Cytokine modulation in sepsis and septic shock

Sepsis and septic shock are a major cause of morbidity and mortality in patients admitted to the intensive care unit. Since the introduction of antibiotic therapy, the mortality associated with sepsis has remained within the 30 – 50% range. Sepsis constitutes the systemic response to infection. This response encompasses both pro-inflammatory and anti-inflammatory phases that are marked by the sequential generation of pro- and anti-inflammatory cytokines. Among the most important pro-inflammatory cytokines are TNF-α and IL-1β. The pro-inflammatory effects of such cytokines are inhibited by soluble receptors/receptor antagonists and anti-inflammatory cytokines including IL-10 and transforming growth factor-β. Modulation of the activity of both pro- and anti-inflammatory cytokines to improve outcome in patients with sepsis has been subject of multiple clinical studies. This review will examine clinical trials evaluating several strategies for blocking or attenuating TNF-α and IL-1β activity. This review will also survey the current state of experimental therapies involving IL-10, transforming growth factor-β, granulocyte colony-stimulating factor and IFN-γ. Finally, newer developments related to less known cytokines such as macrophage migration inhibitory factor and high mobility group 1 protein will be evaluated.

[1]  K. Tracey,et al.  Cytokine appearance in human endotoxemia and primate bacteremia. , 1988, Surgery, gynecology & obstetrics.

[2]  K. Asadullah,et al.  Improvement of Monocyte Function — A New Therapeutic Approach? , 1994 .

[3]  R. Bucala,et al.  Protection from septic shock by neutralization of macrophage migration inhibitory factor , 2000, Nature Medicine.

[4]  R. de Waal Malefyt,et al.  Functional characterization of human IL-10. , 1992, International archives of allergy and immunology.

[5]  M. Feldmann,et al.  Induction of the interleukin 1 receptor antagonist protein by transforming growth factor‐β , 1991, European journal of immunology.

[6]  J. Parrillo,et al.  TRANFORMING GROWTH FACTOR (TGF)-beta INHIBITS HUMAN SEPTIC SERUM-INDUCED DEPRESSION OF CARDIAC MYOCYTE CONTRACTILITY , 1999 .

[7]  R. Strieter,et al.  Expression and Contribution of Endogenous IL-13 in an Experimental Model of Sepsis1 , 2000, The Journal of Immunology.

[8]  C. Nathan,et al.  Modulation of Macrophage Function by Transforming Growth Factor β, Interleukin‐4, and Interleukin‐10 a , 1993, Annals of the New York Academy of Sciences.

[9]  K. Mealy,et al.  Tumor necrosis factor induces adult respiratory distress syndrome in rats. , 1989, Archives of surgery.

[10]  P. Brandtzaeg,et al.  Brief Definitive Report the Complex Pattern of Cytokines in Serum from Patients with Meningococcal Septic Shock Association between Interleukin 6, Interleukin 1, and Fatal Outcome , 2022 .

[11]  J. Parrillo.  Management of septic shock: present and future. , 1991, Annals of internal medicine.

[12]  P. Ghezzi,et al.  Granulocyte colony-stimulating factor and antibiotics in the prophylaxis of a murine model of polymicrobial peritonitis and sepsis. , 1998, Journal of Infectious Diseases.

[13]  Robert C. Thompson,et al.  Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor , 1990, Nature.

[14]  C. Lowenstein,et al.  Arrest of endotoxin-induced hypotension by transforming growth factor beta1. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[15]  T. van der Poll,et al.  Endogenous IL-10 protects mice from death during septic peritonitis. , 1995, Journal of immunology.

[16]  M. Howard,et al.  Interleukin 10 protects mice from lethal endotoxemia , 1993, The Journal of experimental medicine.

[17]  C. Natanson,et al.  Tumor necrosis factor challenges in canines: patterns of cardiovascular dysfunction. , 1992, The American journal of physiology.

[18]  H. Langstein,et al.  Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha. , 1992, Journal of immunology.

[19]  C. Natanson,et al.  Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock , 1989, The Journal of experimental medicine.

[20]  W. Haefeli,et al.  Evidence for activation of the sympathetic nervous system by recombinant human interleukin-1 beta in humans. , 1993, Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy.

[21]  C. Homon,et al.  Synergistic and overlapping activities of tumor necrosis factor-alpha and IL-1. , 1988, Journal of immunology.

[22]  J. Vincent,et al.  Blood interleukin 10 levels parallel the severity of septic shock. , 1997, Journal of critical care.

[23]  M. Tohyama,et al.  Interleukin-10 gene transfer improves the survival rate of mice inoculated with Escherichia coli , 2000, Critical care medicine.

[24]  B. Zingarelli,et al.  Transforming growth factor beta 1 alters rat peritoneal macrophage mediator production and improves survival during endotoxic shock. , 1996, European cytokine network.

[25]  J. Vincent,et al.  Interleukin-6 administration has no acute hemodynamic or hematologic effect in the dog. , 1991, Cytokine.

[26]  K. Laczika,et al.  Prognostic Value of MIP-1α, TGF-β2, sELAM-1, and sVCAM-1 in Patients with Gram-Positive Sepsis , 1998 .

[27]  K. Tracey,et al.  HMG-1 as a late mediator of endotoxin lethality in mice. , 1999, Science.

[28]  J. Oyama,et al.  Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardial dysfunction in dogs in vivo. , 1998, The Journal of clinical investigation.

[29]  C. Dinarello,et al.  Biology of interleukin 1 , 1988, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  S. Nasraway,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. , 1995, JAMA.

[31]  C. Natanson,et al.  Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. , 1997, Critical care medicine.

[32]  S. Wahl.  Transforming growth factor beta (TGF-β) in inflammation: A cause and a cure , 1992, Journal of Clinical Immunology.

[33]  J. Parrillo,et al.  Myocardial dysfunction in septic shock: Part II. Role of cytokines and nitric oxide. , 2001, Journal of cardiothoracic and vascular anesthesia.

[34]  U. Boehm,et al.  Cellular responses to interferon-gamma. , 1997, Annual review of immunology.

[35]  C. Dinarello,et al.  Staphylococcus epidermidis induces complement activation, tumor necrosis factor and interleukin-1, a shock-like state and tissue injury in rabbits without endotoxemia. Comparison to Escherichia coli. , 1991, The Journal of clinical investigation.

[36]  E. Lingaas,et al.  Granulocyte colony-stimulating factor improves myelopoiesis and host defense in fulminant intra-abdominal sepsis in rats. , 1995, Shock.

[37]  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.

[38]  O. Kemmotsu,et al.  Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock. , 1998, Critical care medicine.

[39]  R. Ulevitch,et al.  Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. , 1988, The Journal of clinical investigation.

[40]  A. Billiau,et al.  Interferon gamma, a mediator of lethal lipopolysaccharide-induced Shwartzman-like shock reactions in mice , 1990, The Journal of experimental medicine.

[41]  D. Leroy,et al.  IFN-gamma involvement in the severity of gram-negative infections in mice. , 1993, Journal of immunology.

[42]  S. Opal,et al.  Human neutrophil bactericidal/permeability‐increasing protein reduces mortality rate from endotoxin challenge: A placebo‐controlled study , 1994, Critical care medicine.

[43]  K. Matsushima,et al.  Anti-interleukin-8 monoclonal antibody reduces free radical production and improves hemodynamics and survival rate in endotoxic shock in rabbits. , 1997, Surgery.

[44]  T. van der Poll,et al.  Activation of coagulation after administration of tumor necrosis factor to normal subjects. , 1990, The New England journal of medicine.

[45]  A. Billiau,et al.  Anti‐interferon‐γ antibody protects mice against the generalized Shwartzman reaction , 1987 .

[46]  S. Nasraway,et al.  Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock , 1998, The Lancet.

[47]  J. Dhainaut,et al.  CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group. , 1995, Critical care medicine.

[48]  R. Bone,et al.  Sir Isaac Newton, sepsis, SIRS, and CARS. , 1996, Critical care medicine.

[49]  K. Asadullah,et al.  Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. , 1997, Nature medicine.

[50]  E. Losi,et al.  Role of gamma interferon in a neonatal mouse model of group B streptococcal disease , 1996, Infection and immunity.

[51]  J. Dhainaut,et al.  Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. , 1999, JAMA.

[52]  J. Vincent,et al.  Has the mortality of septic shock changed with time. , 1998, Critical care medicine.

[53]  D. Pittet,et al.  The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. , 1995, JAMA.

[54]  U. Grohmann,et al.  Dual effect of IL-4 on resistance to systemic gram-negative infection and production of TNF-alpha. , 2000, Cytokine.

[55]  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.

[56]  J. Vincent,et al.  Influence of an anti‐tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis , 1993, Critical care medicine.

[57]  J Ean,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis. , 2001, The New England journal of medicine.

[58]  T. Fabian,et al.  Granulocyte colony-stimulating factor improves host defense to resuscitated shock and polymicrobial sepsis without provoking generalized neutrophil-mediated damage. , 1998, The Journal of trauma.

[59]  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.

[60]  A. Satoskar,et al.  Targeted Disruption of Migration Inhibitory Factor Gene Reveals Its Critical Role in Sepsis , 1999, The Journal of experimental medicine.

[61]  S. Garg,et al.  Exogenous interleukin-10 fails to decrease the mortality or morbidity of sepsis. , 1998, Critical care medicine.

[62]  N. Kemeny,et al.  A phase II trial of recombinant tumor necrosis factor in patients with advanced colorectal carcinoma , 1990, Cancer.

[63]  C A Smith,et al.  Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. , 1993, Journal of immunology.

[64]  T. Shimazu,et al.  Changes in granulocyte colony-stimulating factor concentration in patients with trauma and sepsis. , 1996, The Journal of trauma.

[65]  D. Lev,et al.  Systemic leakage and side effects of tumor necrosis factor alpha administered via isolated limb perfusion can be manipulated by flow rate adjustment. , 1995, Archives of surgery.

[66]  D. Remick,et al.  Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. , 1992, The Journal of clinical investigation.

[67]  J Haberstroh,et al.  G-CSF during Escherichia coli versus Staphylococcus aureus pneumonia in rats has fundamentally different and opposite effects. , 1999, American journal of respiratory and critical care medicine.

[68]  U. Losert,et al.  Gene transfer with IL‐4 and IL‐13 improves survival in lethal endotoxemia in the mouse and ameliorates peritoneal macrophages immune competence , 1998, European journal of immunology.

[69]  S. Streat,et al.  Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic responses in patients with severe sepsis--a randomized, clinical trial. , 1998, Critical care medicine.

[70]  A. Chang,et al.  Lethal Staphylococcus aureus-induced shock in primates: prevention of death with anti-TNF antibody. , 1992, The Journal of trauma.

[71]  B. Beutler,et al.  The tumor necrosis factor ligand and receptor families. , 1996, The New England journal of medicine.

[72]  C. Natanson,et al.  Controlled trials of rG-CSF and CD11b-directed MAb during hyperoxia and E. coli pneumonia in rats. , 1996, Journal of applied physiology.

[73]  J. Haberstroh,et al.  EFFECT OF RECOMBINANT HUMAN GRANULOCYTE COLONY‐ STIMULATING FACTOR ON HEMODYNAMIC AND CYTOKINE RESPONSE IN A PORCINE MODEL OF PSEUDOMONAS SEPSIS , 1995, Shock.

[74]  E. Hemminki,et al.  The effect of antibiotics on mortality from infectious diseases in Sweden and Finland. , 1976, American journal of public health.

[75]  W. Knaus,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. , 1992, Chest.

[76]  Anand Kumar,et al.  Experimental and emerging therapies for sepsis and septic shock , 2001, Expert opinion on investigational drugs.

[77]  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.

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

[79]  J. Vincent,et al.  Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study , 2001, Critical care medicine.

[80]  S. Zanotti-Cavazzoni,et al.  Primum [non nocere] lavate manus. , 2001, Critical care medicine.

[81]  R. Bone,et al.  Plasma Cytokine and Endotoxin Levels Correlate with Survival in Patients with the Sepsis Syndrome , 1993, Annals of Internal Medicine.

[82]  M. Sporn,et al.  Role of nitric oxide in antagonistic effects of transforming growth factor-beta and interleukin-1 beta on the beating rate of cultured cardiac myocytes. , 1992, Molecular endocrinology.

[83]  B. Beutler,et al.  Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1 , 1986, The Journal of experimental medicine.

[84]  T. Ikejima,et al.  Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. , 1988, The Journal of clinical investigation.

[85]  M. Colonna,et al.  TREM-1 amplifies inflammation and is a crucial mediator of septic shock , 2001, Nature.

[86]  A. Geist,et al.  EFFECT OF DELAYED TREATMENT WITH RECOMBINANT HUMAN GRANULOCYTE COLONY‐STIMULATING FACTOR ON SURVIVAL AND PLASMA CYTOKINE LEVELS IN A NON‐NEUTROPENIC PORCINE MODEL OF PSEUDOMONAS AERUGINOSA SEPSIS , 1998, Shock.

[87]  John F. Cade,et al.  Plasma granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in critical illness including sepsis and septic shock: Relation to disease severity, multiple organ dysfunction, and mortality , 2000, Critical care medicine.

[88]  J. Schellekens,et al.  Prognostic Values of Tumor Necrosis Factor/Cachectin, Interleukin-l, Interferon-α, and Interferon-γ in the Serum of Patients with Septic Shock , 1990 .

[89]  J. Carlet,et al.  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. , 1996, Critical care medicine.

[90]  Tetsuya Matsumoto,et al.  Effect of Interleukin-10 on Gut-Derived Sepsis Caused by Pseudomonas aeruginosa in Mice , 1998, Antimicrobial Agents and Chemotherapy.

[91]  R. Allen.  Systemic Leakage and Side Effects of Tumor Necrosis Factor α Administered via Isolated Limb Perfusion Can Be Manipulated by Flow Rate Adjustment , 1996 .

[92]  S. Opal,et al.  Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. , 1996, The New England journal of medicine.

[93]  I. Chaudry,et al.  IL-10 mediation of activation-induced TH1 cell apoptosis and lymphoid dysfunction in polymicrobial sepsis. , 2001, Cytokine.

[94]  A. Cerami,et al.  Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings. , 1988, Surgery.

[95]  J. Renauld,et al.  IL-9 Protects Mice from Gram-Negative Bacterial Shock: Suppression of TNF-α, IL-12, and IFN-γ, and Induction of IL-10 , 2000, The Journal of Immunology.

[96]  T. Mosmann,et al.  Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones , 1989, The Journal of experimental medicine.

[97]  F. Heinzel.  The role of IFN-gamma in the pathology of experimental endotoxemia. , 1990, Journal of immunology.

[98]  T. Yamashita,et al.  Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome. , 1999, Critical care medicine.

[99]  H. Bruining,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. , 1997, JAMA.

[100]  C. Natanson,et al.  TNF but not IL-1 in dogs causes lethal lung injury and multiple organ dysfunction similar to human sepsis. , 1991, Journal of applied physiology.

[101]  G. Koch,et al.  Efficacy and Safety of Monoclonal Antibody to Human Tumor Necrosis Factor α in Patients With Sepsis Syndrome: A Randomized, Controlled, Double-blind, Multicenter Clinical Trial , 1995 .

[102]  E. Girardin,et al.  Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. , 1988, The New England journal of medicine.

[103]  B. Beutler,et al.  Cachectin and tumour necrosis factor as two sides of the same biological coin , 1986, Nature.

[104]  S. Opal,et al.  Initial evaluation of human recombinant interleukin‐1 receptor antagonist in the treatment of sepsis syndrome: A randomized, open‐label, placebocontrolled multicenter trial , 1994, Critical care medicine.

[105]  Occurrence of serious bacterial infections since introduction of antibacterial agents. , 1959, Journal of the American Medical Association.

[106]  T. van der Poll,et al.  Attenuation of proinflammatory response by recombinant human IL-10 in human endotoxemia: effect of timing of recombinant human IL-10 administration. , 1997, Journal of immunology.

[107]  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.

[108]  R. Wunderink,et al.  Filgrastim in patients with pneumonia and severe sepsis or septic shock. , 2001, Chest.

[109]  B. Beutler,et al.  Cachectin: more than a tumor necrosis factor. , 1987, The New England journal of medicine.

[110]  J. Nesland,et al.  Granulocyte colony-stimulating factor improves survival rate and reduces concentrations of bacteria, endotoxin, tumor necrosis factor, and endothelin-1 in fulminant intra-abdominal sepsis in rats. , 1996, Critical care medicine.

[111]  W. Fiers,et al.  Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. , 1986, The American journal of pathology.

[112]  I. Chaudry,et al.  IL-4-induced activation of the Stat6 pathway contributes to the suppression of cell-mediated immunity and death in sepsis. , 2000, Surgery.

[113]  Jonathan D. Cohen,et al.  Role of Interferon-γ in Experimental Gram-Negative Sepsis , 1992 .

[114]  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.

[115]  H. Bruining,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 , 1997 .

[116]  J. Kremer,et al.  Transforming Growth Factor-β1 Inhibits Synthesis of Cytokines in Endotoxin-Stimulated Human Whole Blood , 1996 .

[117]  H. Büller,et al.  Effects on leukocytes after injection of tumor necrosis factor into healthy humans , 1992 .

[118]  John I. Gallin,et al.  A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. , 1991, The New England journal of medicine.

[119]  OLAND,et al.  TREATMENT OF SEPTIC SHOCK WITH THE TUMOR NECROSIS FACTOR RECEPTOR : Fc FUSION PROTEIN C , 2000 .

[120]  Kevin J. Tracey,et al.  Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia , 1987, Nature.

[121]  J. Marshall,et al.  Clinical trials of mediator-directed therapy in sepsis: what have we learned? , 2000, Intensive Care Medicine.

[122]  S. Willatts,et al.  Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study. , 1996, Critical care medicine.

[123]  C. Natanson,et al.  rG-CSF reduces endotoxemia and improves survival during E. coli pneumonia. , 1997, Journal of applied physiology.

[124]  Robert C. Thompson,et al.  Interleukin-1 receptor antagonist reduces mortality from endotoxin shock , 1990, Nature.

[125]  T. Standiford,et al.  ANTI‐INTERLEUKIN-12 THERAPY PROTECTS MICE IN LETHAL ENDOTOXEMIA BUT IMPAIRS BACTERIAL CLEARANCE IN MURINE ESCHERICHIA COLI PERITONEAL SEPSIS , 1997, Shock.

[126]  B. Beutler,et al.  Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. , 1986, Science.

[127]  A. Billiau,et al.  Cytokines and their interactions with other inflammatory mediators in the pathogenesis of sepsis and septic shock , 1991, European journal of clinical investigation.

[128]  A. Cerami,et al.  Detection of circulating tumor necrosis factor after endotoxin administration. , 1988, The New England journal of medicine.

[129]  M. Sporn,et al.  Role of transforming growth factor-beta in maintenance of function of cultured neonatal cardiac myocytes. Autocrine action and reversal of damaging effects of interleukin-1. , 1992, The Journal of clinical investigation.

[130]  P. Cannon,et al.  The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta. , 1995, The Journal of clinical investigation.

[131]  T. van der Poll,et al.  Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. , 1991, The American journal of physiology.