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

Salvatore Cuzzocrea, Michelle C. McDonald, Emanuela Mazzon, Laura Dugo, Ivana Serraino, Mike Threadgill, Achille P. Caputi, Christoph Thiemermann

Research output: Contribution to journalArticle

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. The aim of the present study was to evaluate the effects of a novel and potent inhibitor of PARP activity on neutrophil recruitment in the acute inflammation induced by zymosan-activated plasma. Intra-thoracic administration of zymosan-activated plasma leads to an increase in neutrophil infiltration of the lung at 24 hr. The potent PARP inhibitor 5-aminoisoquinolinone (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 injured lung. 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 α, TNFα) was also attenuated by 5-AIQ. These findings provide the first evidence that the activation of PARS participates in neutrophil-mediated lung injury by regulating the expression of P-selectin and ICAM-1.

Original languageEnglish
Pages (from-to)293-304
Number of pages12
JournalBiochemical Pharmacology
Volume63
Issue number2
DOIs
Publication statusPublished - Jan 15 2002

Keywords

  • 5-Aminoisoquinolinone
  • Complement
  • Oxygen radicals
  • Pleurisy
  • Poly (ADP-ribose) synthase
  • Zymosan-activated plasma

ASJC Scopus subject areas

  • Pharmacology

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