RT Journal Article
SR Electronic
T1 Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and the Development of Bleomycin-Induced Lung Injury
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 529
OP 538
DO 10.1124/jpet.104.080705
VO 313
IS 2
A1 Genovese, Tiziana
A1 Mazzon, Emanuela
A1 Paola, Rosanna Di
A1 Muià, Carmelo
A1 Threadgill, Michael D.
A1 Caputi, Achille P.
A1 Thiemermann, Christoph
A1 Cuzzocrea, Salvatore
YR 2005
UL http://jpet.aspetjournals.org/content/313/2/529.abstract
AB Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with inflammation. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in an experimental model of lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury and apoptosis (measured by Annexin V coloration). An increase of immunoreactivity to nitrotyrosine and PARP, as well as a significant loss of body weight and mortality, was observed in the lung of bleomycin-treated mice. Administration of the two PARP inhibitors 3-aminobenzamide (3-AB) or 5-aminoisoquinolinone (5-AIQ) significantly reduced the 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) edema formation, and 5) histological evidence of lung injury. Administration of 3-AB and 5-AIQ also markedly reduced nitrotyrosine formation and PARP activation. These results demonstrate that treatment with PARP inhibitors reduces the development of inflammation and tissue injury events induced by bleomycin administration in the mice. The American Society for Pharmacology and Experimental Therapeutics