title: Prevention of endotoxin-induced lethality, but not of liver apoptosis in poly(ADP-ribose) polymerase-deficient mice.
abstract: Activation of poly-(ADP-ribose) polymerase (PARP) is often associated with cytotoxicity, but its precise role in shock-induced lethality and in different modes of tissue injury is still unknown. We took advantage of the existence of mice with a targeted deletion of the PARP gene (PARP-/-) to examine the differential sensitivity of wild-type (wt) and PARP-/- mice toward endotoxin (LPS)-induced lethality and different forms of liver damage. All PARP-/- animals survived high-dose (20 mg/kg) LPS-mediated shock, which killed 60% of wt animals. Moreover, LPS-induced necrotic liver damage was significantly reduced. In contrast, when apoptotic liver damage was induced via injection of low concentrations of LPS (30 microgram/kg) into D-galactosamine-sensitized mice, or via activation of hepatic cell death receptors, PARP-/- animals 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.
authors.affiliation: Department of Biochemical Pharmacology, University of Konstanz, Konstanz, D-78457, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kühnle
authors.forename: P
authors.initials: P
authors.lastname: Nicotera
authors.forename: A
authors.initials: A
authors.lastname: Wendel
authors.forename: M
authors.initials: M
authors.lastname: Leist
mesh_terms: D000818:Animals; D017209:Apoptosis; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D017093:Liver Failure / Q000209:etiology; D051379:Mice; D008817:Mice, Mutant Strains; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D011065:Poly(ADP-ribose) Polymerases