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02 May 2003 : Case report  

Effect of 5-aminoisoquinolinone, a water soluble, potent inhibitor of the activity of poly (ADP-ribose) polymerase, in a rodent model of lung injury

L. Dugo, S. Cuzzocrea, M. McDonald, E. Mazzon, I. Serraino, M. Threadgill, A. Caputi, C. Thiemermann

Med Sci Monit 2003; 9(1): 22- :: ID: 15069


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

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Science Editor, Medical Science Monitor, International Scientific Information, Inc., Melville, NY, USA

DOI: 10.12659/MSM.941209

Med Sci Monit 2023; 29:e941209


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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750