Abstract

Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with ischaemia-reperfusion injury and inflammation. Continuous or excessive activation of PARP produces extended chains of ADP-ribose on nuclear proteins and results in a substantial depletion of intracellular NAD+ and subsequently ATP, which may lead to cell death [1,2]. Production of reactive oxidants such as hydrogen peroxide, superoxide anions, hydrogen peroxide or hydroxyl radical at the site of inflammation contributes of tissue damage [3].The aim of the present study was to evaluate the effects of a novel and potent inhibitor of PARP activity, 5-Aminoisoquinolinone (5-AIQ), on neutrophil recruitment in the acute inflammation induced by zymosan-activated plasma in mice. Intra-thoracic administration of zymosan-activated plasma leads to an increase in neutrophil infiltration of the lung at 24hr. The potent PARP inhibitor 5-AIQ reduced the degree of lung injury and attenuated the expression of P-selectin and ICAM-1 as well as the recruitment of neutrophils into the lung during acute inflammation. The up-regulation/expression of P-selectin and ICAM-1 in human endothelial cells exposed to oxidative stress (peroxynitrite) or to a pro-inflammatory cytokine (tumor necrosis factor alpha, TNF-a) was also attenuated by 5-AIQ.These findings provide the first evidence that the activation of PARP participates in neutrophil-mediated lung injury by regulating the expression of P-selectin and ICAM-1.References: 1.Schraufstatter IU, Hinshaw DB, Hyslop PA, Spragg RG, Cochrane CG: J Clin Invest, 1986; 77: 1312-20 2.Thies RL, Autor AP: Arch Biochem Biophys, 1991; 286: 353-63 3.Cuzzocrea S, Costantino G, Mazzon E, Caputi AP: Br J Pharmacol, 1999; 126: 407-14

Keywords: 5-aminoisoquinolinone pleurisy, oxygen radicals, poly (ADP-ribose) synthetase, zymosan-activated plasma