Effects of 5-aminoisoquinolinone, a water-soluble, potent inhibitor of the activity of poly (ADP-ribose) polymerase, in a rodent model of lung injury.
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 24hr. 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 alpha, TNFalpha) 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.
Cuzzocrea
Salvatore
S
Institute of Pharmacology, University of Messina, Policlinico Universitario, Via C. Valeria-Gazzi, I-98100, Messina, Italy. salvator@www.unime.it
McDonald
Michelle C
MC
Mazzon
Emanuela
E
Dugo
Laura
L
Serraino
Ivana
I
Threadgill
Mike
M
Caputi
Achille P
AP
Thiemermann
Christoph
C
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009243:NAD / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000201:enzymology*; D015854:Up-Regulation
C411425:5-aminoisoquinolinone; D016207:Cytokines; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D019007:P-Selectin; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D018799:Intercellular Adhesion Molecule-1; D030421:Peroxynitrous Acid; D011065:Poly(ADP-ribose) Polymerases