Immunomodulatory therapy for sepsis: an update

References

• Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit. Care Med.36(1), 296–327 (2008).
   PubMed Web of Science ®Google Scholar
• van der Poll T, Opal SM. Host–pathogen interactions in sepsis. Lancet Infect. Dis.8(1), 32–43 (2008).
   PubMed Web of Science ®Google Scholar
• Opal SM. The host response to endotoxin, antilipopolysaccharide strategies, and the management of severe sepsis. Int. J. Med. Microbiol.297(5), 365–377 (2007).
   PubMed Web of Science ®Google Scholar
• Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol.17(1), 1–14 (2005).
   PubMed Web of Science ®Google Scholar
• Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit. Care Med.37(1), 291–304 (2009).
   PubMed Web of Science ®Google Scholar
• Gibot S. Clinical review: role of triggering receptor expressed on myeloid cells-1 during sepsis. Crit. Care9(5), 485–489 (2005).
   PubMed Web of Science ®Google Scholar
• Senftleben U, Karin M. The IKK/NF-κB pathway. Crit. Care Med.30(1 Suppl.), S18–S26 (2002).
   Web of Science ®Google Scholar
• Casey LC. Immunologic response to infection and its role in septic shock. Crit. Care Clin.16(2), 193–213 (2000).
   PubMed Web of Science ®Google Scholar
• Adib-Conquy M, Adrie C, Fitting C, Gattolliat O, Beyaert R, Cavaillon JM. Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit. Care Med.34(9), 2377–2385 (2006).
   PubMed Web of Science ®Google Scholar
• Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A. Leukocyte apoptosis and its significance in sepsis and shock. J. Leukoc. Biol.78(2), 325–337 (2005).
   PubMed Web of Science ®Google Scholar
• Frazier WJ, Hall MW. Immunoparalysis and adverse outcomes from critical illness. Pediatr. Clin. North Am.55(3), 647–668, xi (2008).
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N. Engl. J. Med.348(2), 138–150 (2003).
   PubMed Web of Science ®Google Scholar
• Cavaillon JM, Adib-Conquy M. Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit. Care10(5), 233 (2006).
   PubMed Web of Science ®Google Scholar
• Osuchowski MF, Welch K, Yang H, Siddiqui J, Remick DG. Chronic sepsis mortality characterized by an individualized inflammatory response. J. Immunol.179(1), 623–630 (2007).
   PubMedGoogle Scholar
• Opal SM, Palardy JE, Chen WH, Parejo NA, Bhattacharjee AK, Cross AS. Active immunization with a detoxified endotoxin vaccine protects against lethal polymicrobial sepsis: its use with CpG adjuvant and potential mechanisms. J. Infect. Dis.192(12), 2074–2080 (2005).
   PubMedGoogle Scholar
• Cross AS, Opal SM, Palardy JE et al. Phase I study of detoxified Escherichia coli J5 lipopolysaccharide (J5dLPS)/group B meningococcal outer membrane protein (OMP) complex vaccine in human subjects. Vaccine21(31), 4576–4587 (2003).
   PubMed Web of Science ®Google Scholar
• Ebrahimi F, Malo MS, Alam SN et al. Local peritoneal irrigation with intestinal alkaline phosphatase is protective against peritonitis in mice. J. Gastrointest. Surg.15(5), 860–869 (2011).
   Google Scholar
• Su F, Brands R, Wang Z et al. Beneficial effects of alkaline phosphatase in septic shock. Crit. Care Med.34(8), 2182–2187 (2006).
   PubMed Web of Science ®Google Scholar
• van Veen SQ, van Vliet AK, Wulferink M, Brands R, Boermeester MA, van Gulik TM. Bovine intestinal alkaline phosphatase attenuates the inflammatory response in secondary peritonitis in mice. Infect. Immun.73(7), 4309–4314 (2005).
   PubMedGoogle Scholar
• Heemskerk S, Masereeuw R, Moesker O et al. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit. Care Med.37(2), 417–423, e1 (2009).
   PubMed Web of Science ®Google Scholar
• Elsbach P. The bactericidal/permeability-increasing protein (BPI) in antibacterial host defense. J. Leukoc. Biol.64(1), 14–18 (1998).
   PubMed Web of Science ®Google Scholar
• Zhang LT, Yao YM, Lu JQ, Yan XJ, Yu Y, Sheng ZY. Recombinant bactericidal/permeability-increasing protein inhibits endotoxin-induced high-mobility group box 1 protein gene expression in sepsis. Shock29(2), 278–284 (2008).
   Google Scholar
• Levin M, Quint PA, Goldstein B 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. Lancet356(9234), 961–967 (2000).
   PubMed Web of Science ®Google Scholar
• Giroir BP, Scannon PJ, Levin M. Bactericidal/permeability-increasing protein – lessons learned from the Phase III, randomized, clinical trial of rBPI21 for adjunctive treatment of children with severe meningococcemia. Crit. Care Med.29(7 Suppl.), S130–S135 (2001).
   Google Scholar
• Zimecki M, Artym J, Chodaczek G, Kocieba M, Kruzel ML. Protective effects of lactoferrin in Escherichia coli-induced bacteremia in mice: relationship to reduced serum TNF α level and increased turnover of neutrophils. Inflamm. Res.53(7), 292–296 (2004).
   PubMed Web of Science ®Google Scholar
• Kruzel ML, Actor JK, Radak Z, Bacsi A, Saavedra-Molina A, Boldogh I. Lactoferrin decreases LPS-induced mitochondrial dysfunction in cultured cells and in animal endotoxemia model. Innate Immun.16(2), 67–79 (2010).
   PubMedGoogle Scholar
• Manzoni P, Rinaldi M, Cattani S et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA302(13), 1421–1428 (2009).
   PubMed Web of Science ®Google Scholar
• Davies B, Cohen J. Endotoxin removal devices for the treatment of sepsis and septic shock. Lancet Infect. Dis.11(1), 65–71 (2011).
   PubMed Web of Science ®Google Scholar
• Vincent JL, Laterre PF, Cohen J et al. A pilot-controlled study of a polymyxin B-immobilized hemoperfusion cartridge in patients with severe sepsis secondary to intra-abdominal infection. Shock23(5), 400–405 (2005).
   PubMed Web of Science ®Google Scholar
• Cruz DN, Antonelli M, Fumagalli R et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA301(23), 2445–2452 (2009).
   PubMed Web of Science ®Google Scholar
• Rachoin JS, Foster D, Dellinger RP. Endotoxin removal: how far from the evidence? From EUPHAS to EUPHRATES. Contrib. Nephrol.167, 111–118 (2010).
   Google Scholar
• Martin EL, Cruz DN, Monti G et al. Endotoxin removal: how far from the evidence? The EUPHAS 2 Project. Contrib. Nephrol.167, 119–125 (2010).
   Google Scholar
• Reinhart K, Meier-Hellmann A, Beale R et al. Open randomized Phase II trial of an extracorporeal endotoxin adsorber in suspected Gram-negative sepsis. Crit. Care Med.32(8), 1662–1668 (2004).
   Google Scholar
• Taniguchi T, Hirai F, Takemoto Y et al. A novel adsorbent of circulating bacterial toxins and cytokines: the effect of direct hemoperfusion with CTR column for the treatment of experimental endotoxemia. Crit. Care Med.34(3), 800–806 (2006).
   Google Scholar
• Rimmele T, Assadi A, Cattenoz M et al. High-volume haemofiltration with a new haemofiltration membrane having enhanced adsorption properties in septic pigs. Nephrol. Dial. Transplant.24(2), 421–427 (2009).
   Google Scholar
• Bengsch S, Boos KS, Nagel D, Seidel D, Inthorn D. Extracorporeal plasma treatment for the removal of endotoxin in patients with sepsis: clinical results of a pilot study. Shock23(6), 494–500 (2005).
   PubMed Web of Science ®Google Scholar
• Lynn M, Rossignol DP, Wheeler JL et al. Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J. Infect. Dis.187(4), 631–639 (2003).
   PubMed Web of Science ®Google Scholar
• Tidswell M, Tillis W, Larosa SP et al. Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis. Crit. Care Med.38(1), 72–83 (2010).
   PubMed Web of Science ®Google Scholar
• Rice TW, Wheeler AP, Bernard GR et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit. Care Med.38(8), 1685–1694 (2010).
   PubMed Web of Science ®Google Scholar
• Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science229(4716), 869–871 (1985).
   PubMed Web of Science ®Google Scholar
• Abraham E, Laterre PF, Garbino J 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.29(3), 503–510 (2001).
   PubMed Web of Science ®Google Scholar
• Panacek EA, Marshall JC, Albertson TE et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab’)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit. Care Med.32(11), 2173–2182 (2004).
   PubMed Web of Science ®Google Scholar
• Rice TW, Wheeler AP, Morris PE et al. Safety and efficacy of affinity-purified, anti-tumor necrosis factor-α, ovine fab for injection (CytoFab) in severe sepsis. Crit. Care Med.34(9), 2271–2281 (2006).
   PubMed Web of Science ®Google Scholar
• Fisher CJ Jr, Dhainaut JF, Opal SM et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA271(23), 1836–1843 (1994).
   PubMed Web of Science ®Google Scholar
• Opal SM, Fisher CJ Jr, Dhainaut JF 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.25(7), 1115–1124 (1997).
   PubMed Web of Science ®Google Scholar
• Barnay-Verdier S, Fattoum L, Borde C, Kaveri S, Gibot S, Marechal V. Emergence of autoantibodies to HMGB1 is associated with survival in patients with septic shock. Intensive Care Med.37(6), 957–962 (2011).
   Google Scholar
• Li J, Kokkola R, Tabibzadeh S et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol. Med.9(1–2), 37–45 (2003).
   PubMed Web of Science ®Google Scholar
• Yang H, Ochani M, Li J et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA101(1), 296–301 (2004).
   PubMed Web of Science ®Google Scholar
• Cristofaro PA, Opal SM, Palardy JE et al. WAY-202196, a selective estrogen receptor-β agonist, protects against death in experimental septic shock. Crit. Care Med.34(8), 2188–2193 (2006).
   PubMed Web of Science ®Google Scholar
• Oh YJ, Youn JH, Min HJ et al. CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, inhibits the lipopolysaccharide-stimulated secretion of HMGB1 by inhibiting PI3K and classical protein kinase C. Int. Immunopharmacol.11(9), 1160–1165 (2011).
   Google Scholar
• Wang HL, Zhang WH, Lei WF, Zhou CQ, Ye T. The inhibitory effect of lidocaine on the release of high mobility group box 1 in lipopolysaccharide-stimulated macrophages. Anesth. Analg.112(4), 839–844 (2011).
   Google Scholar
• Chen G, Li J, Qiang X et al. Suppression of HMGB1 release by stearoyl lysophosphatidylcholine:an additional mechanism for its therapeutic effects in experimental sepsis. J. Lipid Res.46(4), 623–627 (2005).
   Google Scholar
• Chavakis T, Bierhaus A, Al-Fakhri N et al. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J. Exp. Med.198(10), 1507–1515 (2003).
   PubMed Web of Science ®Google Scholar
• Calfee CS, Ware LB, Eisner MD et al. Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury. Thorax63(12), 1083–1089 (2008).
   PubMed Web of Science ®Google Scholar
• Bopp C, Hofer S, Weitz J et al. sRAGE is elevated in septic patients and associated with patients outcome. J. Surg. Res.147(1), 79–83 (2008).
   PubMed Web of Science ®Google Scholar
• Christaki E, Opal SM, Keith JC Jr et al. A monoclonal antibody against RAGE alters gene expression and is protective in experimental models of sepsis and pneumococcal pneumonia. Shock35(5), 492–498 (2011).
   PubMed Web of Science ®Google Scholar
• Lutterloh EC, Opal SM, Pittman DD et al. Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit. Care11(6), R122 (2007).
   PubMed Web of Science ®Google Scholar
• Honore PM, Joannes-Boyau O, Gressens B. Blood and plasma treatments: the rationale of high-volume hemofiltration. Contrib. Nephrol.156, 387–395 (2007).
   Google Scholar
• Rimmele T, Wey PF, Bernard N et al. Hemofiltration with the Cascade system in an experimental porcine model of septic shock. Ther. Apher. Dial.13(1), 63–70 (2009).
   Google Scholar
• Morgera S, Haase M, Kuss T et al. Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure. Crit. Care Med.34(8), 2099–2104 (2006).
   PubMed Web of Science ®Google Scholar
• Ronco C, Brendolan A, Lonnemann G et al. A pilot study of coupled plasma filtration with adsorption in septic shock. Crit. Care Med.30(6), 1250–1255 (2002).
   PubMed Web of Science ®Google Scholar
• Bellomo R, Tetta C, Ronco C. Coupled plasma filtration adsorption. Intensive Care Med.29(8), 1222–1228 (2003).
   PubMedGoogle Scholar
• Peng ZY, Carter MJ, Kellum JA. Effects of hemoadsorption on cytokine removal and short-term survival in septic rats. Crit. Care Med.36(5), 1573–1577 (2008).
   Google Scholar
• Issa N, Messer J, Paganini EP. Renal assist device and treatment of sepsis-induced acute kidney injury in intensive care units. Contrib. Nephrol.156, 419–427 (2007).
   Google Scholar
• Humes HD, Weitzel WF, Bartlett RH et al. Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure. Kidney Int.66(4), 1578–1588 (2004).
   PubMed Web of Science ®Google Scholar
• Tumlin J, Wali R, Williams W et al. Efficacy and safety of renal tubule cell therapy for acute renal failure. J. Am. Soc. Nephrol.19(5), 1034–1040 (2008).
   PubMed Web of Science ®Google Scholar
• Opal SM, Lim YP, Siryaporn E et al. Longitudinal studies of inter-α inhibitor proteins in severely septic patients: a potential clinical marker and mediator of severe sepsis. Crit. Care Med.35(2), 387–392 (2007).
   PubMed Web of Science ®Google Scholar
• Lin HY. [Clinical trial with a new immunomodulatory strategy: treatment of severe sepsis with Ulinastatin and Maipuxin]. Zhonghua Yi Xue Za Zhi87(7), 451–457 (2007).
   PubMedGoogle Scholar
• Zhang Y, Chen H, Li YM et al. Thymosin α1- and ulinastatin-based immunomodulatory strategy for sepsis arising from intra-abdominal infection due to carbapenem-resistant bacteria. J. Infect. Dis.198(5), 723–730 (2008).
   PubMed Web of Science ®Google Scholar
• Chen H, He MY, Li YM. Treatment of patients with severe sepsis using ulinastatin and thymosin α1: a prospective, randomized, controlled pilot study. Chin. Med. J. (Engl.),122(8), 883–888 (2009).
   PubMed Web of Science ®Google Scholar
• Garantziotis S, Hollingsworth JW, Ghanayem RB et al. Inter-α-trypsin inhibitor attenuates complement activation and complement-induced lung injury. J. Immunol.179(6), 4187–4192 (2007).
   PubMed Web of Science ®Google Scholar
• Thiel M, Caldwell CC, Sitkovsky MV. The critical role of adenosine A2A receptors in downregulation of inflammation and immunity in the pathogenesis of infectious diseases. Microbes Infect.5(6), 515–526 (2003).
   PubMed Web of Science ®Google Scholar
• Vuaden FC, Savio LE, Bastos CM, Bogo MR, Bonan CD. Adenosine A(2A) receptor agonist (CGS-21680) prevents endotoxin-induced effects on nucleotidase activities in mouse lymphocytes. Eur. J. Pharmacol.651(1–3), 212–217 (2011).
   Google Scholar
• Moore CC, Martin EN, Lee GH, Obrig T, Linden J, Scheld WM. An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models. BMC Infect. Dis.8, 141 (2008).
   PubMed Web of Science ®Google Scholar
• Chung CS, Chen Y, Grutkoski PS, Doughty L, Ayala A. SOCS-1 is a central mediator of steroid-increased thymocyte apoptosis and decreased survival following sepsis. Apoptosis12(7), 1143–1153 (2007).
   PubMedGoogle Scholar
• Watanabe H, Kubo M, Numata K et al. Overexpression of suppressor of cytokine signaling-5 in T cells augments innate immunity during septic peritonitis. J. Immunol.177(12), 8650–8657 (2006).
   Google Scholar
• Qin H, Roberts KL, Niyongere SA, Cong Y, Elson CO, Benveniste EN. Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. J. Immunol.179(9), 5966–5976 (2007).
   PubMed Web of Science ®Google Scholar
• Saturnino SF, Prado RO, Cunha-Melo JR, Andrade MV. Endotoxin tolerance and cross-tolerance in mast cells involves TLR4, TLR2 and FcεR1 interactions and SOCS expression: perspectives on immunomodulation in infectious and allergic diseases. BMC Infect. Dis.10, 240 (2010).
   PubMed Web of Science ®Google Scholar
• Reddy RC, Narala VR, Keshamouni VG, Milam JE, Newstead MW, Standiford TJ. Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-{γ}. Blood112(10), 4250–4258 (2008).
   Google Scholar
• Blanquart C, Barbier O, Fruchart JC, Staels B, Glineur C. Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation. J. Steroid Biochem. Mol. Biol.85(2–5), 267–273 (2003).
   PubMed Web of Science ®Google Scholar
• Liu D, Zeng BX, Zhang SH et al. Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, reduces acute lung injury in endotoxemic rats. Crit. Care Med.33(10), 2309–2316 (2005).
   Google Scholar
• Lee S, Kim W, Kang KP et al. Agonist of peroxisome proliferator-activated receptor-γ, rosiglitazone, reduces renal injury and dysfunction in a murine sepsis model. Nephrol. Dial. Transplant.20(6), 1057–1065 (2005).
   PubMed Web of Science ®Google Scholar
• Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J. Altern. Complement. Med.9(1), 161–168 (2003).
   PubMed Web of Science ®Google Scholar
• Siddiqui AM, Cui X, Wu R et al. The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-γ. Crit. Care Med.34(7), 1874–1882 (2006).
   PubMed Web of Science ®Google Scholar
• Chen HW, Kuo HT, Chai CY, Ou JL, Yang RC. Pretreatment of curcumin attenuates coagulopathy and renal injury in LPS-induced endotoxemia. J. Endotoxin Res.13(1), 15–23 (2007).
   Google Scholar
• Memis D, Hekimoglu S, Sezer A, Altaner S, Sut N, Usta U. Curcumin attenuates the organ dysfunction caused by endotoxemia in the rat. Nutrition24(11–12), 1133–1138 (2008).
   PubMed Web of Science ®Google Scholar
• Tham CL, Lam KW, Rajajendram R et al. The effects of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone on proinflammatory signaling pathways and CLP-induced lethal sepsis in mice. Eur. J. Pharmacol.652(1–3), 136–144 (2011).
   PubMed Web of Science ®Google Scholar
• Borovikova LV, Ivanova S, Zhang M et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature405(6785), 458–462 (2000).
   PubMed Web of Science ®Google Scholar
• van Westerloo DJ, Giebelen IA, Meijers JC et al. Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats. J. Thromb. Haemost.4(9), 1997–2002 (2006).
   PubMed Web of Science ®Google Scholar
• Pavlov VA, Ochani M, Yang LH et al. Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit. Care Med.35(4), 1139–1144 (2007).
   PubMed Web of Science ®Google Scholar
• Wang H, Liao H, Ochani M et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat. Med.10(11), 1216–1221 (2004).
   PubMed Web of Science ®Google Scholar
• Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M et al. The selective α7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol. Med.15(7–8), 195–202 (2009).
   PubMed Web of Science ®Google Scholar
• Hofer S, Eisenbach C, Lukic IK et al. Pharmacologic cholinesterase inhibition improves survival in experimental sepsis. Crit. Care Med.36(2), 404–408 (2008).
   PubMed Web of Science ®Google Scholar
• Huston JM, Gallowitsch-Puerta M, Ochani M et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit. Care Med.35(12), 2762–2768 (2007).
   PubMed Web of Science ®Google Scholar
• Kreymann KG, de Heer G, Nierhaus A, Kluge S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit. Care Med.35(12), 2677–2685 (2007).
   PubMed Web of Science ®Google Scholar
• Visvanathan K, Charles A, Bannan J, Pugach P, Kashfi K, Zabriskie JB. Inhibition of bacterial superantigens by peptides and antibodies. Infect. Immun.69(2), 875–884 (2001).
   PubMed Web of Science ®Google Scholar
• Miwa K, Fukuyama M, Matsuno N, Shimada K, Ikeda K, Ikeda T. Physiological response to superantigen-adsorbing hemoperfusion in toxin-concentration-controlled septic swine. Blood Purif.24(3), 319–326 (2006).
   Google Scholar
• Steinberg J, Halter J, Schiller H et al. Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model. Shock24(4), 348–356 (2005).
   PubMed Web of Science ®Google Scholar
• Maitra SR, Bhaduri S, Chen E, Shapiro MJ. Role of chemically modified tetracycline on TNF-α and mitogen-activated protein kinases in sepsis. Shock22(5), 478–481 (2004).
   Google Scholar
• Tkalcevic VI, Bosnjak B, Pasalic I et al. The anti-inflammatory activity of clarithromycin inhibits TNFα production and prolongs survival following lipopolysaccharide administration in mice. Int. J. Antimicrob. Agents32(2), 195–196 (2008).
   PubMed Web of Science ®Google Scholar
• Ivetić Tkalcević V, Bosnjak B, Hrvacic B et al. Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice. Eur. J. Pharmacol.539(1–2), 131–138 (2006).
   PubMed Web of Science ®Google Scholar
• Leiva M, Ruiz-Bravo A, Moreno E, Jimenez-Valera M. The anti-inflammatory activity of telithromycin in a mouse model of septic shock. Int. J. Antimicrob. Agents29(3), 364–365 (2007).
   PubMedGoogle Scholar
• Giamarellos-Bourboulis EJ, Pechere JC, Routsi C et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin. Infect. Dis.46(8), 1157–1164 (2008).
   PubMed Web of Science ®Google Scholar
• Merx MW, Liehn EA, Graf J et al. Statin treatment after onset of sepsis in a murine model improves survival. Circulation112(1), 117–124 (2005).
   PubMed Web of Science ®Google Scholar
• Niessner A, Steiner S, Speidl WS et al. Simvastatin suppresses endotoxin-induced upregulation of Toll-like receptors 4 and 2 in vivo. Atherosclerosis189(2), 408–413 (2006).
   PubMed Web of Science ®Google Scholar
• Liappis AP, Kan VL, Rochester CG, Simon GL. The effect of statins on mortality in patients with bacteremia. Clin. Infect. Dis.33(8), 1352–1357 (2001).
   PubMed Web of Science ®Google Scholar
• Almog Y, Shefer A, Novack V et al. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation110(7), 880–885 (2004).
   PubMed Web of Science ®Google Scholar
• Yende S, Milbrandt EB, Kellum JA et al. Understanding the potential role of statins in pneumonia and sepsis. Crit. Care Med.39(8), 1871–1878 (2011).
   PubMedGoogle Scholar
• Terblanche MJ, Pinto R, Whiteley C, Brett S, Beale R, Adhikari NK. Statins do not prevent acute organ failure in ventilated ICU patients: single-centre retrospective cohort study. Crit. Care15(1), R74 (2011).
   PubMed Web of Science ®Google Scholar
• Novack V, Eisinger M, Frenkel A et al. The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial. Intensive Care Med.35(7), 1255–1260 (2009).
   PubMed Web of Science ®Google Scholar
• Kruger PS, Harward ML, Jones MA et al. Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. Am. J. Respir. Crit. Care Med.183(6), 774–781 (2011).
   PubMedGoogle Scholar
• Gressner OA, Koch A, Sanson E, Trautwein C, Tacke F. High C5a levels are associated with increased mortality in sepsis patients – no enhancing effect by actin-free Gc-globulin. Clin. Biochem.41(12), 974–980 (2008).
   Google Scholar
• Czermak BJ, Sarma V, Pierson CL et al. Protective effects of C5a blockade in sepsis. Nat. Med.5(7), 788–792 (1999).
   PubMed Web of Science ®Google Scholar
• Laudes IJ, Chu JC, Sikranth S et al. Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. Am. J. Pathol.160(5), 1867–1875 (2002).
   PubMed Web of Science ®Google Scholar
• Zwijnenburg PJ, van der Poll T, Florquin S et al. C1 inhibitor treatment improves host defense in pneumococcal meningitis in rats and mice. J. Infect. Dis.196(1), 115–123 (2007).
   PubMed Web of Science ®Google Scholar
• Dorresteijn MJ, Visser T, Cox LA et al. C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia. Crit. Care Med.38(11), 2139–2145 (2010).
   PubMed Web of Science ®Google Scholar
• Fein AM, Bernard GR, Criner GJ 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. JAMA277(6), 482–487 (1997).
   PubMed Web of Science ®Google Scholar
• Abraham E, Reinhart K, Opal S et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA290(2), 238–247 (2003).
   PubMed Web of Science ®Google Scholar
• Wunderink RG, Laterre PF, Francois B et al. Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial. Am. J. Respir. Crit. Care Med.183(11), 1561–1568 (2011).
   PubMed Web of Science ®Google Scholar
• Warren BL, Eid A, Singer P et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA286(15), 1869–1878 (2001).
   PubMed Web of Science ®Google Scholar
• Wiedermann CJ, Hoffmann JN, Juers M et al. High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit. Care Med.34(2), 285–292 (2006).
   PubMed Web of Science ®Google Scholar
• Van de Wouwer M, Plaisance S, De Vriese A et al. The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritis. J. Thromb. Haemost.4(8), 1813–1824 (2006).
   PubMed Web of Science ®Google Scholar
• Abeyama K, Stern DM, Ito Y et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J. Clin. Invest.115(5), 1267–1274 (2005).
   PubMed Web of Science ®Google Scholar
• Nagato M, Okamoto K, Abe Y, Higure A, Yamaguchi K. Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia. Crit. Care Med.37(7), 2181–2186 (2009).
   PubMed Web of Science ®Google Scholar
• Saito H, Maruyama I, Shimazaki S et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a Phase III, randomized, double-blind clinical trial. J. Thromb. Haemost.5(1), 31–41 (2007).
   PubMed Web of Science ®Google Scholar
• Yamakawa K, Fujimi S, Mohri T et al. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit. Care15(3), R123 (2011).
   Web of Science ®Google Scholar
• Iba T, Nakarai E, Takayama T, Nakajima K, Sasaoka T, Ohno Y. Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model. Crit. Care13(6), R203 (2009).
   Google Scholar
• Moreno SE, Alves-Filho JC, Rios-Santos F et al. Signaling via platelet-activating factor receptors accounts for the impairment of neutrophil migration in polymicrobial sepsis. J. Immunol.177(2), 1264–1271 (2006).
   PubMedGoogle Scholar
• Gomes RN, Bozza FA, Amancio RT et al. Exogenous platelet-activating factor acetylhydrolase reduces mortality in mice with systemic inflammatory response syndrome and sepsis. Shock26(1), 41–49 (2006).
   PubMed Web of Science ®Google Scholar
• Schuster DP, Metzler M, Opal S et al. Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial. Crit. Care Med.31(6), 1612–1619 (2003).
   PubMed Web of Science ®Google Scholar
• 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.28(3), 638–642 (2000).
   PubMed Web of Science ®Google Scholar
• Albrecht DM, van Ackern K, Bender HJ et al. Efficacy and safety of the platelet-activating factor receptor antagonist BN 52021 (ginkgolide B) in patients with severe sepsis : a randomised, double-blind, placebo-controlled, multicentre trial. Clin. Drug Investig.24(3), 137–147 (2004).
   Google Scholar
• Fink MP. Bench-to-bedside review: cytopathic hypoxia. Crit. Care6(6), 491–499 (2002).
   PubMed Web of Science ®Google Scholar
• Goldfarb RD, Marton A, Szabo E et al. Protective effect of a novel, potent inhibitor of poly(adenosine 5´-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis. Crit. Care Med.30(5), 974–980 (2002).
   PubMed Web of Science ®Google Scholar
• Murakami K, Enkhbaatar P, Shimoda K et al. Inhibition of poly (ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis. Shock21(2), 126–133 (2004).
   PubMed Web of Science ®Google Scholar
• Duntas LH. Selenium and inflammation: underlying anti-inflammatory mechanisms. Horm. Metab. Res.41(6), 443–447 (2009).
   PubMed Web of Science ®Google Scholar
• Andrews PJ, Avenell A, Noble DW et al. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ342, d1542 (2011).
   PubMed Web of Science ®Google Scholar
• de Mello RO, Lunardelli A, Caberlon E et al. Effect of N-acetylcysteine and fructose-1,6-bisphosphate in the treatment of experimental sepsis. Inflammation DOI: 10.1007/s10753-010-9261-9 (2010) (Epub ahead of print).
   Google Scholar
• Hsu BG, Lee RP, Yang FL, Harn HJ, Chen HI. Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats. Life Sci.79(21), 2010–2016 (2006).
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat. Rev. Immunol.6(11), 813–822 (2006).
   PubMed Web of Science ®Google Scholar
• Landelle C, Lepape A, Voirin N et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med.36(11), 1859–1866 (2010).
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. Nat. Med.15(5), 496–497 (2009).
   PubMed Web of Science ®Google Scholar
• Kalil AC. A silent killer: cytomegalovirus infection in the nonimmunocompromised critically ill patient. Crit. Care Med.36(12), 3261–3264 (2008).
   Google Scholar
• Ziemann M, Sedemund-Adib B, Reiland P, Schmucker P, Hennig H. Increased mortality in long-term intensive care patients with active cytomegalovirus infection. Crit. Care Med.36(12), 3145–3150 (2008).
   PubMedGoogle Scholar
• Polk HC Jr, Cheadle WG, Livingston DH et al. A randomized prospective clinical trial to determine the efficacy of interferon-γ in severely injured patients. Am. J. Surg.163(2), 191–196 (1992).
   PubMed Web of Science ®Google Scholar
• Wasserman D, Ioannovich JD, Hinzmann RD, Deichsel G, Steinmann GG. Interferon-γ in the prevention of severe burn-related infections: a European Phase III multicenter trial. The Severe Burns Study Group. Crit. Care Med.26(3), 434–439 (1998).
   PubMed Web of Science ®Google Scholar
• Dries DJ, Jurkovich GJ, Maier RV et al. Effect of interferon γ on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial. Arch Surg.129(10), 1031–1041; discussion 1042 (1994).
   PubMed Web of Science ®Google Scholar
• Nelson S, Belknap SM, Carlson RW et al. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group. J. Infect. Dis.178(4), 1075–1080 (1998).
   PubMedGoogle Scholar
• Weiss M, Gross-Weege W, Schneider M et al. Enhancement of neutrophil function by in vivo filgrastim treatment for prophylaxis of sepsis in surgical intensive care patients. J. Crit. Care10(1), 21–26 (1995).
   PubMed Web of Science ®Google Scholar
• Nelson S, Heyder AM, Stone J et al. A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia. J. Infect. Dis.182(3), 970–973 (2000).
   PubMed Web of Science ®Google Scholar
• Root RK, Lodato RF, Patrick W et al. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit. Care Med.31(2), 367–373 (2003).
   PubMed Web of Science ®Google Scholar
• Meisel C, Schefold JC, Pschowski R et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am. J. Respir. Crit. Care Med.180(7), 640–648 (2009).
   PubMed Web of Science ®Google Scholar
• Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol.26, 677–704 (2008).
   PubMed Web of Science ®Google Scholar
• Guignant C, Lepape A, Huang X et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit. Care15(2), R99 (2011).
   PubMed Web of Science ®Google Scholar
• Huang X, Venet F, Wang YL et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc. Natl Acad. Sci. USA106(15), 6303–6308 (2009).
   PubMed Web of Science ®Google Scholar
• Inoue S, Bo L, Bian J, Unsinger J, Chang K, Hotchkiss RS. Dose-dependent effect of anti-CTLA-4 on survival in sepsis. Shock36(1), 38–44 (2011).
   PubMed Web of Science ®Google Scholar
• Inoue S, Unsinger J, Davis CG et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J. Immunol.184(3), 1401–1409 (2010).
   PubMed Web of Science ®Google Scholar
• Unsinger J, McGlynn M, Kasten KR et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J. Immunol.184(7), 3768–3779 (2010).
   PubMed Web of Science ®Google Scholar
• Steinhauser ML, Hogaboam CM, Kunkel SL, Lukacs NW, Strieter RM, Standiford TJ. IL-10 is a major mediator of sepsis-induced impairment in lung antibacterial host defense. J. Immunol.162(1), 392–399 (1999).
   PubMed Web of Science ®Google Scholar
• Reddy RC, Chen GH, Newstead MW et al. Alveolar macrophage deactivation in murine septic peritonitis: role of interleukin 10. Infect. Immun.69(3), 1394–1401 (2001).
   PubMed Web of Science ®Google Scholar
• Muenzer JT, Davis CG, Chang K et al. Characterization and modulation of the immunosuppressive phase of sepsis. Infect. Immun.78(4), 1582–1592 (2010).
   PubMedGoogle Scholar
• Hotchkiss RS, Chang KC, Swanson PE et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat. Immunol.1(6), 496–501 (2000).
   PubMed Web of Science ®Google Scholar
• Chung CS, Song GY, Lomas J, Simms HH, Chaudry IH, Ayala A. Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity. J. Leukoc. Biol.74(3), 344–351 (2003).
   PubMed Web of Science ®Google Scholar
• Galban C, Montejo JC, Mesejo A et al. An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit. Care Med.28(3), 643–648 (2000).
   PubMed Web of Science ®Google Scholar
• Bower RH, Cerra FB, Bershadsky B et al. Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized, clinical trial. Crit. Care Med.23(3), 436–449 (1995).
   PubMed Web of Science ®Google Scholar
• Kudsk KA, Minard G, Croce MA et al. A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications. Ann. Surg.224(4), 531–540; discussion 540–533 (1996).
   PubMed Web of Science ®Google Scholar
• Houdijk AP, Rijnsburger ER, Jansen J et al. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet352(9130), 772–776 (1998).
   PubMed Web of Science ®Google Scholar
• Esmon CT. Why do animal models (sometimes) fail to mimic human sepsis? Crit. Care Med.32(5 Suppl.), S219–S222 (2004).
   PubMed Web of Science ®Google Scholar
• Dyson A, Singer M. Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Crit. Care Med.37(1 Suppl.), S30–S37 (2009).
   PubMed Web of Science ®Google Scholar
• Opal SM, Cross AS. The use of immunocompromised animals as models for human septic shock. Shock24(Suppl. 1), 64–70 (2005).
   Google Scholar
• Standiford TJ, Strieter RM, Lukacs NW, Kunkel SL. Neutralization of IL-10 increases lethality in endotoxemia. Cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor. J. Immunol.155(4), 2222–2229 (1995).
   PubMed Web of Science ®Google Scholar
• Opal SM. Concept of PIRO as a new conceptual framework to understand sepsis. Pediatr Crit Care Med.6(3 Suppl.), S55–S60 (2005).
   Google Scholar
• Volk HD, Reinke P, Docke WD. Clinical aspects: from systemic inflammation to ‘immunoparalysis’. Chem. Immunol.74, 162–177 (2000).
   PubMedGoogle Scholar
• Kox WJ, Bone RC, Krausch D et al. Interferon γ-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch. Intern. Med.157(4), 389–393 (1997).
   PubMed Web of Science ®Google Scholar
• van der Poll T, van Deventer SJ. Cytokines and anticytokines in the pathogenesis of sepsis. Infect. Dis. Clin. North Am.13(2), 413–426, ix (1999).
   PubMed Web of Science ®Google Scholar
• Reddy RC, Chen GH, Tekchandani PK, Standiford TJ. Sepsis-induced immunosuppression: from bad to worse. Immunol. Res.24(3), 273–287 (2001).
   PubMed Web of Science ®Google Scholar
• Anas AA, Wiersinga WJ, de Vos AF, van der Poll T. Recent insights into the pathogenesis of bacterial sepsis. Neth. J. Med.68(4), 147–152 (2010).
   PubMed Web of Science ®Google Scholar