Journal of Surgical Research
Volume 152, Issue 1 , Pages 46-53 , March 2009

NF-κB and P38 MAPK Inhibition Improve Survival in Endotoxin Shock and in a Cecal Ligation and Puncture Model of Sepsis in Combination With Antibiotic Therapy

  • Adrian W. O'Sullivan, M.B.
  • ,
  • Jiang Huai Wang, Ph.D.
  • ,
  • Henry P. Redmond, M.Ch., F.R.C.S.I.

      Affiliations

    • Corresponding Author InformationTo whom correspondence and reprint requests should be addressed at Department of Academic Surgery, National University of Ireland (NUI) and University College Hospital, Cork, Ireland

Received 23 October 2007

References 

  1. Cerra FB. Infection, the inflammatory response, and multiple organ dysfunction. Norwalk, CT: Appleton and Lange; 1995;
  2. Beal AL, Cerra FB. Multiple organ failure syndrome in the 1990s. J Am Med Assoc. 1994;271:226
  3. Carrico CJ, Meakins JL, Mosh JC, et al. Multiple organ failure syndrome. Arch Surg. 1986;271:196
  4. Zukerman SH, Evans GF, Guthrie L. Transcriptional and post transcriptional mechanisms involved in the differential expression of LPS-induced IL-1 and TNF mRNA. Immunology. 1991;73:460
  5. Song GY, Chung CS, Schwacha MG, et al. Splenic immune suppression in sepsis: A role for IL-10 induced changes in P38 MAPK signaling. J Surg Res. 1999;83:36
  6. Mock CN, Jurkovich GJ, Dries DJ, et al. Clinical significance of antibiotic endotoxin-releasing properties in trauma patients. Arch Surg. 1995;130:1234
  7. McMasters KM, Peyton JC, Hadjiminas DJ, et al. Endotoxin and tumor necrosis factor do not cause mortality from caecal ligation and puncture. Cytokine. 1994;6:530
  8. Hurley J. Antibiotic-induced release of endotoxin (A therapeutic paradox). Drug Safety. 1995;12:183
  9. Chen FV, Castranova X, Shi LM. New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem. 1999;45:7
  10. Tomlinson A, Willoughby D. Inducible enzymes in inflammation: Advances, interactions and conflict. In: Basal, Switzerland: Birkhauser; 1999;p. 187–207
  11. Liu SF, Malik AB. NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol. 2006;290:L622
  12. Lin L, Ghosh S. A glycine-rich region in NFκB p105 functions as a processing signal for the generation of the p50 subunit. Mol Cel Biol. 1996;16:2248
  13. Browder W, Ha T, Chuanfu L, et al. Early activation of pulmonary nuclear factor κB and nuclear factor interleukin-6 polymicrobial sepsis. J Trauma. 1999;46:590
  14. Williams DL, Ha T, Li C, et al. Early activation of hepatic NFκB and NF-IL-6 in polymicrobial sepsis correlates with bacteremia, cytokine expression, and mortality. Ann Surg. 1999;230:95
  15. Arnalich F, Garcia-Palomero E, Lopez J, et al. Predictive value of nuclear factor κB activity and plasma cytokine levels in patients with sepsis. Infect Immun. 2000;6894:1945
  16. Pande V, Ramos MJ. NF-κB in human disease: Current inhibitors and prospects for de novo structure based design of inhibitors. Curr Med Chem. 2005;12:357
  17. Sha WC, Liou HC, Tuomanen EI, et al. Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses. Cell. 1995;80:321
  18. Fujihara SM, Cleaveland JS, Grosmaire LS, et al. A D-amino acid peptide inhibitor of NF-κB nuclear localization is efficacious in models of inflammatory disease. J Immunol. 2000;165:1004
  19. Haddad JJ. Nuclear factor (NF)-κB blockade attenuates but does not abrogate LPS-mediated interleukin (IL)-1 β biosynthesis in alveolar epithelial cells. Biochem Biophys Res Commun. 2002;293:252
  20. D'Acquisto F, Ialenti A, Ianaro A, et al. Local administration of transcription factor decoy oligonucleotides to nuclear factor-κB prevents carrageenin-induced. Gene Ther. 2000;7920:1731
  21. Yan Liu X, Robinson D, Veach RA, et al. Peptide-directed suppression of a proinflammatory cytokine response. J Biol Chem. 2000;275:16774
  22. Shanley TP, Warner RL, Ward PA. The role of cytokines and adhesion molecules in the development of inflammatory injury. Mol Med Today. 1995;1:40
  23. Williams DL, Ha T, Li C, et al. Inhibiting early activation of tissue nuclear factor-κB and nuclear factor interleukin 6 with (1→3)-β-D-glucan increases long-term survival in polymicrobial sepsis. Surgery. 1999;126:54
  24. Zingarelli B, Sheehan M, Hake PW, et al. Peroxisome proliferator activator receptor-γ ligands, 15-deoxy-δ(12,14)-prostaglandin J2, and ciglitazone, reduce systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways. J Immunol. 2003;171:6827
  25. Gil J, Garcia MA, Gomez-Puertas P, et al. TRAF family proteins link PKR with NF-κB activation. Mol Cell Biol. 2004;24:4502
  26. Kraatz J, Clair L, Rodriguez JL, et al. Macrophage TNF secretion in endotoxin tolerance: Role of SAPK, p38, and MAPK. J Surg Res. 1999;83:158
  27. Shames BD, Selzman CH, Pulido EJ, et al. LPS-Induced NF-κB Activation and TNF-L Release in human monocytes are protein tyrosine kinase dependent and protein kinase C independent. J Surg Res. 1999;83:69
  28. Obata T, Brown GE, Yaffe MB. MAP kinase pathways activated by stress: The p38 MAPK pathway. Crit Care Med. 2000;28:67
  29. Song GY, Chung CS, Chaudry IH, et al. MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis. Am J Cell Physiol. 2001;281:C662
  30. Branger J, van Den Blink B, Weijer S, et al. Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol. 2002;168:4070
  31. Peng T, Lu X, Lei M, et al. Inhibition of p38 MAPK decreases myocardial TNF-α expression and improves myocardial function and survival in endotoxemia. Cardiovasc Res. 2003;59:893
  32. Lee JC, Laydon JT, Laydon PC, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372:739
  33. Lu HT, Yang DD, Wysk M, et al. Defective IL-12 production in mitogen activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 1999;18:1845
  34. Zhang C, Baumgarter RA, Yamada K, et al. Mitogen activated protein (MAP) kinase regulates production of tumor necrosis factor-a and release of arachidonic acid in mast cells: Indications of communications between p38 and p42 MAP kinases. J Biol Chem. 1997;272:13397
  35. Smith SJ, Fenwick PS, Nicholson AG, et al. Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol. 2006;149:393
  36. van den Blink B, Juffermans NP, ten Hove T, et al. p38 Mitogen-activated protein kinase inhibition increases cytokine release by macrophages in vitro and during infection in vivo. J Immunol. 2001;166:582
  37. Schlaak JF, Barreiros AP, Pettersson S, et al. Antisense phosphorothioate oligonucleotides to the p65 subunit of NF-κB abrogate fulminant septic shock induced by S (Typhimurium). Scand J Immunol. 2001;54940:396
  38. Gjertsson I, Hultgren OH, Collins LV, et al. Impact of transcription factors AP-1 and NF-κB on the outcome of experimental Staphylococcus aureus arthritis and sepsis. Microbes Infect. 2001;3:527
  39. Song GY, Chung CS, D Jarrar, et al. Evolution of an immune suppression macrophage phenotype as a product of P38 MAPK activation in polymicrobial sepsis. Shock. 2001;15:42
  40. Joshi AR, Chung CS, Song GY, et al. NF-κB activation has tissue-specific effects on immune cell apoptosis during polymicrobial sepsis. Shock. 2002;18:380
  41. Remick DG, Bolgos GB, Siddiqui J, et al. Six at six: Interleukin-6 measured 6 hours after the initiation of sepsis predicts mortality over 3 days. Shock. 2002;17:463
  42. Holzheimer R. The significance of endotoxin release in experimentation and clinical sepsis in surgical patients—evidence for antibiotic-induced endotoxin release?. Infection. 1998;26:77
  43. Norimatsu M, Morrison DC. Correlation of antibiotic-induced endotoxin release and cytokine production in Escherichia coli-inoculated mouse whole blood ex vivo. J Infect Dis. 1998;177:1302
  44. DC Morrison BS. Evidence for antibiotic-mediated endotoxin release as a contributing factor to lethality in experimental gram-negative sepsis. Scand J Infect Dis. 1996;101(Suppl):3
  45. Horn DL, Opal SM, Lomastro E. Antibiotics, cytokines, and endotoxin: A complex and evolving relationship in gram-negative sepsis. Scand J Infect Dis. 1996;101(Suppl):9
  46. Newcomb D, Bolgos G, Green L, et al. Antibiotic treatment influences outcome in murine sepsis: Mediators of increased morbidity. Shock. 1998;10:110
  47. Mercer-Jones MA, Hadjiminas DJ, Heinzelmann M, et al. Continuous antibiotic treatment for experimental abdominal sepsis: Effects on organ inflammatory cytokine expression and neutrophil sequestration. Br J Surg. 1998;85:385
  48. Vianna RC, Gomes RN, Bozza FA, et al. Antibiotic treatment in a murine model of sepsis: Impact on cytokines and endotoxin release. Shock. 2004;21:115
  49. Turnbull IR, Javadi P, Buchman TG, et al. Antibiotics improve survival in sepsis independent of injury severity but do not change mortality in mice with markedly elevated interleukin 6 levels. Shock. 2004;21:121

PII: S0022-4804(08)00320-X

doi: 10.1016/j.jss.2008.04.030

Journal of Surgical Research
Volume 152, Issue 1 , Pages 46-53 , March 2009