Objective: Over dosage of acetaminophen (APAP) administration causes severe acute liver failure. Accumulating evidence suggests that macrophages contribute to APAP-induced liver injury; however, underlying mechanisms of involvement of macrophages remain unknown. We recently reported that thromboxane A₂ (TXA₂) improves chemical-induced liver injury by accumulating macrophages. Here, we examined the role of TXA₂ in macrophages during APAP-induced liver injury.
Methods and Results: APAP (300 mg/kg, ip) was administered to macrophage-specific thromboxane prostanoid receptor (TP) deficient mice (mTPKO) and control mice (Cont). Compared with Cont, mTPKO exhibited severe liver injury as indicated by increased levels of ALT and necrotic area and decreased expression of PCNA, a marker of hepatocyte proliferation at 48 h post-APAP treatment. There was no statistical difference in hepatic GSH levels between the two genotypes. TP and TXA₂ synthase were expressed in CD68-positive cells in the liver. Immunofluorescence revealed CD68-positive cells accumulated extensively into the necrotic regions of livers from Cont as compared with mTPKO. The expression of mRNA encoding pro-inflammatory mediators including TNF-α, IL-1β and IL-6 in mTPKO were higher than in Cont, whereas HGF levels in mTPKO were lower than in Cont.  
 
Conclusions:  TP receptor signaling in macrophages attenuated APAP-induced liver injury by reducing inflammatory cytokines and promoted liver repair by increasing macrophages in the necrotic regions and HGF production.