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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 11, 2005; DOI: 10.1124/jpet.104.080705

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Received for publication November 15, 2004.
Revised January 7, 2005.
Accepted for publication January 7, 2005.

Inhibitors of poly (ADP-ribose) polymerase modulate signal transduction pathways and the development of bleomycin-induced lung injury

Tiziana Genovese 1, Emanuela Mazzon 1, Rosanna Di Paola 1, Carmelo Muia 1, Michael D. Threadgill 2, Achille P. Caputi 1, Christoph Thiemermann 3, Salvatore Cuzzocrea 1*

1 Univerity of Messina 2 University of Bath 3 University of London

* Address correspondence to: E-mail: salvator{at}unime.it

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 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 a significant lung injury and apoptosis (measured by ANNEXIN-V coloration). An increase of immunoreactivity to nitrotyrosine and PARP as well as a significant lost 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 (i) lost of body weight, (ii) mortality rate, (iii) infiltration of the lung with polymorphonuclear neutrophils (MPO activity), (iv) oedema formation and (v) histological evidence of lung injury. Administration of 3-AB and 5-AIQ also markedly reduced the 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.


Key words: PARP, bleomycin, cytokines., lung fibrosis, neutrophils infiltration, reactive oxyne species


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