Effects of pyrrolidine dithiocarbamate on acute apoptotic liver injury in mice

Aim To investigate the effects of pyrrolidine dithiocarbamate (PDTC) on D-galactosamine/lipopolysaccharides (GalN/LPS)-induced acute apoptotic liver injury and its mechanism.Methods All mice were randomly divided into four groups.Mice in GalN/LPS group were co-injected with GalN (600 mg·kg-1,ip) and LPS (20 μg·kg-1,ip).Mice in PDTC+GalN/LPS group were injected with two doses of PDTC,one (100 mg·kg-1,ip) at 24 h before LPS and the other at 2 h before LPS (20 μg·kg-1,ip).Mice in control groups were treated with PDTC (100 mg·kg-1,ip) or saline.Ten mice in each group were observed for animal survival within 72 h after LPS treatment.Six mice in each group were sacrificed 1.5 h after LPS for collecting blood and isolating livers.The expression of hepatic TNF-α mRNA was determined by reverse transcription and polymerase chain reaction (RT-PCR).Hepatic nuclear factor-κB (NF-κB) binding activity was measured with electrophoretic mobility shift assay (EMSA).Twelve mice in each group were sacrificed 8 h after LPS treatment.Serum was collected for measurement of alanine aminotransferase (ALT) and hepatocellular apoptosis and histological examination.Results Co-injection of GalN and LPS markedly increased serum ALT activity.Histopathological examination of liver sections revealed that GalN/LPS induced hepatic congestion,necrosis and massive macrophages infiltration,and increased the number of TUNEL-positive cells in mouse liver.GalN/LPS treatments,led to 90% mortality within 72 h with severe congestion and necrosis in the liver of all the dead mice.PDTC pretreatment significantly inhibited GalN/LPS-induced hepatic NF-κB activation and TNF-α expression.In contrast,PDTC aggravated GalN/LPS-triggered hepatocellular apoptosis,increased serum ALT activity,exacerbated hepatic hemorrhage and necrosis,and accelerated death.Conclusion PDTC aggravates GalN/LPS-induced acute apoptotic liver injury via inhibiting NF-κB-mediated anti-apoptotic effects.