Szabó C
Children's Hospital Medical Center, Division of Critical Care, Cincinnati, OH 45229, USA.
Eur J Pharmacol. 1998 May 29;350(1):1-19. doi: 10.1016/s0014-2999(98)00249-0.
Peroxynitrite and hydroxyl radicals are potent initiators of DNA single strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose)synthetase (PARS). Rapid activation of PARS depletes the intracellular concentration of its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. This process can result in acute cell dysfunction and cell necrosis. Accordingly, inhibitors of PARS protect against cell death under these conditions. In addition to the direct cytotoxic pathway regulated by DNA injury and PARS activation, PARS also appears to modulate the course of inflammation by regulating the expression of a number of genes, including the gene for intercellular adhesion molecule 1, collagenase and the inducible nitric oxide synthase. The research into the role of PARS in inflammatory conditions is now supported by novel tools, such as novel, potent inhibitors of PARS, and genetically engineered animals lacking the gene for PARS. In vivo data demonstrate that inhibition of PARS protects against various forms of inflammation, including zymosan or endotoxin induced multiple organ failure, arthritis, allergic encephalomyelitis, and diabetic islet cell destruction. Pharmacological inhibition of PARS may be a promising novel approach for the experimental therapy of various forms of inflammation.
过氧亚硝酸盐和羟基自由基是DNA单链断裂的强效引发剂，而DNA单链断裂是激活核酶聚（ADP - 核糖）合成酶（PARS）的必要刺激因素。PARS的快速激活会耗尽其底物NAD +的细胞内浓度，减缓糖酵解、电子传递和ATP生成的速率。这个过程会导致急性细胞功能障碍和细胞坏死。因此，在这些情况下，PARS抑制剂可防止细胞死亡。除了由DNA损伤和PARS激活调节的直接细胞毒性途径外，PARS似乎还通过调节许多基因的表达来调节炎症过程，这些基因包括细胞间粘附分子1、胶原酶和诱导型一氧化氮合酶的基因。现在，新型工具，如新型强效PARS抑制剂和缺乏PARS基因的基因工程动物，为研究PARS在炎症状态下的作用提供了支持。体内数据表明，抑制PARS可预防各种形式的炎症，包括酵母聚糖或内毒素诱导的多器官衰竭、关节炎、变应性脑脊髓炎和糖尿病胰岛细胞破坏。对PARS进行药理抑制可能是治疗各种炎症的一种有前景的新方法。
