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

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 × 10(4)-2 × 10(6) 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 × 10(4) 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 × 10(5) 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.

• Authors: Miriam H P van Lieshout, Tom van der Poll, Cornelis van't Veer
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 63 Issue 11 Pg. 927-33 (Nov 2014) ISSN: 1420-908X [Electronic] Switzerland
• PMID: 25118783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Anti-Inflammatory Agents
• Cytokines
• E5564
• Lipid A
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Ceftriaxone

Topics

• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Ascitic Fluid (microbiology)
• Bacterial Load
• Ceftriaxone (pharmacology, therapeutic use)
• Cytokines (blood, immunology)
• Escherichia coli (isolation & purification)
• Escherichia coli Infections (blood, drug therapy, immunology, microbiology)
• Female
• Lipid A (analogs & derivatives, pharmacology, therapeutic use)
• Liver (microbiology)
• Lung (microbiology)
• Mice, Inbred C57BL
• Peritoneal Lavage
• Peritonitis (blood, drug therapy, immunology, microbiology)
• Sepsis (blood, drug therapy, immunology, microbiology)
• Toll-Like Receptor 4 (antagonists & inhibitors, immunology)