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INFLAMMATION AND IMMUNOPHARMACOLOGY

Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and the Development of Bleomycin-Induced Lung Injury

Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina Torre Biologica, Policlinico Universitario, Messina, Italy (T.G., E.M., R.D., A.P.C., S.C.); Department of Pharmacy & Pharmacology, University of Bath, Bath, United Kingdom (M.D.T.); and Centre for Experimental Medicine, Nephrology & Critical Care, William Harvey Research Institute, Queen Mary–University of London, London, United Kingdom (C.T.)

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.

Address correspondence to: Prof. Salvatore Cuzzocrea, Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario, Via C. Valeria–Gazzi, 98100 Messina, Italy. E-mail: salvator{at}unime.it

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