Combination of Imipenem and TAK-242, a Toll-Like Receptor 4 Signal Transduction Inhibitor, Improves Survival in a Murine Model of Polymicrobial Sepsis

Abstract

Sepsis is characterized by an excessive host response to infection. Toll-like receptors (TLRs) are essential for triggering this type of host immune response. Toll-like receptor 4 mediates recognition of LPS from gram-negative bacteria and is an important initiator of sepsis. In the present study, we evaluated the efficacy of TAK-242, a novel TLR4 signal transduction inhibitor, in a murine cecal ligation and puncture (CLP) model. Treatment with TAK-242 (10 mg/kg i.v.) in combination with imipenem (1 mg/kg s.c.) 1 h after CLP significantly increased the survival rates of mice from 17% to 50% (P ≤ 0.01) and suppressed CLP-induced increases in serum levels of IL-1[beta], IL-6, IL-10, and macrophage inflammatory protein 2 by 64%, 73%, 79%, and 81%, respectively (P ≤ 0.025). Additionally, coadministration of TAK-242 with imipenem after CLP significantly inhibited CLP-induced decreases in blood platelet counts by 37% (P ≤ 0.025) and increases in serum levels of alanine aminotransferase by 32% (P ≤ 0.025) and blood urea nitrogen by 43% (P ≤ 0.025). TAK-242 at a dose of 10 mg/kg had no effect on bacterial counts in blood, suggesting that it does not affect blood bacteria spread. These results indicate that TAK-242 shows therapeutic effects in murine polymicrobial sepsis, and it may be a potential therapeutic agent for the treatment of sepsis.

Celecoxib Enhances the Efficacy of Low-Dose Antibiotic Treatment against Polymicrobial Sepsis in Mice and Clinical Isolates of ESKAPE Pathogens

“…Our results are in agreement with earlier studies (Camara-Lemarroy et al, 2015). The results are also similar to earlier studies using imipenem and TAK-242, a toll-like receptor4 inhibitor (Sha et al, 2011). …”

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

“…Inflammation, tissue damage, and lethality are diminished in the absence of TLR4 signaling (29). However, in the setting of infection with live bacteria, the contribution of TLR4 varies depending on the experimental model and type of organism used in the study (13)(14)(15)(30)(31)(32)(33)(34)(35)(36)(37). Most early studies used mouse strains with mutant forms of TLR4.…”

Renal effects of treatment with a TLR4-inhibitor in conscious septic sheep

“…When LPS binds to TLR4, an inflammatory response is initiated via production and release of cytokines as well as stimulation of inflammatory cells [11]. Targeting TLR4 with antibodies or specific inhibitors has shown beneficial effects by reducing mortality in experimental models of Gram-negative sepsis [12][13][14][15][16][17]. Initial clinical trials also showed beneficial effects of blocking TLR4 in sepsis [18], but in larger follow-up investigations, survival was not improved [19,20].…”