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

Abstract

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.