Skip to main content

Advertisement

SpringerLink
Log in

Pretreatment with anti-flagellin serum delays acute lung injury in rats with sepsis

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

Abstract

Objective

This study examined the reduction of sepsis-induced ALI by inhibition of flagellin-stimulated TLR5 signaling.

Methods

Rats were randomly divided into three groups: one group served as the sham-operated group (control group), and the other two groups received the induction of sepsis (sepsis and treatment groups). The treatment group was injected with anti-flagellin serum before induction of sepsis. At 2, 4, 6, 12, 24, and 48 h following induction of sepsis (six time-point subgroups, n = 10 per subgroup), arterial PaO2, wet/dry (W/D) lung weight ratios, levels of serum and BALF flagellin and TNF-α, pulmonary pathological alterations, and TLR5 mRNA expression in the lungs were examined.

Results

Compared to sham-operated rats, septic rats had: increased levels of serum and BALF flagellin at 6, 12, 24, and 48 h; reduced arterial PaO2; elevated W/D lung weight ratio; increased serum and BALF TNF-α levels; and up-regulated TLR5 mRNA expression at 12, 24, and 48 h (P < 0.01). Pretreatment with anti-flagellin serum, however, significantly inhibited sepsis-associated declines in arterial PaO2, increased W/D lung weight ratios, elevated serum and BALF TNF-α levels, and up-regulated TLR5 mRNA expression at 24 and 48 h (P < 0.01).

Conclusion

Neutralizing the actions of circulating flagellin with anti-flagellin serum delayed the development of ALI in rats with 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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Zambon M, Vincent JL. Mortality rates for patients with acute lung injury/ARDS have decreased over time. Chest. 2008;133(5):1120–7.

    Article  PubMed  Google Scholar 

  2. Rojas M, Woods CR, Mora AL, Xu J, Brigham KL. Endotoxin-induced lung injury in mice: structural, functional, and biochemical responses. Am J Physiol Lung Cell Mol Physiol. 2005;288(2):L333–41.

    Article  PubMed  CAS  Google Scholar 

  3. Asti C, Ruggieri V, Porzio S, Chiusaroli R, Melillo G, Caselli GF. Lipopolysaccharide-induced lung injury in mice. I. Concomitant evaluation of inflammatory cells and haemorrhagic lung damage. Pulm Pharmacol Ther. 2000;13(2):61–9.

    Article  PubMed  CAS  Google Scholar 

  4. Wiener-Kronish JP, Albertine KH, Matthay MA. Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest. 1991;88(3):864–75.

    Article  PubMed  CAS  Google Scholar 

  5. Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 2007;4(9):e269.

    Article  PubMed  Google Scholar 

  6. Bone RC, Balk RA, Fein AM, Perl TM, Wenzel RP, Reines HD, Quenzer RW, Iberti TJ, Macintyre N, Schein RM. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group. Crit Care Med. 1995;23(6):994–1006.

    Article  PubMed  CAS  Google Scholar 

  7. Zhou CX, Xu JC, Hu MD, Yang Y. Significance of changes in serum and BALF flagellin levels in septic rats with acute lung injury. Chin J Intern Med. 2006;45(10):842–3.

    CAS  Google Scholar 

  8. Eaves-Pyles T, Murthy K, Liaudet L, Virág L, Ross G, Soriano FG, Szabó C, Salzman AL. Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation: I kappa B alpha degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction. J Immunol. 2001;166(2):1248–60.

    PubMed  CAS  Google Scholar 

  9. Liaudet L, Szabó C, Evgenov OV, Murthy KG, Pacher P, Virág L, Mabley JG, Marton A, Soriano FG, Kirov MY, Bjertnaes LJ, Salzman AL. Flagellin from gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis. Shock. 2003;19(2):131–7.

    Article  PubMed  CAS  Google Scholar 

  10. Liaudet L, Murthy KG, Mabley JG, Pacher P, Soriano FG, Salzman AL, Szabό C. Comparison of inflammation, organ damage, and oxidant stress induced by Salmonella enterica serovar Muenchen flagellin and serovar enteritidis lipopolysaccharide. Infect Immun. 2002;70(1):192–8.

    Article  PubMed  CAS  Google Scholar 

  11. Rolli J, Loukili N, Levrand S, Rosenblatt-Velin N, Rignault-Clerc S, Waeber B, Feihl F, Pacher P, Liaudet L. Bacterial flagellin elicits widespread innate immune defense mechanisms, apoptotic signaling, and a sepsis-like systemic inflammatory response in mice. Crit Care. 2010;14(4):R160.

    Article  PubMed  Google Scholar 

  12. Hawn TR, Berrington WR, Smith IA, Uematsu S, Akira S, Aderem A, Smith KD, Skerrett SJ. Altered inflammatory responses in TLR5-deficient mice infected with Legionella pneumophila. J Immunol. 2007;179(10):6981–7.

    PubMed  CAS  Google Scholar 

  13. Liaudet L, Deb A, Pacher P, Mabley JG, Murthy KG, Salzman AL, Szabo C. The flagellin-TLR5 axis: rherapeutic opportunities. Drug News Perspect. 2002;15(7):397–409.

    Article  PubMed  CAS  Google Scholar 

  14. Hu MD, Xu JC, Feng YK, Zhou CX, Gong CM. Isolation and purification of flagellin from Salmonella paratyphi A and preparation of its specific antiserum. Acta Academiae Medicinae Militaris Tertiae. 2005;27(7):607–9.

    CAS  Google Scholar 

  15. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2008;295(3):L379–99.

    Article  PubMed  CAS  Google Scholar 

  16. Daniel R, Markus SH, Michael AF, Peter AW. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc. 2009;4(1):31–6.

    Google Scholar 

  17. You ZC, Shi Z, Gao QJ, Zhou K, Li X, Lu YB. The study of preventive and therapeutic effects of edaravone against paraquat-induced acute lung injury. Chongqing Med J. 2008;37(22):2517–9.

    CAS  Google Scholar 

  18. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49.

    Article  PubMed  CAS  Google Scholar 

  19. Perl M, Lomas-Neira J, Chung CS, Ayala A. Epithelial cell apoptosis and neutrophil recruitment in acute lung injury-a unifying hypothesis? What we have learned from small interfering RNAs. Mol Med. 2008;14(7–8):465–75.

    PubMed  CAS  Google Scholar 

  20. Szabó C. Role of flagellin in the pathogenesis of shock and acute respiratory distress syndrome: therapeutic opportunities. Crit Care Med. 2003;31(1):S39–45.

    Article  PubMed  Google Scholar 

  21. Hu MD, Xu JC, Xhou CX, Yang Y. A study of acute lung injury in different time phases after injection of flagellin via vena caudalis. Chin J Crit Care Med. 2008;28(7):614–7.

    CAS  Google Scholar 

  22. Barnea Y, Carmeli Y, Neville LF, Kahel-Reifer H, Eren R, Dagan S, Navon-Venezia S. Therapy with anti-flagellin A monoclonal antibody limits Pseudomonas aeruginosa invasiveness in a mouse burn wound sepsis model. Burns. 2009;35(3):390–6.

    Article  PubMed  Google Scholar 

  23. O’Neill LA, Greene C. Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J Leukoc Biol. 1998;63(6):650–7.

    PubMed  Google Scholar 

  24. Muir A, et al. Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am J Respir Cell Mol Biol. 2004;30(6):777–83.

    Article  PubMed  CAS  Google Scholar 

  25. Li JM, Shah AM. Endothelial cell super-oxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol. 2004;287(5):R1014–30.

    Article  PubMed  CAS  Google Scholar 

  26. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410(6823):1099–103.

    Article  PubMed  CAS  Google Scholar 

  27. Bambou JC, Giraud A, Menard S, Begue B, Rakotobe S, Heyman M, Taddei F, Cerf-Bensussan N, Gaboriau-Routhiau V. In vitro and ex vivo activation of the TLR5 signaling pathway in intestinal epithelial cells by a commensal Escherichia coli strain. J Biol Chem. 2004;279(41):42984–92.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant (No. 30801366) from the National Natural Science Foundation of China.

Author information

Authors and Affiliations

  1. Institute of Respiratory Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China

    Ming-Dong Hu, Yu Yang, Qi Li, Wang Yi, Gui-Sheng Qian & Jian-Cheng Xu

  2. Department of Respiratory Medicine, General Hospital of PLA, Beijing, China

    Chang-Xi Zhou

  3. Department of Respiratory Medicine, Wuhan General Hospital of Guangzhou Military Command, Wuhan, 430061, China

    Mei Mao

Authors
  1. Ming-Dong Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang-Xi Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wang Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gui-Sheng Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mei Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jian-Cheng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jian-Cheng Xu.

Additional information

Responsible Editor: Kumar Visvanathan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hu, MD., Yang, Y., Zhou, CX. et al. Pretreatment with anti-flagellin serum delays acute lung injury in rats with sepsis. Inflamm. Res. 61, 837–844 (2012). https://doi.org/10.1007/s00011-012-0475-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-012-0475-1

Keywords

Search

Navigation