BLT(1) signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils

Leukotriene B(4) (LTB(4)) is a potent chemoattractant for neutrophils. Signalling of LTB(4) receptor type 1 (BLT(1)) has pro-inflammatory functions through neutrophil recruitment. In this study, we investigated whether BLT(1) signalling plays a role in acetaminophen (APAP)-induced liver injury by affecting inflammatory responses including the accumulation of hepatic neutrophils. BLT(1)-knockout (BLT(1)(−/−)) mice and their wild-type (WT) counterparts were subjected to a single APAP overdose (300 mg/kg), and various parameters compared within 24 h after treatment. Compared with WT mice, BLT(1)(−/−) mice exhibited exacerbation of APAP-induced liver injury as evidenced by enhancement of alanine aminotransferase level, necrotic area, hepatic neutrophil accumulation, and expression of cytokines and chemokines. WT mice co-treated with APAP and ONO-0457, a specific antagonist for BLT(1), displayed amplification of the injury, and similar results to those observed in BLT(1)(−/−) mice. Hepatic neutrophils in BLT(1)(−/−) mice during APAP hepatotoxicity showed increases in the production of reactive oxygen species and matrix metalloproteinase-9. Administration of isolated BLT(1)-deficient neutrophils into WT mice aggravated the liver injury elicited by APAP. These results demonstrate that BLT(1) signalling dampens the progression of APAP hepatotoxicity through inhibiting an excessive accumulation of activated neutrophils. The development of a specific agonist for BLT(1) could be useful for the prevention of APAP hepatotoxicity.