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Sepsis: in search of cure

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Abstract

Introduction

Sepsis is a complex inflammatory disorder believed to originate from an infection by any types of microbes and/or their products. It is the leading cause of death in intensive care units (ICUs) throughout the globe. The mortality rates depend both on the severity of infection and the host’s response to infection.

Methods

Literature survey on pathobiology of sepsis in general and failure of more than hundred clinical trials conducted so far in search of a possible cure for sepsis resulted in the preparation of this manuscript.

Findings

Sepsis lacks a suitable animal model that mimics human sepsis. However, based on the results obtained in animal models of sepsis, clinical trials conducted so far have been disappointing. Although involvement of multiple mediators and pathways in sepsis has been recognized, only few components are being targeted and this could be the major reason behind the failure of clinical trials.

Conclusion

Inability to recognize a single critical mediator of sepsis may be the underlying cause for the poor therapeutic intervention of sepsis. Therefore, sepsis is still considered as a disease—in search of cure.

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References

  1. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther. 2012;10:701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ma J, Chen C, Barth AS, Cheadle C, Guan X, Gao L. Lysosome and cytoskeleton pathways are robustly enriched in the blood of septic patients: a meta-analysis of transcriptomic data. Mediators Inflamm. 2015;2015:984825.

    PubMed  PubMed Central  Google Scholar 

  3. Rossaint J, Zarbock A. Pathogenesis of multiple organ failure in sepsis. Crit Rev Immunol. 2015;35:277–91.

    Article  PubMed  Google Scholar 

  4. Chaudhry N, Duggal AK. Sepsis associated encephalopathy. Adv Med 2014; 2014.

  5. Organization WH. Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat. 1999;6:35–47.

    Article  Google Scholar 

  6. Garciarena CD, McHale TM, Watkin RL, Kerrigan SW. Coordinated molecular cross-talk between staphylococcus aureus, endothelial cells and platelets in bloodstream infection. Pathogens. 2015;4:869–82.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ribet D, Cossart P. How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect. 2015;17:173–83.

    Article  CAS  PubMed  Google Scholar 

  8. Van Kaer L, Parekh VV, Wu L. The response of CD1d-restricted invariant NKT cells to microbial pathogens and their products. Front Immunol. 2015;6:226.

    PubMed  PubMed Central  Google Scholar 

  9. Ramachandran G. Gram-positive and gram-negative bacterial toxins in sepsis: a brief review. Virulence. 2014;5:213–8.

    Article  PubMed  Google Scholar 

  10. Martin L, van Meegern A, Doemming S, Schuerholz T. Antimicrobial peptides in human sepsis. Front Immunol. 2015;6:404.

    PubMed  PubMed Central  Google Scholar 

  11. Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med. 2003;9:517–24.

    Article  CAS  PubMed  Google Scholar 

  12. Tse MT. Trial watch: sepsis study failure highlights need for trial design rethink. Nat Rev Drug Discov. 2013;12:334.

    Article  CAS  PubMed  Google Scholar 

  13. Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11:R49.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Malmir J, Bolvardi E, Afzal Aghaee M. Serum lactate is a useful predictor of death in severe sepsis and septic shock. Rev Clin Med. 2014;1:97–104.

    Google Scholar 

  15. Masson S, Caironi P, Fanizza C, Thomae R, Bernasconi R, Noto A, et al. Circulating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial. Intensive Care Med. 2015;41:12–20.

    Article  CAS  PubMed  Google Scholar 

  16. Chuang TY, Chang HT, Chung KP, Cheng HS, Liu CY, Liu YC, et al. High levels of serum macrophage migration inhibitory factor and interleukin 10 are associated with a rapidly fatal outcome in patients with severe sepsis. Int J Infect Dis. 2014;20:13–7.

    Article  CAS  PubMed  Google Scholar 

  17. Donadello K, Scolletta S, Covajes C, Vincent JL. suPAR as a prognostic biomarker in sepsis. BMC Med. 2012;10:2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sandquist M, Wong HR. Biomarkers of sepsis and their potential value in diagnosis, prognosis and treatment. Expert Rev Clin Immunol. 2014;10:1349–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Donadello K, Scolletta S, Taccone FS, Covajes C, Santonocito C, Cortes DO, et al. Soluble urokinase-type plasminogen activator receptor as a prognostic biomarker in critically ill patients. J Crit Care. 2014;29:144–9.

    Article  CAS  PubMed  Google Scholar 

  20. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20:195–203.

    Article  PubMed  Google Scholar 

  21. Marik PE. The demise of early goal-directed therapy for severe sepsis and septic shock. Acta Anaesthesiol Scand. 2015;59:561–7.

    Article  CAS  PubMed  Google Scholar 

  22. Rittirsch D, Hoesel LM, Ward PA. The disconnect between animal models of sepsis and human sepsis. J Leukoc Biol. 2007;81:137–43.

    Article  CAS  PubMed  Google Scholar 

  23. Vincent JL. Definition of sepsis and non-infectious SIRS. Sepsis and non-infectious systemic inflammation: from biology to critical care 2009; pp. 1–12.

  24. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, 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. 1992;101:1644–55.

    Article  CAS  PubMed  Google Scholar 

  25. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250–6.

    Article  PubMed  Google Scholar 

  26. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580–637.

    Article  PubMed  Google Scholar 

  27. Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R, et al. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Intensive Care Med. 2014;40:1623–33.

    Article  PubMed  Google Scholar 

  28. de Pablo R, Monserrat J, Prieto A, Alvarez-Mon M. Role of circulating lymphocytes in patients with sepsis. BioMed Res Int. 2014;2014:671087.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Perman SM, Goyal M, Gaieski DF. Initial emergency department diagnosis and management of adult patients with severe sepsis and septic shock. Scand J Trauma Resusc Emerg Med. 2012;20:41.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Schmidt GA, Mandel J, Parsons PE, Sexton DJ, Hockberger RS, Finlay G. Evaluation and management of severe sepsis and septic shock in adults. Uptodate com 2013.

  31. Torres-Rosas R, Yehia G, Pena G, Mishra P, del Rocio Thompson-Bonilla M, Moreno-Eutimio MA, et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med. 2014;20:291–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Todi S, Chatterjee S, Sahu S, Bhattacharyya M. Epidemiology of severe sepsis in India: an update. Crit Care. 2010;14:1.

    Article  Google Scholar 

  33. Van Amersfoort ES, Van Berkel TJ, Kuiper J. Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clin Microbiol Rev. 2003;16:379–414.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Chang AH, Parsonnet J. Role of bacteria in oncogenesis. Clin Microbiol Rev. 2010;23:837–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Widmeier K, Wesley K. Infection detection: identifying and understanding sepsis in the prehospital setting, part 1 of 2. JEMS. 2014;39:34–7.

    PubMed  Google Scholar 

  36. Merrell RC. The abdomen as source of sepsis in critically ill patients. Crit Care Clin. 1995;11:255–72.

    CAS  PubMed  Google Scholar 

  37. Hugonnet S, Sax H, Eggimann P, Chevrolet JC, Pittet D. Nosocomial bloodstream infection and clinical sepsis. Emerg Infect Dis. 2004;10:76–81.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bewick T, Simmonds M, Chikhani M, Meyer J, Lim WS. Pneumonia in the context of severe sepsis: a significant diagnostic problem. Eur Respir J. 2008;32:1417–8.

    Article  CAS  PubMed  Google Scholar 

  39. Todar K. Immune defense against bacterial pathogens: innate immunity. Todar’s online textbook of bacteriology 2008.

  40. Willatts SM, Radford S, Leitermann M. Effect of the antiendotoxic agent, taurolidine, in the treatment of sepsis syndrome: a placebo-controlled, double-blind trial. Crit Care Med. 1995;23:1033–9.

    Article  CAS  PubMed  Google Scholar 

  41. Levin M, Quint PA, Goldstein B, Barton P, Bradley JS, Shemie SD, et al. Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet. 2000;356:961–7.

    Article  CAS  PubMed  Google Scholar 

  42. Phua J, Ngerng W, See K, Tay C, Kiong T, Lim H, et al. Characteristics and outcomes of culture-negative versus culture-positive severe sepsis. Crit Care. 2013;17:R202.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Fildes P. Richard Friedrich Johannes Pfeiffer. 1858–1945. Biogr Memoirs Fellows Royal Soc 1956; 2:237–247.

  44. Nair SR, Geetha CS, Mohanan PV. Analysis of IL-1 beta release from cryopreserved pooled lymphocytes in response to lipopolysaccharide and lipoteichoic acid. BioMed Res Int. 2013;2013:689642.

    PubMed  PubMed Central  Google Scholar 

  45. Le Brun AP, Clifton LA, Halbert CE, Lin B, Meron M, Holden PJ, et al. Structural characterization of a model gram-negative bacterial surface using lipopolysaccharides from rough strains of Escherichia coli. Biomacromolecules. 2013;14:2014–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, et al. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J Off Publ Feder Am Soc Exp Biol. 1994;8:217–25.

    CAS  Google Scholar 

  47. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Schumann RR, Leong SR, Flaggs GW, Gray PW, Wright SD, Mathison JC, et al. Structure and function of lipopolysaccharide binding protein. Science. 1990;249:1429–31.

    Article  CAS  PubMed  Google Scholar 

  49. Hailman E, Lichenstein HS, Wurfel MM, Miller DS, Johnson DA, Kelley M, et al. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J Exp Med. 1994;179:269–77.

    Article  CAS  PubMed  Google Scholar 

  50. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17:1–14.

    Article  CAS  PubMed  Google Scholar 

  51. Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008;42:145–51.

    Article  CAS  PubMed  Google Scholar 

  52. Geng Y, Zhang B, Lotz M. Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J Immunol. 1993;151:6692–700.

    CAS  PubMed  Google Scholar 

  53. Frost RA, Nystrom GJ, Lang CH. Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2002;283:R698–709.

    Article  CAS  PubMed  Google Scholar 

  54. Nii T, Sonoda Y, Isobe N, Yoshimura Y. Effects of lipopolysaccharide on the expression of proinflammatory cytokines and chemokines and the subsequent recruitment of immunocompetent cells in the oviduct of laying and molting hens. Poult Sci. 2011;90:2332–41.

    Article  CAS  PubMed  Google Scholar 

  55. Birrell MA, McCluskie K, Wong S, Donnelly LE, Barnes PJ, Belvisi MG. Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF-kappaB-independent mechanism. FASEB J Off Publ Feder Am Soc Exp Biol. 2005;19:840–1.

    CAS  Google Scholar 

  56. Freudenberg MA, Galanos C. Tumor necrosis factor alpha mediates lethal activity of killed gram-negative and gram-positive bacteria in d-galactosamine-treated mice. Infect Immun. 1991;59:2110–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Neilsen PO, Zimmerman GA, McIntyre TM. Escherichia coli Braun lipoprotein induces a lipopolysaccharide-like endotoxic response from primary human endothelial cells. J Immunol. 2001;167:5231–9.

    Article  CAS  PubMed  Google Scholar 

  58. Ma Y, Weis JJ. Borrelia burgdorferi outer surface lipoproteins OspA and OspB possess B-cell mitogenic and cytokine-stimulatory properties. Infect Immun. 1993;61:3843–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Barrenschee M, Lex D, Uhlig S. Effects of the TLR2 agonists MALP-2 and Pam3Cys in isolated mouse lungs. PLoS One. 2010;5:e13889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009;22:240–73 (Table of Contents).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Babu MM, Priya ML, Selvan AT, Madera M, Gough J, Aravind L, et al. A database of bacterial lipoproteins (DOLOP) with functional assignments to predicted lipoproteins. J Bacteriol. 2006;188:2761–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vollmer W, Holtje JV. The architecture of the murein (peptidoglycan) in gram-negative bacteria: vertical scaffold or horizontal layer(s)? J Bacteriol. 2004;186:5978–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Braun V, Rehn K. Chemical characterization, spatial distribution and function of a lipoprotein (murein-lipoprotein) of the E. coli cell wall. The specific effect of trypsin on the membrane structure. Eur J Biochem. 1969;10:426–38.

    Article  CAS  PubMed  Google Scholar 

  64. Tamta H, Pugh ND, Balachandran P, Moraes R, Sumiyanto J, Pasco DS. Variability in in vitro macrophage activation by commercially diverse bulk echinacea plant material is predominantly due to bacterial lipoproteins and lipopolysaccharides. J Agric Food Chem. 2008;56:10552–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bastian M, Braun T, Bruns H, Rollinghoff M, Stenger S. Mycobacterial lipopeptides elicit CD4 + CTLs in Mycobacterium tuberculosis-infected humans. J Immunol. 2008;180:3436–46.

    Article  CAS  PubMed  Google Scholar 

  66. Calandra T, Froidevaux C, Martin C, Roger T. Macrophage migration inhibitory factor and host innate immune defenses against bacterial sepsis. J Infect Dis. 2003;187:S385–90.

    Article  CAS  PubMed  Google Scholar 

  67. Chuang CC, Wang ST, Chen WC, Chen CC, Hor LI, Chuang YC. Increases in serum macrophage migration inhibitory factor in patients with severe sepsis predict early mortality. Shock. 2007;27:503–6.

    Article  CAS  PubMed  Google Scholar 

  68. Soni N, Samson D, Galaydick J, Vats V, Pitrak D, Aronson N. Procalcitonin-guided antibiotic therapy. Comparative Effectiveness Review No. 78. Effective Health Care Program AHRQ Publication, p. 13.

  69. Meisner M, Tschaikowsky K, Palmaers T, Schmidt J. Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS. Crit Care. 1999;3:45.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Ulla M, Pizzolato E, Lucchiari M, Loiacono M, Soardo F, Forno D, et al. Diagnostic and prognostic value of presepsin in the management of sepsis in the emergency department: a multicenter prospective study. Crit Care. 2013;17:R168.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Blomkalns AL. Lactate-a marker for sepsis and trauma. Emergency Medicine Cardiac Research and Education Group 2006; 2.

  72. Koch T, Geiger S, Ragaller MJ. Monitoring of organ dysfunction in sepsis/systemic inflammatory response syndrome: novel strategies. J Am Soc Nephrol. 2001;12(Suppl 17):S53–9.

    PubMed  Google Scholar 

  73. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock*. Crit Care Med. 2009;37:1670–7.

    Article  CAS  PubMed  Google Scholar 

  74. Gustafsson A, Ljunggren L, Bodelsson M, Berkestedt I. The prognostic value of suPAR compared to other inflammatory markers in patients with severe sepsis. Biomarker Insights. 2012;7:39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Williams SC. After Xigris, researchers look to new targets to combat sepsis. Nat Med. 2012;18:1001.

    Article  CAS  PubMed  Google Scholar 

  76. Focus on sepsis. Nat Med 2012; 18:997.

  77. 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.

    Article  CAS  PubMed  Google Scholar 

  78. Calandra T, Glauser MP, Schellekens J, Verhoef J. Treatment of gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial. J Infect Dis. 1988;158:312–9.

    Article  CAS  PubMed  Google Scholar 

  79. Ziegler EJ, Fisher CJ Jr, Sprung CL, Straube RC, Sadoff JC, Foulke GE, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med. 1991;324:429–36.

    Article  CAS  PubMed  Google Scholar 

  80. Bone RC, Balk RA, Fein AM, Perl TM, Wenzel RP, Reines HD, 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. 1995;23:994–1006.

    Article  CAS  PubMed  Google Scholar 

  81. Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995;273:934–41.

    Article  CAS  PubMed  Google Scholar 

  82. Cohen J, Carlet J. INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med. 1996;24:1431–40.

    Article  CAS  PubMed  Google Scholar 

  83. Fisher CJ Jr, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, et al. Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med. 1996;334:1697–702.

    Article  CAS  PubMed  Google Scholar 

  84. 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 1342 patients. Crit Care Med. 2001;29:503–10.

    Article  CAS  PubMed  Google Scholar 

  85. 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.

    Article  CAS  PubMed  Google Scholar 

  86. Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309:1154–62.

    Article  CAS  PubMed  Google Scholar 

  87. Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med. 2010;38:1685–94.

    Article  CAS  PubMed  Google Scholar 

  88. 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;25:1115–24.

    Article  CAS  PubMed  Google Scholar 

  89. Fein AM, Bernard GR, Criner GJ, Fletcher EC, Good JT Jr, Knaus WA, et al. Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and Sepsis Study Group. JAMA. 1997;277:482–7.

    Article  CAS  PubMed  Google Scholar 

  90. 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.

    Article  CAS  PubMed  Google Scholar 

  91. Vincent JL, Ramesh MK, Ernest D, LaRosa SP, Pachl J, Aikawa N, et al. A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med. 2013;41:2069–79.

    Article  CAS  PubMed  Google Scholar 

  92. Dhainaut JF, Tenaillon A, Hemmer M, Damas P, Le Tulzo Y, Radermacher P, et al. Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 Sepsis Investigator Group. Crit Care Med. 1998;26:1963–71.

    Article  CAS  PubMed  Google Scholar 

  93. Opal S, Laterre PF, Abraham E, Francois B, Wittebole X, Lowry S, et al. Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med. 2004;32:332–41.

    Article  CAS  PubMed  Google Scholar 

  94. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370:1683–93.

    Article  CAS  PubMed  Google Scholar 

  95. Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371:1496–506.

    Article  CAS  PubMed  Google Scholar 

  96. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372:1301–11.

    Article  CAS  PubMed  Google Scholar 

  97. Nemzek JA, Hugunin KM, Opp MR. Modeling sepsis in the laboratory: merging sound science with animal well-being. Comp Med. 2008;58:120–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. deSa LA, Sathe MJ, Bapat RD. Factors influencing wound infection (a prospective study of 280 cases). J Postgrad Med. 1984;30:232–6.

    CAS  PubMed  Google Scholar 

  99. Du Pont-Thibodeau G, Joyal JS, Lacroix J. Management of neonatal sepsis in term newborns. F1000prime reports 2014; 6:67.

  100. Toscano MG, Ganea D, Gamero AM. Cecal ligation puncture procedure. J Vis Exp 2011.

  101. Traeger T, Koerner P, Kessler W, Cziupka K, Diedrich S, Busemann A, et al. Colon ascendens stent peritonitis (CASP)–a standardized model for polymicrobial abdominal sepsis. J Vis Exp 2010.

  102. Maier S, Traeger T, Entleutner M, Westerholt A, Kleist B, Huser N, et al. Cecal ligation and puncture versus colon ascendens stent peritonitis: two distinct animal models for polymicrobial sepsis. Shock. 2004;21:505–11.

    Article  PubMed  Google Scholar 

  103. 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.

    Article  CAS  PubMed  Google Scholar 

  104. Bauhofer A, Torossian A, Lorenz W, Middeke M, Plaul U, Schutz P, et al. Dependence of positive effects of granulocyte colony-stimulating factor on the antibiotic regimen: evaluation in rats with polymicrobial peritonitis. World J Surg. 2004;28:834–44.

    Article  PubMed  Google Scholar 

  105. Gonnert FA, Recknagel P, Seidel M, Jbeily N, Dahlke K, Bockmeyer CL, et al. Characteristics of clinical sepsis reflected in a reliable and reproducible rodent sepsis model. J Surg Res. 2011;170:e123–34.

    Article  PubMed  Google Scholar 

  106. Otto GP, Grunwald B, Geis C, Kothe S, Hurtado-Oliveros J, Chung HY, et al. Impact of antibiotic treatment intensity on long-term sepsis-associated kidney injury in a polymicrobial peritoneal contamination and infection model. Nephron. 2015;129:137–42.

    Article  CAS  PubMed  Google Scholar 

  107. Recknagel P, Gonnert FA, Halilbasic E, Gajda M, Jbeily N, Lupp A, et al. Mechanisms and functional consequences of liver failure substantially differ between endotoxaemia and faecal peritonitis in rats. Liver Int. 2013;33:283–93.

    Article  CAS  PubMed  Google Scholar 

  108. Randerath E, Randerath K, Reddy R, Lucier GW. Sexual dimorphism of the chromatographic profiles of I-compounds (endogenous deoxyribonucleic acid modifications) in rat liver. Endocrinology. 1991;129:3093–100.

    Article  CAS  PubMed  Google Scholar 

  109. Seidel M, Winning J, Claus RA, Bauer M, Losche W. Beneficial effect of clopidogrel in a mouse model of polymicrobial sepsis. J Thromb Haemost. 2009;7:1030–2.

    Article  CAS  PubMed  Google Scholar 

  110. Toky V, Sharma S, Arora BB, Chhibber S. Establishment of a sepsis model following implantation of Klebsiella pneumoniae-infected fibrin clot into the peritoneal cavity of mice. Folia Microbiol (Praha). 2003;48:665–9.

    Article  CAS  Google Scholar 

  111. Warren HS. Editorial: mouse models to study sepsis syndrome in humans. J Leukoc Biol. 2009;86:199–201.

    Article  CAS  PubMed  Google Scholar 

  112. 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.

    Article  CAS  PubMed  Google Scholar 

  113. Xiang Y, Wang X, Yan C, Gao Q, Li SA, Liu J, et al. Adenosine-5’-triphosphate (ATP) protects mice against bacterial infection by activation of the NLRP3 inflammasome. PLoS One. 2013;8:e63759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Remick DG, Newcomb DE, Bolgos GL, Call DR. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock. 2000;13:110–6.

    Article  CAS  PubMed  Google Scholar 

  115. Copeland S, Warren HS, Lowry SF, Calvano SE, Remick D. Acute inflammatory response to endotoxin in mice and humans. Clin Diagn Lab Immunol. 2005;12:60–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Garrido AG, Figueiredo LFPd. Experimental models of sepsis and septic shock: an overview. Acta Cirurgica Brasileira. 2004;19:82–8.

    Article  Google Scholar 

  117. Yang IV, Alper S, Lackford B, Rutledge H, Warg LA, Burch LH, et al. Novel regulators of the systemic response to lipopolysaccharide. Am J Respir Cell Mol Biol. 2011;45:393–402.

    Article  CAS  PubMed  Google Scholar 

  118. Doi K, Leelahavanichkul A, Yuen PS, Star RA. Animal models of sepsis and sepsis-induced kidney injury. J Clin Investig. 2009;119:2868–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Aydin S, Caylan R, Aydin K, Yulug E, Yenilmez E, Koksal I. The influence of G-CSF addition to antibiotic treatment of experimental sepsis on pulmonary tissue. J Natl Med Assoc. 2005;97:1489–95.

    PubMed  PubMed Central  Google Scholar 

  120. Fei Y, Wang W, Kwiecinski J, Josefsson E, Pullerits R, Jonsson IM, et al. The combination of a tumor necrosis factor inhibitor and antibiotic alleviates staphylococcal arthritis and sepsis in mice. J Infect Dis. 2011;204:348–57.

    Article  CAS  PubMed  Google Scholar 

  121. Christ WJ, Asano O, Robidoux AL, Perez M, Wang Y, Dubuc GR, et al. E5531, a pure endotoxin antagonist of high potency. Science. 1995;268:80–3.

    Article  CAS  PubMed  Google Scholar 

  122. Suberviola B, Marquez-Lopez A, Castellanos-Ortega A, Fernandez-Mazarrasa C, Santibanez M, Martinez LM. Microbiological diagnosis of sepsis: polymerase chain reaction system versus blood cultures. Am J Crit Care. 2016;25:68–75.

    Article  PubMed  Google Scholar 

  123. Plettig R, Nowak A, Balau V, Hahnenkamp K, Usichenko T. Prospective comparison of a PCR assay and a microbiological culture technique for identification of pathogens from blood and non-blood samples in septic patients. J Intensive Care. 2015;3:51.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Semeraro N, Ammollo CT, Semeraro F, Colucci M. Sepsis-associated disseminated intravascular coagulation and thromboembolic disease. Mediterr J Hematol Infect Dis. 2010;2:e2010024.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Kuiper GJ, Kleinegris MC, van Oerle R, Spronk HM, Lance MD, Ten Cate H, et al. Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity. Thromb J. 2016;14:1.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Garcia-Simon M, Morales JM, Modesto-Alapont V, Gonzalez-Marrachelli V, Vento-Rehues R, Jorda-Minana A, et al. Prognosis biomarkers of severe sepsis and septic shock by 1H NMR urine metabolomics in the intensive care unit. PLoS One. 2015;10:e0140993.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Merx MW, Weber C. Sepsis and the heart. Circulation. 2007;116:793–802.

    Article  CAS  PubMed  Google Scholar 

  128. Fries M, Ince C, Rossaint R, Bleilevens C, Bickenbach J, Rex S, et al. Levosimendan but not norepinephrine improves microvascular oxygenation during experimental septic shock. Crit Care Med. 2008;36:1886–91.

    Article  CAS  PubMed  Google Scholar 

  129. Garcia-Septien J, Lorente JA, Delgado MA, de Paula M, Nin N, Moscoso A, et al. Levosimendan increases portal blood flow and attenuates intestinal intramucosal acidosis in experimental septic shock. Shock. 2010;34:275–80.

    Article  CAS  PubMed  Google Scholar 

  130. Morelli A, Donati A, Ertmer C, Rehberg S, Lange M, Orecchioni A, et al. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Care. 2010;14:R232.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Maybauer MO, Maybauer DM, Enkhbaatar P, Laporte R, Wisniewska H, Traber LD, et al. The selective vasopressin type 1a receptor agonist selepressin (FE 202158) blocks vascular leak in ovine severe sepsis*. Crit Care Med. 2014;42:e525–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Boucheix OB, Milano SP, Henriksson M, Reinheimer TM. Selepressin, a new V1A receptor agonist: hemodynamic comparison to vasopressin in dogs. Shock. 2013;39:533–8.

    Article  CAS  PubMed  Google Scholar 

  133. Stanley WC, Marzilli M. Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine. Fundam Clin Pharmacol. 2003;17:133–45.

    Article  CAS  PubMed  Google Scholar 

  134. Tanoglu A, Yamanel L, Inal V, Ocal R, Comert B, Bilgi C. Appreciation of trimetazidine treatment in experimental sepsis rat model. Bratisl Lek Listy. 2015;116:124–7.

    CAS  PubMed  Google Scholar 

  135. Chen J, Lai J, Yang L, Ruan G, Chaugai S, Ning Q, et al. Trimetazidine prevents macrophage mediated septic myocardial dysfunction via Sirt1. Br J Pharmacol 2015.

  136. Peters E, Heemskerk S, Masereeuw R, Pickkers P. Alkaline phosphatase: a possible treatment for sepsis-associated acute kidney injury in critically ill patients. Am J Kidney Dis. 2014;63:1038–48.

    Article  CAS  PubMed  Google Scholar 

  137. Thiengo Dda A, Lugon JR, Graciano ML. Troponin I serum levels predict the need of dialysis in incident sepsis patients with acute kidney injury in the intensive care unit. J Bras Nefrol. 2015;37:433–8.

    PubMed  Google Scholar 

  138. Pickkers P, Heemskerk S, Schouten J, Laterre P-F, Vincent J-L, Beishuizen A, et al. Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial. Crit Care. 2012;16:R14.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, Rai V, Wong KK, Hasan MS, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med 2016.

  140. Marino-Ramirez L, Kann MG, Shoemaker BA, Landsman D. Histone structure and nucleosome stability. Expert Rev Proteomics. 2005;2:719–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Chen R, Kang R, Fan XG, Tang D. Release and activity of histone in diseases. Cell Death Dis. 2014;5:e1370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15:1318–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol. 2011;187:2626–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Alhamdi Y, Zi M, Abrams ST, Liu T, Su D, Welters I, et al. Circulating histone concentrations differentially affect the predominance of left or right ventricular dysfunction in critical illness. Crit Care Med 2015.

  145. Iba T, Hashiguchi N, Nagaoka I, Tabe Y, Kadota K, Sato K. Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction. Intensive Care Med Exp. 2015;3:36.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Wildhagen KC, Wiewel MA, Schultz MJ, Horn J, Schrijver R, Reutelingsperger CP, et al. Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients. Thromb Res. 2015;136:542–7.

    Article  CAS  PubMed  Google Scholar 

  147. Bustin M, Reeves R. High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol. 1996;54:35–100.

    Article  CAS  PubMed  Google Scholar 

  148. Bianchi ME, Agresti A. HMG proteins: dynamic players in gene regulation and differentiation. Curr Opin Genet Dev. 2005;15:496–506.

    Article  CAS  PubMed  Google Scholar 

  149. Hock R, Furusawa T, Ueda T, Bustin M. HMG chromosomal proteins in development and disease. Trends Cell Biol. 2007;17:72–9.

    Article  CAS  PubMed  Google Scholar 

  150. Huang W, Tang Y, Li L. HMGB1, a potent proinflammatory cytokine in sepsis. Cytokine. 2010;51:119–26.

    Article  CAS  PubMed  Google Scholar 

  151. 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.

    Article  CAS  PubMed  Google Scholar 

  152. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Schierbeck H, Wahamaa H, Andersson U, Harris HE. Immunomodulatory drugs regulate HMGB1 release from activated human monocytes. Mol Med. 2010;16:343–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Tang D, Shi Y, Kang R, Li T, Xiao W, Wang H, et al. Hydrogen peroxide stimulates macrophages and monocytes to actively release HMGB1. J Leukoc Biol. 2007;81:741–7.

    Article  CAS  PubMed  Google Scholar 

  155. Pisetsky DS, Jiang W. Role of Toll-like receptors in HMGB1 release from macrophages. Ann N Y Acad Sci. 2007;1109:58–65.

    Article  CAS  PubMed  Google Scholar 

  156. Chen G, Li J, Ochani M, Rendon-Mitchell B, Qiang X, Susarla S, et al. Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms. J Leukoc Biol. 2004;76:994–1001.

    Article  CAS  PubMed  Google Scholar 

  157. Dumitriu IE, Baruah P, Valentinis B, Voll RE, Herrmann M, Nawroth PP, et al. Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol. 2005;174:7506–15.

    Article  CAS  PubMed  Google Scholar 

  158. Li M, Song L, Gao X, Chang W, Qin X. Toll-like receptor 4 on islet beta cells senses expression changes in high-mobility group box 1 and contributes to the initiation of type 1 diabetes. Exp Mol Med. 2012;44:260–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Zong M, Bruton JD, Grundtman C, Yang H, Li JH, Alexanderson H, et al. TLR4 as receptor for HMGB1 induced muscle dysfunction in myositis. Ann Rheum Dis. 2013;72:1390–9.

    Article  CAS  PubMed  Google Scholar 

  160. Qin YH, Dai SM, Tang GS, Zhang J, Ren D, Wang ZW, et al. HMGB1 enhances the proinflammatory activity of lipopolysaccharide by promoting the phosphorylation of MAPK p38 through receptor for advanced glycation end products. J Immunol. 2009;183:6244–50.

    Article  CAS  PubMed  Google Scholar 

  161. He ZW, Qin YH, Wang ZW, Chen Y, Shen Q, Dai SM. HMGB1 acts in synergy with lipopolysaccharide in activating rheumatoid synovial fibroblasts via p38 MAPK and NF-kappaB signaling pathways. Mediators Inflamm. 2013;2013:596716.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Schiraldi M, Raucci A, Munoz LM, Livoti E, Celona B, Venereau E, et al. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med. 2012;209:551–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zheng YJ, Xu WP, Ding G, Gao YH, Wang HR, Pan SM. Expression of HMGB1 in septic serum induces vascular endothelial hyperpermeability. Mol Med Rep. 2016;13:513–21.

    CAS  PubMed  Google Scholar 

  164. Jung B, Kang H, Lee W, Noh HJ, Kim YS, Han MS, et al. Anti-septic effects of dabrafenib on HMGB1-mediated inflammatory responses. BMB Rep 2015.

  165. 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.

    Article  CAS  PubMed  Google Scholar 

  166. Dear JW, Yasuda H, Hu X, Hieny S, Yuen PS, Hewitt SM, et al. Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis. Kidney Int. 2006;69:832–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kwon WY, Suh GJ, Kim KS, Jung YS, Kim SH, Kim JS, et al. Niacin and Selenium Attenuate Sepsis-Induced Lung Injury by Up-Regulating Nuclear Factor Erythroid 2-Related Factor 2 Signaling. Crit Care Med 2015.

  168. Lima CX, Souza DG, Amaral FA, Fagundes CT, Rodrigues IP, Alves-Filho JC, et al. Therapeutic effects of treatment with anti-TLR2 and anti-TLR4 monoclonal antibodies in polymicrobial sepsis. PLoS One. 2015;10:e0132336.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin. 2013;34:747–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol. 2007;179:1855–63.

    Article  CAS  PubMed  Google Scholar 

  171. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126:2601–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, Abbate M, et al. Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol. 2004;15:1794–804.

    Article  PubMed  Google Scholar 

  173. Berardis S, Dwisthi Sattwika P, Najimi M, Sokal EM. Use of mesenchymal stem cells to treat liver fibrosis: current situation and future prospects. World J Gastroenterol. 2015;21:742–58.

    PubMed  PubMed Central  Google Scholar 

  174. Zhao Y, Yang C, Wang H, Li H, Du J, Gu W, et al. Therapeutic effects of bone marrow-derived mesenchymal stem cells on pulmonary impact injury complicated with endotoxemia in rats. Int Immunopharmacol. 2013;15:246–53.

    Article  CAS  PubMed  Google Scholar 

  175. Weil BR, Herrmann JL, Abarbanell AM, Manukyan MC, Poynter JA, Meldrum DR. Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia. Shock. 2011;36:235–41.

    Article  PubMed  Google Scholar 

  176. Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doix K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42–9.

    Article  CAS  PubMed  Google Scholar 

  177. Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182:1047–57.

    Article  CAS  PubMed  Google Scholar 

  178. Monsel A, Zhu YG, Gennai S, Hao Q, Liu J, Lee JW. Cell-based therapy for acute organ injury: preclinical evidence and ongoing clinical trials using mesenchymal stem cells. Anesthesiology. 2014;121:1099–121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Rodriguez A, Rello J, Neira J, Maskin B, Ceraso D, Vasta L, et al. Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. Shock. 2005;23:298–304.

    Article  CAS  PubMed  Google Scholar 

  180. Hamano N, Nishi K, Onose A, Okamoto A, Umegaki T, Yamazaki E, et al. Efficacy of single-dose intravenous immunoglobulin administration for severe sepsis and septic shock. J Intensive Care. 2013;1:4.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Lombardo E, van der Poll T, DelaRosa O, Dalemans W. Mesenchymal stem cells as a therapeutic tool to treat sepsis. World J Stem Cells. 2015;7:368–79.

    Article  PubMed  PubMed Central  Google Scholar 

  182. 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.

    Article  CAS  PubMed  Google Scholar 

  183. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA. Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome. Chest. 1987;92:1032–6.

    Article  CAS  PubMed  Google Scholar 

  184. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. Sepsis syndrome: a valid clinical entity. Methylprednisolone Severe Sepsis Study Group. Crit Care Med. 1989;17:389–93.

    Article  CAS  PubMed  Google Scholar 

  185. McCloskey RV, Straube RC, Sanders C, Smith SM, Smith CR. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann Intern Med. 1994;121:1–5.

    Article  CAS  PubMed  Google Scholar 

  186. The French National Registry of HA-1A (Centoxin) in septic shock. A cohort study of 600 patients. The National Committee for the Evaluation of Centoxin. Arch Intern Med. 1994;154:2484–91.

    Article  Google Scholar 

  187. Dhainaut JF, Tenaillon A, Le Tulzo Y, Schlemmer B, Solet JP, Wolff M, et al. Platelet-activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group. Crit Care Med. 1994;22:1720–8.

    Article  CAS  PubMed  Google Scholar 

  188. Panacek EA, MacArthur RD, Johnson SB, Albertson TE, Maki D, Tobias J, et al. Results of a phase III clinical trial of the human monoclonal antibody mab-t88 versus placebo in gram negative sepsis. Crit Care Med. 1995;23:A170.

    Article  Google Scholar 

  189. Abraham E, Glauser MP, Butler T, Garbino J, Gelmont D, Laterre PF, et al. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group. Jama. 1997;277:1531–8.

    Article  CAS  PubMed  Google Scholar 

  190. Christopher TA, Ma XL, Gauthier TW, Lefer AM. Beneficial actions of CP-0127, a novel bradykinin receptor antagonist, in murine traumatic shock. Am J Physiol. 1994;266:H867–73.

    CAS  PubMed  Google Scholar 

  191. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997;336:912–8.

    Article  CAS  PubMed  Google Scholar 

  192. Angus DC, Birmingham MC, Balk RA, Scannon PJ, Collins D, Kruse JA, et al. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. Jama. 2000;283:1723–30.

    Article  CAS  PubMed  Google Scholar 

  193. Suputtamongkol Y, Intaranongpai S, Smith MD, Angus B, Chaowagul W, Permpikul C, et al. A double-blind placebo-controlled study of an infusion of lexipafant (Platelet-activating factor receptor antagonist) in patients with severe sepsis. Antimicrob Agents Chemother. 2000;44:693–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Vincent JL, Spapen H, Bakker J, Webster NR, Curtis L. Phase II multicenter clinical study of the platelet-activating factor receptor antagonist BB-882 in the treatment of sepsis. Crit Care Med. 2000;28:638–42.

    Article  CAS  PubMed  Google Scholar 

  195. Abraham E, Naum C, Bandi V, Gervich D, Lowry SF, Wunderink R, et al. Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure. Crit Care Med. 2003;31:718–28.

    Article  CAS  PubMed  Google Scholar 

  196. 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.

    Article  CAS  PubMed  Google Scholar 

  197. Watson D, Grover R, Anzueto A, Lorente J, Smithies M, Bellomo R, et al. Cardiovascular effects of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit Care Med. 2004;32:13–20.

    Article  CAS  PubMed  Google Scholar 

  198. Abraham E, Laterre P, Garg R, Levy H, Talwar D, Trzaskoma B, et al. Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353:1332–41.

    Article  CAS  PubMed  Google Scholar 

  199. Zeiher BG, Steingrub J, Laterre PF, Dmitrienko A, Fukiishi Y, Abraham E. LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis. Crit Care Med. 2005;33:1741–8.

    Article  CAS  PubMed  Google Scholar 

  200. Annane D, Sebille V, Bellissant E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med. 2006;34:22–30.

    Article  CAS  PubMed  Google Scholar 

  201. Nadel S, Goldstein B, Williams M, Dalton H, Peters M, Macias W, et al. REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective (RESOLVE) study group: Drotrecogin alfa (activated) in children with severe sepsis: A multicentre phase III randomised controlled trial. Lancet. 2007;369:836–43.

    Article  CAS  PubMed  Google Scholar 

  202. 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.

    Article  CAS  PubMed  Google Scholar 

  203. Dellinger RP, Tomayko JF, Angus DC, Opal S, Cupo MA, McDermott S, et al. Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial. Crit Care Med. 2009;37:2929–38.

    Article  PubMed  CAS  Google Scholar 

  204. Tidswell M, Tillis W, Larosa SP, Lynn M, Wittek AE, Kao R, et al. Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med. 2010;38:72–83.

    Article  CAS  PubMed  Google Scholar 

  205. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055–64.

    Article  CAS  PubMed  Google Scholar 

  206. Vincent JL, Privalle CT, Singer M, Lorente JA, Boehm E, Meier-Hellmann A, et al. Multicenter, randomized, placebo-controlled phase III study of pyridoxalated hemoglobin polyoxyethylene in distributive shock (PHOENIX)*. Crit Care Med. 2015;43:57–64.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge University Grants Commission for financial support. University Grants Commission Basic Science Research fellowship [F.7-366/2012]—to LCL; University Grants Commission Non-NET Fellowship [F. 87-1-2012(SU-1)2]—to SPJ; UGC-Major Research Project [F. No: 41-128/2012-13 (SR)]—to GMK, Vision Group of Science and Technology (VGST) [VGST/K-FIST (2010-11)/GRD-36/2013-14], Government of Karnataka and UGC-Special Assistance Program (UGC-SAP) [F3-14/2012 (SAP II)].

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  1. Department of Studies in Biochemistry, University of Mysore, Manasagangothri, Mysore, 570 006, India

    Chikkamenahalli Lakshminarayana Lakshmikanth, Shancy Petsel Jacob, Vyala Hanumanthareddy Chaithra & Gopal Kedihithlu Marathe

  2. Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fundacão Oswaldo Cruz, Rio de Janeiro, Brazil

    Hugo Caire de Castro-Faria-Neto

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  1. Chikkamenahalli Lakshminarayana Lakshmikanth
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Lakshmikanth, C.L., Jacob, S.P., Chaithra, V.H. et al. Sepsis: in search of cure. Inflamm. Res. 65, 587–602 (2016). https://doi.org/10.1007/s00011-016-0937-y

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