Constitutive expression of cyclo-oxygenase 2 transgene in hepatocytes protects against liver injury

Abstract

The effect of COX-2-dependent prostaglandins (PGs) in acute liver injury has been investigated in transgenic mice that express human COX-2 in hepatocytes. We have used three well established models of liver injury: Lipopolysaccharide injury in D-galactosamine preconditioned mice (LPS/D-GalN), the hepatitis induced by concanavalin A (ConA) and the proliferation of hepatocytes in regenerating liver after partial hepatectomy (PH). Our data demonstrate that PGs synthesis decreases in hepatocytes the susceptibility to LPS/D-GalN or ConA-induced liver injury as deduced by significant lower levels of the pro-inflammatory profile and plasmatic aminotransferases in transgenic mice, an effect suppressed by COX-2 selective inhibitors. These transgenic animals express higher levels of anti-apoptotic proteins and exhibit activation of proteins implicated in cell survival, such as Akt and AMP-kinase after injury. The resistance to LPS/D-GalN induced liver apoptosis involves an impairment of procaspase 3 and 8 activation. Protection against ConA-induced injury implies a significant reduction in necrosis. Moreover, hepatocyte commitment to start replication is anticipated in Tg mice after PH, due to the expression of PCNA, cyclin D1 and E. These results show, in a genetic model, that tissue-specific COX-2 dependent PGs exert an efficient protection against acute liver injury by an antiapoptotic/antinecrotic effect and by accelerated early hepatocyte proliferation.