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TLR4 inhibition impairs bacterial clearance in a therapeutic setting in murine abdominal sepsis

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Abstract

Objective and design

To investigate the therapeutic effect of E5564 (a clinically used TLR4 inhibitor) in murine abdominal sepsis elicited by intraperitoneal infection with a highly virulent Escherichia coli in the context of concurrent antibiotic therapy.

Methods

Mice were infected with different doses (~2 × 104–2 × 106 CFU) of E. coli O18:K1 and treated after 8 h with ceftriaxone 20 mg/kg i.p. combined with either E5564 10 mg/kg i.v. or vehicle. For survival studies this treatment was repeated every 12 h. Bacterial loads and inflammatory parameters were determined after 20 h in peritoneal lavage fluid, blood, liver and lung tissue. Plasma creatinin, AST, ALT and LDH were determined to assess organ injury.

Results

E5564 impaired bacterial clearance under the antibiotic regime after infection with a low dose E. coli (1.7 × 104 CFU) while renal function was slightly preserved. No differences were observed in bacterial load and organ damage after infection with a tenfold higher (1.7 × 105 E. coli) bacterial dose. While treatment with E5564 slightly attenuated inflammatory markers provoked by the sublethal doses of 104–105 E. coli under the antibiotic regime, it did not affect lethality evoked by infection with 1.7 × 106 E. coli.

Conclusions

The impact of TLR4 inhibition during abdominal sepsis by virulent E. coli bacteria is only beneficial at low infection grade at cost of bactericidal activity.

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Acknowledgments

We acknowledge Eisai Inc., Woodcliff Lake, NJ for the supply of E5564 and Joost Daalhuisen and Marieke ten Brink for expert technical assistance. This work was supported by the AMC Graduate School of Medical Science (to M. H. P. v. L.).

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Authors and Affiliations

  1. Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Miriam H. P. van Lieshout, Tom van der Poll & Cornelis van’t Veer

  2. Academic Medical Center, Center for Experimental and Molecular Medicine, University of Amsterdam, Meibergdreef 9, Room G2-130, 1105 AZ, Amsterdam, The Netherlands

    Miriam H. P. van Lieshout, Tom van der Poll & Cornelis van’t Veer

  3. Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Tom van der Poll

Authors
  1. Miriam H. P. van Lieshout
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  2. Tom van der Poll
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  3. Cornelis van’t Veer
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Correspondence to Miriam H. P. van Lieshout.

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Responsible Editor: Artur Bauhofer.

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van Lieshout, M.H.P., van der Poll, T. & van’t Veer, C. TLR4 inhibition impairs bacterial clearance in a therapeutic setting in murine abdominal sepsis. Inflamm. Res. 63, 927–933 (2014). https://doi.org/10.1007/s00011-014-0766-9

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  • DOI: https://doi.org/10.1007/s00011-014-0766-9

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