Skip to main content
SpringerLink
Log in

Effect of Toll-like receptor 4 inhibitor on LPS-induced lung injury

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

Abstract

Objective and design

Toll-like receptor 4 (TLR4) plays important roles in the recognition of lipopolysaccharide (LPS) and the activation of inflammatory cascade. In this study, we evaluated the effect of TAK-242, a selective TLR4 signal transduction inhibitor, on acute lung injury (ALI).

Materials and methods

C57BL/6J mice were intravenously treated with TAK-242 15 min before the intratracheal administration of LPS or Pam3CSK4, a synthetic lipopeptide. Six hours after the challenge, bronchoalveolar lavage fluid was obtained for a differential cell count and the measurement of cytokine and myeloperoxidase levels. Lung permeability and nuclear factor-κB (NF-κB) DNA binding activity were also evaluated.

Results

TAK-242 effectively attenuated the neutrophil accumulation and activation in the lungs, the increase in lung permeability, production of inflammatory mediators, and NF-κB DNA-binding activity induced by the LPS challenge. In contrast, TAK-242 did not suppress inflammatory changes induced by Pam3CSK4.

Conclusion

TAK-242 may be a promising therapeutic agent for ALI, especially injuries associated with pneumonia caused by Gram-negative bacteria.

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

Similar content being viewed by others

References

  1. McIntyre RC Jr, Pulido EJ, Bensard DD, Shames BD, Abraham E. Thirty years of clinical trials in acute respiratory distress syndrome. Crit Care Med. 2000;28:3314–31.

    Article  CAS  PubMed  Google Scholar 

  2. Bersten AD, Edibam C, Hunt T, Moran J. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian states. Am J Respir Crit Care Med. 2002;165:443–8.

    PubMed  Google Scholar 

  3. Brigham KL, Meyrick B. Endotoxin and lung injury. Am Rev Respir Dis. 1986;133:913–27.

    CAS  PubMed  Google Scholar 

  4. Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004;16:3–9.

    Article  CAS  PubMed  Google Scholar 

  5. Morrison DC, Ryan JL. Bacterial endotoxins and host immune responses. Adv Immunol. 1979;28:293–450.

    Article  CAS  PubMed  Google Scholar 

  6. Jeyaseelan S, Chu HW, Young SK, Freeman MW, Worthen GS. Distinct roles of pattern recognition receptors CD14 and Toll-like receptor 4 in acute lung injury. Infect Immun. 2005;73:1754–63.

    Article  CAS  PubMed  Google Scholar 

  7. Togbe D, Schnyder-Candrian S, Schnyder B, Couillin I, Maillet I, Bihl F, et al. TLR4 gene dosage contributes to endotoxin-induced acute respiratory inflammation. J Leukoc Biol. 2006;80:451–7.

    Article  CAS  PubMed  Google Scholar 

  8. Abraham E, Laterre PF, Garbino J, Pingleton S, Butler T, Dugernier T, et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early 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. Crit Care Med. 2001;29:503–10.

    Article  CAS  PubMed  Google Scholar 

  9. Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, 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. Crit Care Med. 1997;25:1115–24.

    Article  CAS  PubMed  Google Scholar 

  10. Shiozaki M, Doi H, Tanaka D, Shimozato T, Kurakata S. Syntheses of glucose analogues of E5564 as a highly potent anti-sepsis drug candidate. Bioorg Med Chem. 2006;14:3011–6.

    Article  CAS  PubMed  Google Scholar 

  11. Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, et al. A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits Toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol. 2006;69:1288–95.

    Article  CAS  PubMed  Google Scholar 

  12. Sha T, Sunamoto M, Kitazaki T, Sato J, Ii M, Iizawa Y. Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. Eur J Pharmacol. 2007;571:231–9.

    Article  CAS  PubMed  Google Scholar 

  13. Shirley E. A non-parametric equivalent of Williams’ test for contrasting increasing dose levels of a treatment. Biometrics. 1977;33:386–9.

    Article  CAS  PubMed  Google Scholar 

  14. Williams DA. A note on Shirley’s nonparametric test for comparing several dose levels with a zero-dose control. Biometrics. 1986;42:183–6.

    Article  CAS  PubMed  Google Scholar 

  15. Olson TS, Ley K. Chemokines and chemokine receptors in leukocyte trafficking. Am J Physiol Regul Integr Comp Physiol. 2002;283:R7–28.

    CAS  PubMed  Google Scholar 

  16. Hayden MS, West AP, Ghosh S. NF-κB and the immune response. Oncogene. 2006;25:6758–80.

    Article  CAS  PubMed  Google Scholar 

  17. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem. 1999;274:10689–92.

    Article  CAS  PubMed  Google Scholar 

  18. Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol. 1995;13:437–57.

    Article  CAS  PubMed  Google Scholar 

  19. Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med. 1999;189:1777–82.

    Article  CAS  PubMed  Google Scholar 

  20. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990;249:1431–3.

    Article  CAS  PubMed  Google Scholar 

  21. Christman JW, Lancaster LH, Blackwell TS. Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy. Intensive Care Med. 1998;24:1131–8.

    Article  CAS  PubMed  Google Scholar 

  22. Xu WY, Wang L, Wang HM, Wang YQ, Liang YF, Zhao TT, et al. TLR2 and TLR4 agonists synergistically up-regulate SR-A in RAW264.7 through p38. Mol Immunol. 2007;44:2315–23.

    Article  CAS  PubMed  Google Scholar 

  23. Hirschfeld M, Ma Y, Weis JH, Vogel SN, Weis JJ. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol. 2000;165:618–22.

    CAS  PubMed  Google Scholar 

  24. Xue Y, Yun D, Esmon A, Zou P, Zuo S, Yu Y, et al. Proteomic dissection of agonist-specific TLR-mediated inflammatory responses on macrophages at subcellular resolution. J Proteome Res. 2008;7:3180–93.

    Article  CAS  PubMed  Google Scholar 

  25. Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H. Tak-242 selectively suppresses toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008;584:40–8.

    Article  CAS  PubMed  Google Scholar 

  26. Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol. 2009;157(7):1250–62.

    Article  CAS  PubMed  Google Scholar 

  27. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol. 2004;202:145–56.

    Article  CAS  PubMed  Google Scholar 

  28. Nathan CF. Secretory products of macrophages. J Clin Invest. 1987;79:319–26.

    Article  CAS  PubMed  Google Scholar 

  29. Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson LD. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;150:113–22.

    CAS  PubMed  Google Scholar 

  30. Parsons PE, Fowler AA, Hyers TM, Henson PM. Chemotactic activity in bronchoalveolar lavage fluid from patients with adult respiratory distress syndrome. Am Rev Respir Dis. 1985;132:490–3.

    CAS  PubMed  Google Scholar 

  31. Matthay MA. Conference summary: acute lung injury. Chest. 1999;116:119S–26S.

    Article  CAS  PubMed  Google Scholar 

  32. Reutershan J, Ley K. Bench-to-bedside review: acute respiratory distress syndrome—how neutrophils migrate into the lung. Crit Care. 2004;8:453–61.

    Article  PubMed  Google Scholar 

  33. Schurr JR, Young E, Byrne P, Steele C, Shellito JE, Kolls JK. Central role of Toll-like receptor 4 signaling and host defense in experimental pneumonia caused by gram-negative bacteria. Infect Immun. 2005;73:532–45.

    Article  CAS  PubMed  Google Scholar 

  34. Mann PB, Kennett MJ, Harvill ET. Toll-like receptor 4 is critical to innate host defense in a murine model of bordetellosis. J Infect Dis. 2004;189:833–6.

    Article  CAS  PubMed  Google Scholar 

  35. Lettinga KD, Florquin S, Speelman P, van Ketel R, van der Poll T, Verbon A. Toll-like receptor 4 is not involved in host defense against pulmonary Legionella pneumophila infection in a mouse model. J Infect Dis. 2002;186:570–3.

    Article  CAS  PubMed  Google Scholar 

  36. Lee JS, Frevert CW, Matute-Bello G, Wurfel MM, Wong VA, Lin SM, et al. TLR-4 pathway mediates the inflammatory response but not bacterial elimination in E. coli pneumonia. Am J Physiol Lung Cell Mol Physiol. 2005;289:L731–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Miyuki Yamamoto of Keio University School of Medicine and Masumi Uekata of Takeda Pharmaceutical Co. Ltd. for their technical assistance. This study was supported in part by a grant-in-aid for scientific research from the Ministry of Health, Labour and Welfare of Japan (no. 19590913) (S. T.).

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan

    Hiroyuki Seki, Kiyoshi Moriyama & Junzo Takeda

  2. Division of Pulmonary Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Sadatomo Tasaka, Koichi Fukunaga, Yoshiki Shiraishi, Keisuke Miyamoto, Yasushi Nakano & Akitoshi Ishizaka

  3. Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Osaka, Japan

    Naoko Matsunaga, Katsunori Takashima, Tatsumi Matsumoto & Masayuki Ii

Authors
  1. Hiroyuki Seki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sadatomo Tasaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koichi Fukunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshiki Shiraishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kiyoshi Moriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Keisuke Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasushi Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naoko Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Katsunori Takashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tatsumi Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masayuki Ii
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Akitoshi Ishizaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Junzo Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sadatomo Tasaka.

Additional information

Responsible Editor: K. Visvanathan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seki, H., Tasaka, S., Fukunaga, K. et al. Effect of Toll-like receptor 4 inhibitor on LPS-induced lung injury. Inflamm. Res. 59, 837–845 (2010). https://doi.org/10.1007/s00011-010-0195-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-010-0195-3

Keywords

Search

Navigation