  9. Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. Immunobiology 35–91 (Garland, New York, 2001).

    Google Scholar 

  10. Aderem, A. & Ulevitch, R. J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).

    CAS  PubMed  Google Scholar 

  11. Gordon, S. Pattern recognition receptors: doubling up for the innate immune response. Cell 111, 927–930 (2002).

    CAS  PubMed  Google Scholar 

  12. Bouchon, A., Dietrich, J. & Colonna, M. Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164, 4991–4995 (2000).

    CAS  PubMed  Google Scholar 

  13. Inohara, N., Ogura, Y. & Nunez, G. Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr. Opin. Microbiol. 5, 76–80 (2002).

    CAS  PubMed  Google Scholar 

  14. Papageorgious, A. C. & Acharya, K. R. Microbial superantigens: from structure to function. Trends Microbiol. 8, 369–375 (2000).

    Google Scholar 

  15. Faust, S. N. Dysfunction of endothelial protein C activation in severe menigococcal sepsis. N. Engl. J. Med. 345, 408–416 (2001).

    CAS  PubMed  Google Scholar 

  16. Esmon, C. T. Regulation of blood coagulation. Biochim. Biophys. Acta 1477, 349–360 (2000).

    CAS  PubMed  Google Scholar 

  17. Rivers, E. et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 345, 1368–1377 (2001).

    CAS  PubMed  Google Scholar 

  18. Lebbos, J., Bradsher, J. & Kirkpatrick, P. Drotrecogin alpha (activated). Nature Rev. Drug Discov. 2, 13–14 (2003).

    CAS  Google Scholar 

  19. Bernard, G. R. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699–709 (2001).

    CAS  PubMed  Google Scholar 

  20. Matthay, M. A. Severe sepsis — a new treatment with both anticoagulant and anti-inflamamtory properties. N. Engl. J. Med. 344, 759–762 (2001).

    CAS  PubMed  Google Scholar 

  21. Schimmer, B. P. & Parker, K. L. Goodman & Gilman's The Pharmacological Basis of Therapeutics (eds Harmann, J. G. & Limbird, L. E.) 1649–1678 (McGraw Hill, Columbus, 2001).

    Google Scholar 

  22. Lefering, R. & Neugebauer, E. A. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit. Care Med. 23, 1294–303 (1995).

    CAS  PubMed  Google Scholar 

  23. Cronin, L. et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit. Care Med. 23, 1430–1439 (1995).

    CAS  PubMed  Google Scholar 

  24. Annane, D. et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283, 1038–1045 (2000).

    CAS  PubMed  Google Scholar 

  25. Annane, D. et al. Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve. Br. J. Clin. Pharmacol. 46, 589–597 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Molijn, G. J. et al. Differential adaptation of glucocorticoid sensitivity of peripheral blood mononuclear leukocytes in patients with sepsis or septic shock. J. Clin. Endocrinol. Metab. 80, 1799–1803 (1995).

    CAS  PubMed  Google Scholar 

  27. Annane, D. et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288, 862–871 (2002).

    CAS  PubMed  Google Scholar 

  28. Ziegler, E. J. et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N. Engl. J. Med. 307, 1225–1230 (1982).

    CAS  PubMed  Google Scholar 

  29. Baumgartner, J. D. et al. Prevention of gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet 2, 59–63 (1985).

    CAS  PubMed  Google Scholar 

  30. Schedel, I. et al. Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. Crit. Care Med. 19, 1104–1113 (1991).

    CAS  PubMed  Google Scholar 

  31. Greenman, R. L. et al. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group. JAMA 266, 1097–1102 (1991).

    CAS  PubMed  Google Scholar 

  32. Bone, R. C. et al. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group. Crit. Care Med. 23, 994–1006 (1995).

    CAS  PubMed  Google Scholar 

  33. Angus, D. C. et al. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA 283, 1723–1730 (2000).

    CAS  PubMed  Google Scholar 

  34. The National Committee for the Evaluation of Centoxin. The French National Registry of HA-1A (Centoxin) in septic shock. A cohort study of 600 patients. Arch. Intern. Med. 154, 2484–2491 (1994).

  35. McCloskey, R. V., Straube, R. C., Sanders, C., Smith, S. M. & Smith, C. R. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann. Intern. Med. 121, 1–5 (1994).

    CAS  PubMed  Google Scholar 

  36. Nakamura, T. et al. Hemoperfusion with polymyxin B-immobilized fiber attenuates the increased plasma levels of thrombomodulin and von Willebrand factor from patients with septic shock. Blood Purif. 16, 179–186 (1998).

    CAS  PubMed  Google Scholar 

  37. Ebihara, I., Nakamura, T., Shimada, N., Shoji, H. & Koide, H. Effect of hemoperfusion with polymyxin B-immobilized fiber on plasma endothelin-1 and endothelin-1 mRNA in monocytes from patients with sepsis. Am. J. Kidney Dis. 32, 953–961 (1998).

    CAS  PubMed  Google Scholar 

  38. Nakamura, T. et al. Treatment with polymyxin B-immobilized fiber reduces platelet activation in septic shock patients: decrease in plasma levels of soluble P-selectin, platelet factor 4 and β-thromboglobulin. Inflamm. Res. 48, 171–175 (1999).

    CAS  PubMed  Google Scholar 

  39. Bucklin, S. E., Lake, P., Logdberg, L. & Morrison, D. C. Therapeutic efficacy of a polymyxin B–dextran 70 conjugate in experimental model of endotoxemia. Antimicrob. Agents Chemother. 39, 1462–1466 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Doig, G. S., Martin, C. M. & Sibbald, W. J. Polymyxin–dextran antiendotoxin pretreatment in an ovine model of normotensive sepsis. Crit. Care Med. 25, 1956–1961 (1997).

    CAS  PubMed  Google Scholar 

  41. Warren, H. S. et al. Assessment of ability of murine and human anti-lipid A monoclonal antibodies to bind and neutralize lipopolysaccharide. J. Exp. Med. 177, 89–97 (1993).

    CAS  PubMed  Google Scholar 

  42. Dinarello, C. A. & Wolff, S. M. The role of interleukin-1 in disease. N. Engl. J. Med. 328, 106–113 (1993).

    CAS  PubMed  Google Scholar 

  43. Ruddle, N. H. & Waksman, B. H. Cytotoxic effect of lymphocyte–antigen interactions in delayed hypersensitivity. Science 157, 1060–1062 (1967).

    CAS  PubMed  Google Scholar 

  44. Carswell, E. A. et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl Acad. Sci. USA 72, 3666–3670 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Maini, R. et al. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354, 1932–1939 (1999).

    CAS  PubMed  Google Scholar 

  46. Targan, S. R. et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. Crohn's Disease cA2 Study Group. N. Engl. J. Med. 337, 1029–1035 (1997).

    CAS  PubMed  Google Scholar 

  47. Baugh, J. & Bucala, R. Mechanisms for modulating TNFα in immune and inflammatory disease. Curr. Opin. Drug Discov. Dev. 4, 635–650 (2001).

    CAS  Google Scholar 

  48. Abraham, E. Why immunomodulatory therapies have not worked in sepsis. Intensive Care Med. 25, 556–566 (2002).

    Google Scholar 

  49. Zeni, F., Freeman, B. & Natanson, C. Anti-inflammatory therapies to treat sepsis and septic shock: A reassessment. Crit. Care Med. 25, 1095–1100 (1997).

    CAS  PubMed  Google Scholar 

  50. Fisher, C. J. J. et al. Treatment of septic shock with the tumor necrosis factor receptor Fc fusion protein. N. Engl. J. Med. 334, 1697–1702 (1996).

    CAS  PubMed  Google Scholar 

  51. Nunez-Martinez, O. et al. Reactivation tuberculosis in a patient with anti-TNF-α treatment. Am. J. Gastroenterol. 96, 1665–1666 (2001).

    CAS  PubMed  Google Scholar 

  52. Roth, S. et al. Anti-TNF-α monoclonal antibodies (infliximab) and tuberculosis: apropos of 3 cases. Rev. Med. Intern. 23, 312–316 (2002).

    CAS  Google Scholar 

  53. Reinhart, K. & Karzai, W. Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned. Crit. Care Med. 29, 121–125 (2001).

    Google Scholar 

  54. Vincent, J. -L., Sun, Q. & Dunois, M. -J. Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin. Infect. Dis. 34, 1084–1093 (2002).

    CAS  PubMed  Google Scholar 

  55. Bevilacqua, M. P. et al. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc. Natl Acad. Sci. USA 83, 4533–4537 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Conkling, P. R., Greenberg, C. S. & Weinberg, J. B. Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes. Blood 72, 128–133 (1988).

    CAS  PubMed  Google Scholar 

  57. Esmon, C. T., Taylor, F. B. Jr & Snow, T. R. Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C. Thromb. Haemost. 66, 160–165 (1991).

    CAS  PubMed  Google Scholar 

  58. Stouthard, J. M. et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb. Haemost. 76, 738–742 (1996).

    CAS  PubMed  Google Scholar 

  59. Yan, Z. et al. Structural requirements of platelet chemokines for neutrophil activation. Blood 84, 2329–2339 (1994).

    CAS  PubMed  Google Scholar 

  60. Abraham, E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit. Care Med. 28, 31–33 (2000).

    Google Scholar 

  61. Wolfe, R. R., Herndon, D. N., Jahoor, F., Miyoshi, H. & Wolfe, M. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N. Engl. J. Med. 317, 403–408 (1987).

    CAS  PubMed  Google Scholar 

  62. Mizock, B. A. Alterations in carbohydrate metabolism during stress: a review of the literature. Am. J. Med. 98, 75–84 (1995).

    CAS  PubMed  Google Scholar 

  63. Malmberg, K. Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 314, 1512–1515 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Malmberg, K., Norhammar, A., Wedel, H. & Ryden, L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose in Acute Myocardial Infarction (DIGAMI) study. Circulation 99, 2626–2632 (1999).

    CAS  PubMed  Google Scholar 

  65. Van den Berghe, G. et al. Intensive insulin therapy in critically ill patients. N. Engl. J. Med. 345, 1359–1367 (2001).

    CAS  PubMed  Google Scholar 

  66. Emanuelli, B. et al. SOCS-3 is an insulin-induced negative regulator of insulin signaling. J. Biol. Chem. 275, 15985–15991 (2000).

    CAS  PubMed  Google Scholar 

  67. Czermak, B. J. et al. Protective effects of C5a blockade in sepsis. Nature Med. 5, 788–792 (1999).

    CAS  PubMed  Google Scholar 

  68. Riedermann, N. C. et al. Increased C5a receptor expression in sepsis. J. Clin. Invest. 110, 101–108 (2002).

    Google Scholar 

  69. Bernhagen, J. et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365, 756–759 (1993).

    CAS  PubMed  Google Scholar 

  70. Calandra, T. et al. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377, 68–71 (1995).

    CAS  PubMed  Google Scholar 

  71. Bozza, M. et al. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J. Exp. Med. 189, 341–346 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Calandra, T. et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nature Med. 6, 164–169 (2000).

    CAS  PubMed  Google Scholar 

  73. Mitchell, R. A. et al. Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc. Natl Acad. Sci. USA 99, 345–350 (2002).

    CAS  PubMed  Google Scholar 

  74. Roger, T., David, J., Glauser, M. P. & Calandra, T. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414, 920–924 (2001).

    CAS  PubMed  Google Scholar 

  75. Calandra, T., Spiegel, L. A., Metz, C. N. & 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 95, 11383–11388 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Beishuizen, A., Thijs, L. G., Haanen, C. & Vermes, I. Macrophage migration inhibitory factor and hypothalamo-pituitary-adrenal function during critical illness. J. Clin. Endocrinol. Metab. 86, 2811–2816 (2001).

    CAS  PubMed  Google Scholar 

  77. Joshi, P. C., Poole, G. V., Sachdev, V. Z. X. & Jones, Q. Trauma patients with positive cultures have higher levels of circulating macrophage migration inhibitory factor. Res. Commun. Mol. Pathol. Pharmacol. 107, 13–20 (2000).

    CAS  PubMed  Google Scholar 

  78. Heumann, D. & Glauser, M. P. Anti-cytokine strategies for the treatment of septic shock: relevance of animal models. Curr. Top. Microbiol. Immunol. 216, 299–311 (1996).

    CAS  PubMed  Google Scholar 

  79. Echtenacher, B., Falk, W., Mannel, D. N. & Krammer, P. H. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J. Immunol. 145, 3762–3766 (1990).

    CAS  PubMed  Google Scholar 

  80. Bagby, G. J., Plessala, K. J., Wilson, L. A., Thompson, J. J. & Nelson, S. Divergent efficacy of antibody to tumor necrosis factor-α in intravascular and peritonitis models of sepsis. J. Infect. Dis. 163, 83–88 (1991).

    CAS  PubMed  Google Scholar 

  81. Eskandari, M. K. et al. Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. J. Immunol. 148, 2724–2730 (1992).

    CAS  PubMed  Google Scholar 

  82. Remick, D. et al. Blockade of tumor necrosis factor reduces lipopolysaccharide lethality, but not the lethality of cecal ligation and puncture. Shock 4, 89–95 (1995).

    CAS  PubMed  Google Scholar 

  83. Baugh, J. A. et al. A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun. 3, 170–176 (2002).

    CAS  PubMed  Google Scholar 

  84. Suzuki, M. et al. Crystal structure of the macrophage migration inhibitory factor from rat liver. Nature Struct. Biol. 3, 259–266 (1996).

    CAS  PubMed  Google Scholar 

  85. Sun, H. W., Bernhagen, J., Bucala, R. & Lolis, E. Crystal structure at 2.6-Å resolution of human macrophage migration inhibitory factor. Proc. Natl Acad. Sci. USA 93, 5191–5196 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Swope, M., Sun, H. W., Blake, P. R. & Lolis, E. Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor. EMBO J. 17, 3534–3541 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lubetsky, J. B., 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 38, 7346–7354 (1999).

    CAS  PubMed  Google Scholar 

  88. Taylor, A. B. et al. Crystal structure of macrophage migration inhibitory factor complexed with (E)-2-fluoro-p-hydroxycinnamate at 1.8 Å resolution: implications for enzymatic catalysis and inhibition. Biochemistry 38, 7444–7454 (1998).

    Google Scholar 

  89. Senter, P. D. et al. Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites. Proc. Natl Acad. Sci. USA 99, 144–149 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Lubetsky, J. B. et al. The tautomerase activity of MIF is a potential target for discovery of novel anti-inflammatory agents. J. Biol. Chem. 277, 24976–24982 (2002).

    CAS  PubMed  Google Scholar 

  91. Dios, A. et al. Inhibition of MIF bioactivity by rational design of pharmacological inhibitors of MIF tautomerase activity. J. Med. Chem. 45, 2410–2416 (2002).

    CAS  PubMed  Google Scholar 

  92. Leng, L. et al. MIF signal transduction initiated by binding to CD74. J. Exp. Med. 197, 1467–1476 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

    CAS  PubMed  Google Scholar 

  94. Bustin, M. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol. Cell. Biol. 19, 5237–5246 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Yang, H., Wang, H., Czura, C. J. & Tracey, K. J. HMGB1 as a cytokine and therapeutic target. Endotoxin. Res. 8, 469–472 (2002).

    CAS  Google Scholar 

  96. Ulloa, L. et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc. Natl Acad. Sci. USA 19, 12351–12356 (2002).

    Google Scholar 

  97. Cross, A. S. & Opal, S. M. A new paradigm for the treatment of sepsis: is it time to consider combination therapy? Ann. Intern. Med. 138, 502–505 (2003).

    PubMed  Google Scholar 

  98. Marshall, J. C. Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nature Rev. Drug Discov. 2, 391–405 (2003).

    CAS  Google Scholar 

  99. Ebong, S. et al. Immunopathologic alterations in murine models of sepsis of increasing severity. Infect. Immun. 67, 6603–6610 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Eichacker, P. Q. et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am. J. Respir. Crit. Care Med. 166, 1197–1205 (2002).

    PubMed  Google Scholar 

  101. Cooke, G. S. & Hill, A. V. Genetics of susceptibility to human infectious disease. Nature Rev. Genet. 2, 967–977 (2001).

    CAS  PubMed  Google Scholar 

  102. Stuber, F., Petersen, M., Bokelmann, F. & Schade, U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-α concentrations and outcome of patients with severe sepsis. Crit. Care Med. 24, 381–384 (1996).

    CAS  PubMed  Google Scholar 

  103. Lorenz, E., Mira, J. P., Frees, K. L. & Schwartz, D. A. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch. Intern. Med. 162, 1028–1032 (2002).

    CAS  PubMed  Google Scholar 

  104. Picard, C., Puel, A., Bonnet, M., Ku, C. L. & Bustamante, J. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076–2079 (2003).

    CAS  PubMed  Google Scholar 

  105. Bochud, P. Y., Hawn, T. R. & Aderem, A. Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J. Immunol. 170, 3451–3454 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the participants of the 2003 Keystone Symposium: The Molecular and Cellular Basis of Septic Shock (6–9 March 2003, Lake Tahoe, California) for providing a valuable update to many of the concepts discussed in this article. The authors acknowledge research support from the Arthritis Foundation and the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Elias Lolis

  2. Departments of Medicine and Pathology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Richard Bucala

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  1. Elias Lolis
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DATABASES

LocusLink

DAP-12

E-selectin

HMGB-1

ICAM-1

ICAM-2

MD-2

MDL-1

NOD-1

NOD-2

P-selectin

TLR-1

TLR-2

TLR-3

TLR-4

TLR-5

TLR-6

TLR-7

TLR-8

TLR-9

TLR-10

TNF-α

TREM-1

FURTHER INFORMATION

Encyclopedia of Life Sciences

Septicaemic shock

Glossary

INDWELLING DEVICE

A device that is invasive, and is associated with risk of infection.

LEUKOCYTOSIS

An increase in leukocyte number in blood, generally caused by infection.

TACHYPNEA

An abnormally rapid respiratory rate.

ZYMOSAN

An insoluble carbohydrate from the cell wall of yeast.

LECTIN

A protein which specifically binds carbohydrates.

TOXIC-SHOCK SYNDROME

A cluster of symptoms that involve many systems of the body, caused by Staphylococcus aureus or Streptococcus pyognenes.

SUPERANTIGENS

Molecules produced by microbes that act independently to stimulate T-cell activities, including cytokine release.

ENDOGENOUS PYROGEN

A cytokine that can induce a rise in body temperature.

INFLAMMATORY ARTHRITIS

A form of arthritis, in which the membrane that lines the joint (the synovial membrane) becomes inflamed, producing pain and swelling.

INFLAMMATORY BOWEL DISEASE

(IBD). This term refers to ulcerative colitis and Crohn's disease, both incurable chronic diseases of the intestinal tract. The two diseases are often grouped together under the rubric of IBD because of their similar symptoms.

APACHE II

Systems to estimate the risk of hospital death based on severity of disease scoring was first introduced with Acute Physiology And Chronic Health Evaluation (APACHE) in 1981 followed by the Simplified Acute Physiology Score (SAPS) in 1988. Further research resulted in 'improved' editions, APACHE II in 1985, and SAPS II in 1993. APACHE III is now coming into general use.

CACHEXIA

A catabolic, wasting state, that is often a consequence of chronic infection or malignancy

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Lolis, E., Bucala, R. Therapeutic approaches to innate immunity: severe sepsis and septic shock. Nat Rev Drug Discov 2, 635–645 (2003). https://doi.org/10.1038/nrd1153

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