Prevention of endotoxin-induced lethality, but not of liver apoptosis in poly(ADP-ribose) polymerase-deficient mice

Activation of poly-(ADP-ribose) polymerase (PARP) is often associated with cytotoxicity, but its precise role in shock-induced lethality and in differ ent modes of tissue injury is still unknown. We took advantage of the exist ence of mice with a targeted deletion of the PARP gene (PARP-/-) to examine the differential sensitivity of wild-type (wt) and PARP-/- mice toward end otoxin (LPS)-induced lethality and different forms of liver damage. All PAR P-/- animals survived high-dose (20 mg/kg) LPS-mediated shock, which killed 60% of wt animals. Moreover, LPS-induced necrotic liver damage was signifi cantly reduced. In contrast, when apoptotic liver damage was induced via in jection of low concentrations of LPS (30 mu g/kg) into D-galactosamine-sens itized mice, or via activation of hepatic cell death receptors, PARP-/- ani mals were not protected. We conclude that PARP is involved in systemic LPS toxicity, while it plays a minor role in apoptotic liver damage mediated by TNF or CD95. (C) 1999 Academic Press.