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Inflammation research : official journal of the European Histamine Research Society ... [et al.]

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


PMID 25118783

Abstract

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. Mice were infected with different doses (~2xa0×xa010(4)-2xa0×xa010(6) CFU) of E. coli O18:K1 and treated after 8xa0h with ceftriaxone 20xa0mg/kg i.p. combined with either E5564 10xa0mg/kg i.v. or vehicle. For survival studies this treatment was repeated every 12xa0h. Bacterial loads and inflammatory parameters were determined after 20xa0h in peritoneal lavage fluid, blood, liver and lung tissue. Plasma creatinin, AST, ALT and LDH were determined to assess organ injury. E5564 impaired bacterial clearance under the antibiotic regime after infection with a low dose E. coli (1.7xa0×xa010(4) CFU) while renal function was slightly preserved. No differences were observed in bacterial load and organ damage after infection with a tenfold higher (1.7xa0×xa010(5) E. coli) bacterial dose. While treatment with E5564 slightly attenuated inflammatory markers provoked by the sublethal doses of 104-105xa0E. colixa0under the antibiotic regime, it did not affect lethality evoked by infection with 1.7xa0×xa0106xa0E. coli. 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.