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 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.
Footnotes
-
doi:10.1124/jpet.104.080705.
-
ABBREVIATIONS: ROS, reactive oxygen species; PARP, poly(ADP-ribose) polymerase; BLEO, bleomycin; 3-AB, 3-aminobenzamide; GPI6150 1,11b-dihydro-[2H]benzopyrano[4,3,2-de]isoquinolin-3-one; PJ34, dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; 5-AIQ, 5-aminoisoquinolinone [5-aminoisoquinolin-1(2H)-one]; 1,5-DHIQ, 1,5-dihydroxyisoquinoline (5-hydroxyisoquinolin-1(2H)-one); PBS, phosphate-buffered saline; PAR, poly(ADP-ribose); MPO, myeloperoxidase; BLM, basolateral membrane; PMN, polymorphonuclear leukocyte; TNF, tumor necrosis factor, IL, interleukin; PI, propidium iodide; FITC, fluorescein isothiocyanate; EMSA, electrophoretic mobility shift assay; NF, nuclear factor; FR-167653, 1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo [5,1-c][1,2,4] triazin-2-yl]-2-phenylethanedione sulfate monohydrate.
- Received November 15, 2004.
- Accepted January 7, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|