Role of poly(ADP-ribose)synthetase in inflammation

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 fbr 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. (C) 1998 Elsevier Science B.V. All rights reserved.