Role of Toll‐Like Receptor 4 in Mediating Multiorgan Dysfunction in Mice With Acetaminophen Induced Acute Liver Failure

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