Immunomodulatory therapy for sepsis: an update

Currently the treatment mainstay of sepsis is early and appropriate antibiotic therapy, accompanied by aggressive fluid administration, the use of vasopressors when needed and the prompt initiation of measures to support each failing organ. Activated protein C and hydrocortisone, when used accordingly can affect mortality. As the pathophysiologic events that take place during sepsis are being elucidated, new molecules that target each step of those pathways are being tested. However, a lot of those molecules affect various mediators of the sepsis cascade including inflammatory cytokines, cellular receptors, nuclear transcription factors, coagulation activators and apoptosis regulators. Over the last decade, a multitude of clinical trials and animal studies have investigated strategies that aimed to restore immune homeostasis either by reducing inflammation or by stimulating the innate and adaptive immune responses. Antibiotics, statins and other molecules with multipotent immunomodulatory actions have also been studied in the treatment of sepsis.

[1]  S. Opal,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. , 1997, Critical care medicine.

[2]  M. Wolzt,et al.  Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. , 2006, Atherosclerosis.

[3]  A. K. Vinnikova,et al.  Efficacy and safety of renal tubule cell therapy for acute renal failure. , 2008, Journal of the American Society of Nephrology : JASN.

[4]  K. Kostner,et al.  Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. , 2011, American journal of respiratory and critical care medicine.

[5]  T. Baumann,et al.  Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. , 2009, American journal of respiratory and critical care medicine.

[6]  J. Vincent,et al.  Beneficial effects of alkaline phosphatase in septic shock , 2006, Critical care medicine.

[7]  J. Linden,et al.  An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models , 2008, BMC infectious diseases.

[8]  J. G. van der Hoeven,et al.  Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients* , 2009, Critical care medicine.

[9]  J. L. Rodriguez,et al.  A randomized prospective clinical trial to determine the efficacy of interferon-γ in severely injured patients☆ , 1992 .

[10]  D. Schwartz,et al.  Inter-alpha-trypsin inhibitor attenuates complement activation and complement-induced lung injury. , 2007, Journal of immunology.

[11]  E. Paganini,et al.  Renal assist device and treatment of sepsis-induced acute kidney injury in intensive care units. , 2007, Contributions to nephrology.

[12]  S. Opal,et al.  WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock , 2006, Critical care medicine.

[13]  A. Kalil A silent killer: cytomegalovirus infection in the nonimmunocompromised critically ill patient. , 2008, Critical care medicine.

[14]  D. Rossignol,et al.  Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. , 2003, The Journal of infectious diseases.

[15]  S. Opal Concept of PIRO as a new conceptual framework to understand sepsis , 2005, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[16]  Rinaldo Bellomo,et al.  A pilot study of coupled plasma filtration with adsorption in septic shock* , 2002, Critical care medicine.

[17]  T. Rimmele,et al.  Hemofiltration With the Cascade System in an Experimental Porcine Model of Septic Shock , 2009, Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy.

[18]  Jeon-Soo Shin,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. , 2011, International immunopharmacology.

[19]  T. Fabian,et al.  A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications. , 1996, Annals of surgery.

[20]  M. Levy,et al.  Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 , 2007, Intensive Care Medicine.

[21]  P. Honore,et al.  Blood and plasma treatments: the rationale of high-volume hemofiltration. , 2007, Contributions to nephrology.

[22]  S. Opal The host response to endotoxin, antilipopolysaccharide strategies, and the management of severe sepsis. , 2007, International journal of medical microbiology : IJMM.

[23]  R. F. Johnston,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 , 1994 .

[24]  G. Bernard,et al.  Safety and efficacy of affinity-purified, anti–tumor necrosis factor-&agr;, ovine fab for injection (CytoFab) in severe sepsis* , 2006, Critical care medicine.

[25]  S. Zanotti-Cavazzoni Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock: The EUPHAS Randomized Controlled Trial , 2010 .

[26]  M. Levy,et al.  Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 , 2007, Intensive Care Medicine.

[27]  N. Lajis,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. , 2011, European journal of pharmacology.

[28]  C. Esmon,et al.  Why do animal models (sometimes) fail to mimic human sepsis? , 2004, Critical care medicine.

[29]  K. Tracey,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 , 2009, Molecular medicine.

[30]  J. Vincent,et al.  A PILOT-CONTROLLED STUDY OF A POLYMYXIN B-IMMOBILIZED HEMOPERFUSION CARTRIDGE IN PATIENTS WITH SEVERE SEPSIS SECONDARY TO INTRA-ABDOMINAL INFECTION , 2005, Shock.

[31]  I. Marzi,et al.  Efficacy and Safety of the Platelet-Activating Factor Receptor Antagonist BN 52021 (Ginkgolide B) in Patients with Severe Sepsis , 2004, Clinical drug investigation.

[32]  Haiyang Xie,et al.  Thymosin alpha1- and ulinastatin-based immunomodulatory strategy for sepsis arising from intra-abdominal infection due to carbapenem-resistant bacteria. , 2008, The Journal of infectious diseases.

[33]  G. Steinmann,et al.  Interferon-gamma in the prevention of severe burn-related infections: a European phase III multicenter trial. The Severe Burns Study Group. , 1998, Critical care medicine.

[34]  Denizar Alberto Silva Melo,et al.  Effect of N-Acetylcysteine and Fructose-1,6-Bisphosphate in the Treatment of Experimental Sepsis , 2011, Inflammation.

[35]  S. Kaveri,et al.  Emergence of autoantibodies to HMGB1 is associated with survival in patients with septic shock , 2011, Intensive Care Medicine.

[36]  Marion K Campbell,et al.  Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients , 2011, BMJ : British Medical Journal.

[37]  C. Chung,et al.  PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis , 2009, Proceedings of the National Academy of Sciences.

[38]  F. Lewis,et al.  Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial. , 1994, Archives of surgery.

[39]  L. Casey,et al.  Immunologic response to infection and its role in septic shock. , 2000, Critical care clinics.

[40]  M. Kubo,et al.  Overexpression of Suppressor of Cytokine Signaling-5 in T Cells Augments Innate Immunity during Septic Peritonitis1 , 2006, The Journal of Immunology.

[41]  Ting Ye,et al.  The Inhibitory Effect of Lidocaine on the Release of High Mobility Group Box 1 in Lipopolysaccharide-Stimulated Macrophages , 2011, Anesthesia and analgesia.

[42]  O. Tasaki,et al.  Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study , 2011, Critical care.

[43]  M. Karin,et al.  The IKK/NF-kappa B pathway. , 2002 .

[44]  S. Opal,et al.  Phase I study of detoxified Escherichia coli J5 lipopolysaccharide (J5dLPS)/group B meningococcal outer membrane protein (OMP) complex vaccine in human subjects. , 2003, Vaccine.

[45]  B. Staels,et al.  Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation , 2003, The Journal of Steroid Biochemistry and Molecular Biology.

[46]  S. Belknap,et al.  A Randomized Controlled Trial of Filgrastim as an Adjunct to Antibiotics for Treatment of Hospitalized Patients with Community-Acquired Pneumonia , 1998 .

[47]  S. Opal,et al.  A Monoclonal Antibody Against RAGE Alters Gene Expression and is Protective in Experimental Models of Sepsis and Pneumococcal Pneumonia , 2011, Shock.

[48]  M. Teixeira,et al.  Signaling via Platelet-Activating Factor Receptors Accounts for the Impairment of Neutrophil Migration in Polymicrobial Sepsis1 , 2006, The Journal of Immunology.

[49]  A. Nierhaus,et al.  Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock * , 2007, Critical care medicine.

[50]  M. Bogo,et al.  Adenosine A(2A) receptor agonist (CGS-21680) prevents endotoxin-induced effects on nucleotidase activities in mouse lymphocytes. , 2011, European journal of pharmacology.

[51]  B. Allaouchiche,et al.  Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients , 2011, Critical care.

[52]  Yan Yu,et al.  RECOMBINANT BACTERICIDAL/PERMEABILITY-INCREASING PROTEIN INHIBITS ENDOTOXIN-INDUCED HIGH-MOBILITY GROUP BOX 1 PROTEIN GENE EXPRESSION IN SEPSIS , 2008, Shock.

[53]  S. K. Park,et al.  Agonist of peroxisome proliferator-activated receptor-gamma, rosiglitazone, reduces renal injury and dysfunction in a murine sepsis model. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[54]  F. Tacke,et al.  High C5a levels are associated with increased mortality in sepsis patients--no enhancing effect by actin-free Gc-globulin. , 2008, Clinical biochemistry.

[55]  V. Pavlov,et al.  Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis * , 2007, Critical care medicine.

[56]  Hiroshi Yamamoto,et al.  The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. , 2005, The Journal of clinical investigation.

[57]  D. J. Bryg,et al.  An immune‐enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients , 2000, Critical care medicine.

[58]  M. Zimecki,et al.  Protective effects of lactoferrin in Escherichia coli-induced bacteremia in mice: Relationship to reduced serum TNF alpha level and increased turnover of neutrophils , 2004, Inflammation Research.

[59]  T. Iba,et al.  Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model , 2009, Critical care.

[60]  P. Parsons,et al.  Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury , 2008, Thorax.

[61]  P. Wernet,et al.  Enhancement of neutrophil function by in vivo filgrastim treatment for prophylaxis of sepsis in surgical intensive care patients. , 1995, Journal of critical care.

[62]  Rinaldo Bellomo,et al.  Coupled Plasma Filtration Adsorption , 2002, Blood Purification.

[63]  C. Coopersmith,et al.  IL-15 Prevents Apoptosis, Reverses Innate and Adaptive Immune Dysfunction, and Improves Survival in Sepsis , 2009, The Journal of Immunology.

[64]  K. Tracey,et al.  Reversing established sepsis with antagonists of endogenous high-mobility group box 1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[65]  N. Aoki,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 , 2007, Journal of thrombosis and haemostasis : JTH.

[66]  T. Standiford,et al.  Sepsis-induced immunosuppression , 2001, Immunologic research.

[67]  M. Adib-Conquy,et al.  Bench-to-bedside review: Endotoxin tolerance as a model of leukocyte reprogramming in sepsis , 2006, Critical care.

[68]  N. Adhikari,et al.  Statins do not prevent acute organ failure in ventilated ICU patients: single-centre retrospective cohort study , 2011, Critical care.

[69]  B. Beutler,et al.  Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. , 1985, Science.

[70]  C. Roussos,et al.  Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[71]  Understanding the potential role of statins in pneumonia and sepsis , 2012 .

[72]  A. Liappis,et al.  The effect of statins on mortality in patients with bacteremia. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[73]  D. Inthorn,et al.  EXTRACORPOREAL PLASMA TREATMENT FOR THE REMOVAL OF ENDOTOXIN IN PATIENTS WITH SEPSIS: CLINICAL RESULTS OF A PILOT STUDY , 2005, Shock.

[74]  T. Butler,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 , 2001, Critical care medicine.

[75]  T. van der Poll,et al.  C1 inhibitor treatment improves host defense in pneumococcal meningitis in rats and mice. , 2007, The Journal of infectious diseases.

[76]  Phil Barton,et al.  Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial , 2000, The Lancet.

[77]  R. Hotchkiss,et al.  IL-7 Promotes T Cell Viability, Trafficking, and Functionality and Improves Survival in Sepsis , 2010, The Journal of Immunology.

[78]  S. Opal,et al.  Active immunization with a detoxified endotoxin vaccine protects against lethal polymicrobial sepsis: its use with CpG adjuvant and potential mechanisms. , 2005, The Journal of infectious diseases.

[79]  J. Zabriskie,et al.  Inhibition of Bacterial Superantigens by Peptides and Antibodies , 2001, Infection and Immunity.

[80]  S. Opal,et al.  Longitudinal studies of inter-alpha inhibitor proteins in severely septic patients: A potential clinical marker and mediator of severe sepsis* , 2007, Critical care medicine.

[81]  J. Encke,et al.  Pharmacologic cholinesterase inhibition improves survival in experimental sepsis* , 2008, Critical care medicine.

[82]  M. Bergeron,et al.  A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia. , 2000, The Journal of infectious diseases.

[83]  T. van der Poll,et al.  Host-pathogen interactions in sepsis. , 2008, The Lancet. Infectious diseases.

[84]  S. Deventer,et al.  CYTOKINES AND ANTICYTOKINES IN THE PATHOGENESIS OF SEPSIS , 1999 .

[85]  L. Duntas,et al.  Selenium and Inflammation: Underlying Anti-inflammatory Mechanisms , 2009, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[86]  R. Hotchkiss,et al.  Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte , 2000, Nature Immunology.

[87]  A. Sezer,et al.  Curcumin attenuates the organ dysfunction caused by endotoxemia in the rat. , 2008, Nutrition.

[88]  C. Coopersmith,et al.  Characterization and Modulation of the Immunosuppressive Phase of Sepsis , 2010, Infection and Immunity.

[89]  F. Cerra,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. , 1995, Critical care medicine.

[90]  Ping Wang,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* , 2006 .

[91]  Huan Yang,et al.  Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response1 , 2007, The Journal of Immunology.

[92]  C. Elson,et al.  Molecular Mechanism of Lipopolysaccharide-Induced SOCS-3 Gene Expression in Macrophages and Microglia1 , 2007, The Journal of Immunology.

[93]  M. Büchler,et al.  sRAGE is elevated in septic patients and associated with patients outcome. , 2008, The Journal of surgical research.

[94]  K. Preissner,et al.  The Pattern Recognition Receptor (RAGE) Is a Counterreceptor for Leukocyte Integrins , 2003, The Journal of experimental medicine.

[95]  R. Hotchkiss,et al.  The pathophysiology and treatment of sepsis. , 2003, The New England journal of medicine.

[96]  E. Hohmann,et al.  Local Peritoneal Irrigation with Intestinal Alkaline Phosphatase Is Protective Against Peritonitis in Mice , 2011, Journal of Gastrointestinal Surgery.

[97]  A. Schmaier,et al.  Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis. , 2002, The American journal of pathology.

[98]  M. Shapiro,et al.  ROLE OF CHEMICALLY MODIFIED TETRACYCLINE ON TNF-α AND MITOGEN-ACTIVATED PROTEIN KINASES IN SEPSIS , 2004, Shock.

[99]  S. Opal,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. , 1994, JAMA.

[100]  M. Fink Bench-to-bedside review: Cytopathic hypoxia , 2002, Critical care.

[101]  C. Sprung,et al.  Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. , 2003, JAMA.

[102]  S. Opal,et al.  Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection , 2007, Critical care.

[103]  P. Ward,et al.  Protective effects of C5a blockade in sepsis , 1999, Nature Medicine.

[104]  N. Voirin,et al.  Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock , 2010, Intensive Care Medicine.

[105]  W. Knaus,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. , 1997, JAMA.

[106]  C. Chung,et al.  Leukocyte apoptosis and its significance in sepsis and shock , 2005, Journal of leukocyte biology.

[107]  Shenmin Zhang,et al.  Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, reduces acute lung injury in endotoxemic rats* , 2005, Critical care medicine.

[108]  M. Levin,et al.  Bactericidal/permeability-increasing protein—Lessons learned from the phase III, randomized, clinical trial of rBPI21 for adjunctive treatment of children with severe meningococcemia , 2001, Critical care medicine.

[109]  I. Boldogh,et al.  Lactoferrin decreases LPS-induced mitochondrial dysfunction in cultured cells and in animal endotoxemia model , 2010, Innate immunity.

[110]  K. Asadullah,et al.  Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. , 1997, Archives of internal medicine.

[111]  M. Sitkovsky,et al.  The critical role of adenosine A2A receptors in downregulation of inflammation and immunity in the pathogenesis of infectious diseases. , 2003, Microbes and infection.

[112]  S. Opal,et al.  THE USE OF IMMUNOCOMPROMISED ANIMALS AS MODELS FOR HUMAN SEPTIC SHOCK , 2005, Shock.

[113]  S. Opal,et al.  Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. , 2001, JAMA.

[114]  V. Pavlov,et al.  Selective &agr;7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis* , 2007, Critical care medicine.

[115]  S. Opal,et al.  Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial. , 2011, American journal of respiratory and critical care medicine.

[116]  Hong Wang,et al.  Structural Basis for the Proinflammatory Cytokine Activity of High Mobility Group Box 1 , 2003, Molecular medicine.

[117]  R. Bellomo,et al.  Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure* , 2006, Critical care medicine.

[118]  Hong-yuan Lin [Clinical trial with a new immunomodulatory strategy: treatment of severe sepsis with Ulinastatin and Maipuxin]. , 2007, Zhonghua yi xue za zhi.

[119]  S. Opal,et al.  High-Dose Antithrombin III in Severe Sepsis: A Randomized Controlled Trial , 2001 .

[120]  M. Daha,et al.  The lectin‐like domain of thrombomodulin interferes with complement activation and protects against arthritis , 2006, Journal of thrombosis and haemostasis : JTH.

[121]  T. Rimmele,et al.  High-volume haemofiltration with a new haemofiltration membrane having enhanced adsorption properties in septic pigs. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[122]  S. Belknap,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. , 1998, The Journal of infectious diseases.

[123]  John A Kellum,et al.  Effects of hemoadsorption on cytokine removal and short-term survival in septic rats , 2008, Critical care medicine.

[124]  S. Opal,et al.  Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis* , 2010, Critical care medicine.

[125]  R. Dellinger,et al.  Endotoxin removal: how far from the evidence? From EUPHAS to EUPHRATES. , 2010, Contributions to nephrology.

[126]  J. Parrillo,et al.  Protective effect of a novel, potent inhibitor of poly(adenosine 5′-diphosphate-ribose) synthetase in a porcine model of severe bacterial sepsis* , 2002, Critical care medicine.

[127]  L. Thijs,et al.  Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma , 1998, The Lancet.

[128]  T. van der Poll,et al.  Recent insights into the pathogenesis of bacterial sepsis. , 2010, The Netherlands journal of medicine.

[129]  T. Standiford,et al.  IL-10 is a major mediator of sepsis-induced impairment in lung antibacterial host defense. , 1999, Journal of immunology.

[130]  I. Chaudry,et al.  Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity , 2003, Journal of leukocyte biology.

[131]  G. Zimmerman,et al.  EXOGENOUS PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE REDUCES MORTALITY IN MICE WITH SYSTEMIC INFLAMMATORY RESPONSE SYNDROME AND SEPSIS , 2006, Shock.

[132]  D. Adamkin Bovine Lactoferrin Supplementation for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight Neonates: A Randomized Trial , 2010 .

[133]  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. , 1997, JAMA.

[134]  R. Balogun,et al.  Open randomized phase II trial of an extracorporeal endotoxin adsorber in suspected gram-negative sepsis. , 2005, Critical care medicine.

[135]  R. Hotchkiss,et al.  Apoptosis and caspases regulate death and inflammation in sepsis , 2006, Nature Reviews Immunology.

[136]  K. Tracey,et al.  Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin , 2000, Nature.

[137]  William F Weitzel,et al.  Initial clinical results of the bioartificial kidney containing human cells in ICU patients with acute renal failure. , 2004, Kidney international.

[138]  R. Hotchkiss,et al.  Dose-Dependent Effect of Anti-CTLA-4 on Survival in Sepsis , 2011, Shock.

[139]  S. Opal,et al.  High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: Efficacy and safety* , 2006, Critical care medicine.

[140]  S. Gibot Clinical review: Role of triggering receptor expressed on myeloid cells-1 during sepsis , 2005, Critical care.

[141]  P. Schmucker,et al.  Increased mortality in long-term intensive care patients with active cytomegalovirus infection* , 2008, Critical care medicine.

[142]  H. Harn,et al.  Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats. , 2006, Life sciences.

[143]  Rudi Beyaert,et al.  Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients* , 2006, Critical care medicine.

[144]  V. Novack,et al.  Prior Statin Therapy Is Associated With a Decreased Rate of Severe Sepsis , 2004, Circulation.

[145]  V. Novack,et al.  The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial , 2009, Intensive Care Medicine.

[146]  P. Elsbach,et al.  The bactericidal/permeability‐increasing protein (BPI) in antibacterial host defense , 1998, Journal of leukocyte biology.

[147]  M. Boermeester,et al.  Bovine Intestinal Alkaline Phosphatase Attenuates the Inflammatory Response in Secondary Peritonitis in Mice , 2005, Infection and Immunity.

[148]  S. Akira,et al.  Toll-like receptors in innate immunity. , 2004, International immunology.

[149]  M. Hall,et al.  Immunoparalysis and adverse outcomes from critical illness. , 2008, Pediatric clinics of North America.

[150]  A. Higure,et al.  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 , 2009, Critical care medicine.

[151]  T. van der Poll,et al.  Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats , 2006, Journal of thrombosis and haemostasis : JTH.

[152]  Fumiyasu Hirai,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* , 2006, Critical care medicine.

[153]  N. Chainani-Wu Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). , 2003, Journal of alternative and complementary medicine.

[154]  T. Standiford,et al.  Neutralization of IL-10 increases lethality in endotoxemia. Cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor. , 1995, Journal of immunology.

[155]  G. Freeman,et al.  PD-1 and its ligands in tolerance and immunity. , 2008, Annual review of immunology.

[156]  Jon Cohen,et al.  A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis* , 2010, Critical care medicine.

[157]  T. Standiford,et al.  Alveolar Macrophage Deactivation in Murine Septic Peritonitis: Role of Interleukin 10 , 2001, Infection and Immunity.

[158]  M. Singer,et al.  Animal models of sepsis: Why does preclinical efficacy fail to translate to the clinical setting? , 2009, Critical care medicine.

[159]  Rei-Cheng Yang,et al.  Pretreatment of curcumin attenuates coagulopathy and renal injury in LPS-induced endotoxemia , 2007, Journal of endotoxin research.

[160]  V. Keshamouni,et al.  Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-{gamma}. , 2008, Blood.

[161]  A. Ruiz-Bravo,et al.  The anti-inflammatory activity of telithromycin in a mouse model of septic shock. , 2007, International journal of antimicrobial agents.

[162]  C. Szabó,et al.  Inhibition of Poly (ADP-ribose) Polymerase Attenuates Acute Lung Injury in an Ovine Model of Sepsis , 2004, Shock.

[163]  G. Nieman,et al.  CHEMICALLY MODIFIED TETRACYCLINE PREVENTS THE DEVELOPMENT OF SEPTIC SHOCK AND ACUTE RESPIRATORY DISTRESS SYNDROME IN A CLINICALLY APPLICABLE PORCINE MODEL , 2005, Shock.

[164]  H. Volk,et al.  Clinical aspects: from systemic inflammation to 'immunoparalysis'. , 2000, Chemical immunology.

[165]  C. Coopersmith,et al.  The sepsis seesaw: tilting toward immunosuppression , 2009, Nature Medicine.

[166]  S. Opal,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. , 2003, Critical care medicine.

[167]  J. Vincent,et al.  Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis* , 2003, Critical care medicine.

[168]  J. Cunha-Melo,et al.  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 , 2010, BMC infectious diseases.

[169]  Steven B. Johnson,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* , 2004, Critical care medicine.

[170]  J. Vincent,et al.  Phase II multicenter clinical study of the platelet‐activating factor receptor antagonist BB‐882 in the treatment of sepsis , 2000, Critical care medicine.

[171]  Yu-min Li,et al.  Treatment of patients with severe sepsis using ulinastatin and thymosin alpha1: a prospective, randomized, controlled pilot study. , 2009, Chinese medical journal.

[172]  K. Tracey,et al.  Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis , 2004, Nature Medicine.

[173]  J. Cohen,et al.  Endotoxin removal devices for the treatment of sepsis and septic shock. , 2011, The Lancet. Infectious diseases.

[174]  B. Bošnjak,et al.  Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice. , 2006, European journal of pharmacology.

[175]  Thomas R. Riley,et al.  A Randomized Double-blind Placebo-controlled Trial , 2004 .

[176]  C. Weber,et al.  Statin Treatment After Onset of Sepsis in a Murine Model Improves Survival , 2005, Circulation.

[177]  S. Opal,et al.  Molecular biology of inflammation and sepsis: A primer* , 2009, Critical care medicine.

[178]  L. Koenderman,et al.  C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia , 2010, Critical care medicine.

[179]  K. Tracey,et al.  Suppression of HMGB1 release by stearoyl lysophosphatidylcholine:an additional mechanism for its therapeutic effects in experimental sepsis. , 2005, Journal of lipid research.

[180]  L. Doughty,et al.  SOCS-1 is a central mediator of steroid-increased thymocyte apoptosis and decreased survival following sepsis , 2007, Apoptosis.