Kühnle S, Nicotera P, Wendel A, Leist M
Department of Biochemical Pharmacology, University of Konstanz, Konstanz, D-78457, Germany.
Biochem Biophys Res Commun. 1999 Sep 24;263(2):433-8. doi: 10.1006/bbrc.1999.1393.
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.
聚(ADP - 核糖)聚合酶(PARP)的激活常与细胞毒性相关,但其在休克诱导的致死率及不同组织损伤模式中的精确作用仍不清楚。我们利用PARP基因靶向缺失的小鼠(PARP - / - )来研究野生型(wt)和PARP - / - 小鼠对内毒素(LPS)诱导的致死率及不同形式肝损伤的差异敏感性。所有PARP - / - 动物均在高剂量(20 mg/kg)LPS介导的休克中存活,而该剂量使60%的野生型动物死亡。此外,LPS诱导的坏死性肝损伤显著减轻。相反,当通过向D - 半乳糖胺致敏小鼠注射低浓度LPS(30微克/千克)或激活肝细胞死亡受体诱导凋亡性肝损伤时,PARP - / - 动物未得到保护。我们得出结论,PARP参与全身LPS毒性作用,而在TNF或CD95介导的凋亡性肝损伤中起次要作用。