Strategies for the prevention of multiorgan dysfunction (MOD) in
acetaminophen (
APAP)-induced
acute liver failure (ALF) are an unmet need. Our study tested the hypothesis that sterile
inflammation induced by
APAP in a mouse model would activate
toll-like receptor 4 (TLR4) in the liver and extrahepatic organs and lead to the progression of ALF and MOD and that the administration of the novel TLR4 antagonist
STM28 (a
peptide formed of 17
amino-acids) would prevent liver injury and associated MOD. ALF and, subsequently, MOD were induced in TLR4-knockout (KO) mice (B6.B10ScN-Tlr4 (lpsdel) /JthJ) and wild-type (WT) mice (C57BL/6) with
APAP (500 mg/kg). A second set of experiments was conducted to evaluate the effects of a pretreatment with a novel TLR4 antagonist,
STM28, on
APAP-induced MOD in CD1 mice. Animals were sacrificed at the
coma stage, and plasma, peripheral blood cells, liver, kidneys, and brain were collected. Biochemistry values and
cytokines were measured. Liver and kidneys were studied histologically and were stained for TLR4 and activated Kupffer cells, and the expression of nuclear factor kappa B-p65 was quantified with western blotting. Brain water was measured in the frontal cortex. After
APAP administration, TLR4-KO (NFkBp65) mice were relatively protected from liver
necrosis and end-organ dysfunction and had significantly better survival than WT controls (P < 0.01).
STM28 attenuated liver injury and
necrosis, reduced
creatinine levels, and delayed the time to a
coma significantly. The increases in
cytokines in the plasma and liver, including TLR4 expression and the activation of Kupffer cells, after
APAP administration were reduced significantly in the STM28-treated animals. The increased number of circulating myeloid cells was reduced significantly after
STM28 treatment. In conclusion, these data provide evidence for an important role of the TLR4 antagonist in the prevention of the progression of
APAP-induced ALF and MOD.