Skip to main content
SpringerLink
Log in

LPS pretreatment ameliorates multiple organ injuries and improves survival in a murine model of polymicrobial sepsis

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

The endotoxin tolerance phenotype is characterized with decreased inflammation and increased phagocytosis. We hypothesized that endotoxin tolerance would provide protective effects on experimental sepsis with multiple organ injuries induced by cecal ligation and puncture (CLP).

Methods

Endotoxin tolerance was induced in male Sprague–Dawley rats with daily intraperitoneal injection of either 0.6 mg/kg of lipopolysaccharide (LPS) or vehicle for four consecutive days before subsequent CLP. Biochemical parameters, histological changes, inflammatory cytokine production, and lung tissue nuclear factor-κB (NF-κB) activation were assessed post-CLP. In a separate experiment, survival rate was monitored for 7 days after CLP.

Results

In vehicle-treated animals, CLP caused multiple organ injuries confirmed by the biochemical variables and histological examination. This was accompanied by an early activation of NF-κB in the lung and a substantial increase in plasma levels of tumor necrosis factor-α, interleukin-6, and interleukin-10. In contrast, pretreatment with LPS not only alleviated the development of multiple organ injuries after CLP, but also decreased sepsis-induced activation of pulmonary NF-κB and reduced plasma cytokines production. In addition, LPS pretreatment improved the survival in rats subjected to CLP.

Conclusions

The beneficial effects of endotoxin tolerance indicate the potential of immunomodulatory strategies in the management of severe sepsis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Eng J Med. 2003;348:1546–54.

    Article  Google Scholar 

  2. Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. BMJ. 2007;335:879–83.

    Article  PubMed  CAS  Google Scholar 

  3. Wheeler AP. Recent developments in the diagnosis and management of severe sepsis. Chest. 2007;132:1967–76.

    Article  PubMed  Google Scholar 

  4. Vincent JL, Abraham E. The last 100 years in sepsis. Am J Resp Crit Care Med. 2006;173:256–63.

    Article  PubMed  Google Scholar 

  5. Deans KJ, Haley M, Natanson C, Eichacker PQ, Minneci PC. Novel therapies for sepsis: a review. J Trauma. 2005;58:867–74.

    Article  PubMed  Google Scholar 

  6. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63–78.

    Article  PubMed  CAS  Google Scholar 

  7. Remick DG. Pathophysiology of sepsis. Am J Pathol. 2007;170:1435–44.

    Article  PubMed  CAS  Google Scholar 

  8. Nduka OO, Parrillo JE. The pathophysiology of septic shock. Crit Care Clin. 2009;25:677–702.

    Article  PubMed  CAS  Google Scholar 

  9. Cohen J. Non-antibiotic strategies for sepsis. Clin Microbiol Infect. 2009;15:302–7.

    Article  PubMed  CAS  Google Scholar 

  10. Schefold JC, Hasper D, Volk HD, Reinke P. Sepsis: time has come to focus on the later stages. Med Hypotheses. 2008;71:203–8.

    Article  PubMed  Google Scholar 

  11. West MA, Heagy W. Endotoxin tolerance: a review. Crit Care Med. 2002;30(1 supp):S64–73.

    Article  CAS  Google Scholar 

  12. Fan H, Cook JA. Molecular mechanisms of endotoxin tolerance. J Endotoxin Res. 2004;10:71–84.

    Article  PubMed  CAS  Google Scholar 

  13. Beeson PB. Development of tolerance to typhoid bacterial pyrogen and its abolition by reticuloendothelial blockade. Proc Soc Exp Biol Med. 1946;61:248–50.

    PubMed  CAS  Google Scholar 

  14. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30:475–87.

    Article  PubMed  CAS  Google Scholar 

  15. Rayhane N, Fitting C, Lortholary O, Dromer F, Cavaillon JM. Administration of endotoxin associated with lipopolysaccharide tolerance protects mice against fungal infection. Infect Immun. 2000;68:3748–53.

    Article  PubMed  CAS  Google Scholar 

  16. Lehner MD, Ittner J, Bundschuh DS, van Rooijen N, Wendel A, Hartung T. Improved innate immunity of endotoxin-tolerant mice increases resistance to Salmonella enterica serovar typhimurium infection despite attenuated cytokine response. Infect Immun. 2001;69:463–71.

    Article  PubMed  CAS  Google Scholar 

  17. Wheeler DS, Lahni PM, Denenberg AG, Poynter SE, Wong HR, Cook JA, et al. Induction of endotoxin tolerance enhances bacterial clearance and survival in murine polymicrobial sepsis. Shock. 2008;30:267–73.

    PubMed  CAS  Google Scholar 

  18. Poli-de-Figueiredo LF, Garrido AG, Nakagawa N, Sannomiya P. Experimental models of sepsis and their clinical relevance. Shock. 2008;30(Suppl 1):53–9.

    Article  PubMed  CAS  Google Scholar 

  19. Sheehan M, Wong HR, Hake PW, Zingarelli B. Parthenolide improves systemic hemodynamics and decreases tissue leukosequestration in rats with polymicrobial sepsis. Crit Care Med. 2003;31:2263–70.

    Article  PubMed  CAS  Google Scholar 

  20. Qu J, Zhang J, Pan J, He L, Ou Z, Zhang X, et al. Endotoxin tolerance inhibits lipopolysaccharide-initiated acute pulmonary inflammation and lung injury in rats by the mechanism of nuclear factor-kappaB. Scand J Immunol. 2003;58:613–9.

    Article  PubMed  CAS  Google Scholar 

  21. Sener G, Toklu H, Kapucu C, Ercan F, Erkanli G, Kaçmaz A, et al. Melatonin protects against oxidative organ injury in a rat model of sepsis. Surg Today. 2005;35:52–9.

    Article  PubMed  CAS  Google Scholar 

  22. Wheeler DS, Lahni PM, Hake PW, Denenberg AG, Wong HR, Snead C, et al. The green tea polyphenol epigallocatechin-3-gallate improves systemic hemodynamics and survival in rodent models of polymicrobial sepsis. Shock. 2007;28:353–9.

    Article  PubMed  CAS  Google Scholar 

  23. Singleton KD, Beckey VE, Wischmeyer PE. Glutamine prevents activation of NF-kappaB and stress kinase pathways, attenuates inflammatory cytokine release, and prevents acute respiratory distress syndrome (ARDS) following sepsis. Shock. 2005;24:583–9.

    Article  PubMed  CAS  Google Scholar 

  24. Osuchowski MF, Welch K, Siddiqui J, Remick DG. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol. 2006;177:1967–74.

    PubMed  CAS  Google Scholar 

  25. Varma TK, Durham M, Murphey ED, Cui W, Huang Z, Lin CY, et al. Endotoxin priming improves clearance of Pseudomonas aeruginosa in wild-type and interleukin-10 knockout mice. Infect Immun. 2005;73:7340–7.

    Article  PubMed  CAS  Google Scholar 

  26. Cavaillon JM, Adib-Conquy M. Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care. 2006;10:233–41.

    Article  PubMed  Google Scholar 

  27. Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 2007;447:972–8.

    PubMed  CAS  Google Scholar 

  28. Zhang J, Qu JM, He LX. IL-12 suppression, enhanced endocytosis and up-regulation of MHC-II and CD80 in dendritic cells during experimental endotoxin tolerance. Acta Pharmacol Sin. 2009;30:582–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Dr. Hong-liang Zong for his excellent technical assistance and Dr. Vincent VanBuren (Texas A&M University, Health Science Center) for his careful review of the article. This work was supported by Grants from the State Natural Sciences Foundation project (No. 30770930), the Program of Shanghai Subject Chief Scientist (No. 07XD14012), Shanghai Leading Talent Projects (2010No.036 to JMQ), and National Basic Research Program of China (973 Program) (No. 2007CB513004).

Author information

Authors and Affiliations

  1. Department of Emergency Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

    Dong-Wei Shi, Chao-Yang Tong & Guo-Rong Gu

  2. Department of Pulmonary Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

    Jing Zhang & Hong-Ni Jiang

  3. Department of Pathology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

    Yuan Ji

  4. Department of Pulmonary Medicine, Huadong Hospital, Shanghai Medical College, Fudan University, 200040, Shanghai, China

    Hanssa Summah & Jie-Ming Qu

Authors
  1. Dong-Wei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong-Ni Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chao-Yang Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guo-Rong Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuan Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hanssa Summah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jie-Ming Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jie-Ming Qu.

Additional information

Responsible Editor: Artur Bauhofer.

Dong-Wei Shi and Jing Zhang contributed equally to this article.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, DW., Zhang, J., Jiang, HN. et al. LPS pretreatment ameliorates multiple organ injuries and improves survival in a murine model of polymicrobial sepsis. Inflamm. Res. 60, 841–849 (2011). https://doi.org/10.1007/s00011-011-0342-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-011-0342-5

Keywords

Search

Navigation