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Published on: May 2, 2018
TLR4 inhibition impairs bacterial clearance in a therapeutic setting in murine abdominal sepsis
Miriam H P van Lieshout1, Tom van der Poll, Cornelis van't Veer
1Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, m.h.vanlieshout@amc.nl.
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.
Insights
Toll-like receptor 4 (TLR4) inhibition with E5564 in murine abdominal sepsis showed benefits only at low bacterial infection levels. This therapeutic approach came at the cost of reduced bactericidal activity when combined with antibiotics.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Sepsis remains a leading cause of mortality, often caused by bacterial infections.
- Escherichia coli (E. coli) is a common pathogen in abdominal sepsis.
- Toll-like receptor 4 (TLR4) plays a critical role in the inflammatory response to bacterial infections.
Purpose of the Study:
- To evaluate the therapeutic efficacy of E5564, a TLR4 inhibitor, in a murine model of abdominal sepsis.
- To assess the combined effect of E5564 and antibiotic therapy (ceftriaxone) on sepsis outcomes.
- To investigate the impact of TLR4 inhibition on bacterial clearance and inflammatory markers.
Main Methods:
- Murine model of abdominal sepsis induced by intraperitoneal E. coli infection.
- Treatment with ceftriaxone combined with either E5564 or vehicle.
- Assessment of bacterial loads, inflammatory parameters, and organ injury markers.
- Survival studies were conducted with repeated treatment cycles.
Main Results:
- E5564 impaired bacterial clearance at low E. coli doses but preserved renal function.
- No significant differences in bacterial load or organ damage were observed at higher E. coli doses.
- TLR4 inhibition moderately reduced inflammatory markers at sublethal bacterial doses but did not impact lethality at high doses.
Conclusions:
- TLR4 inhibition may offer benefits in early or low-grade abdominal sepsis.
- The potential benefits of TLR4 inhibition are counterbalanced by reduced bacterial clearance.
- Careful consideration of infection severity is crucial when evaluating TLR4 inhibitors in sepsis treatment.
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