BML-111 ameliorates endotoxin-induced liver injury through increasing prostaglandin J 2 production via ERK / COX 2 pathway

Endotoxemia-induced fulminant hepatic failure causes an extremely poor prognosis and high mortality due to lack of effective therapy. BML-111, a commercial available lipoxin A4 receptor agonist, has been found to antiinflammtory and hepatoprotective actions. Here we showed that pretreatment with BML111 protected mice against Lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced liver injury, as indicated by the alleviation of mortality and hepatic pathological damage, the reduction of serum aminotransferases activities, and suppression of tumor necrosis factor (TNF)-α production. Notably, BML-111 dose-dependently enhanced prostaglandin (PG) J2 production, cyclooxygenase (COX)-2 expression, and extracellular signal-regulated kinase (ERK) activation in the liver tissues of LPS/D-GalN-primed mice. Further, exogenous PGJ2 treatment attenuated LPS/D-GalN-induced liver injury and inflammatory response, but administration of NS398 (a COX-2 specific inhibitor) or ERK inhibitor PD98059 reversed the protective effect of BML-111 against LPS/D-GalN-induced liver injury as well as PGJ2 production. These results suggest that BML-111 can effectively prevent LPS/D-GalN-induced liver injury by inhibition of TNF-α and the underlying mechanism may be related to enhancement of ERK activation, up-regulation of COX-2 expression and PGJ2 production.