C Szabo, C Saunders, M O'Connor and AL Salzman
Division of Critical Care, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Recent studies show that peroxynitrite is a potent trigger of DNA strand breakage, which in turn activates the nuclear repair enzyme poly (ADP-ribose) synthetase (PARS), resulting in a cellular energy deficit. Here we present evidence that treatment of A549 human pulmonary epithelial cells with peroxynitrite (1 mM) results in ADP-ribosylation, NAD+ depletion, inhibition of mitochondrial respiration, and increased epithelial paracellular permeability. The PARS inhibitor 3- aminobenzamide (1 mM) provided a significant, partial protection against the energetic and functional changes. Similarly, inhibition of PARS activity by 3-aminobenzamide reduced the peroxynitrite-induced suppression of mitochondrial respiration in BEAS-2B human bronchial epithelial cells. Thus, PARS activation and energy depletion represents one of the pathways of peroxynitrite-mediated epithelial toxicity. Inhibition of PARS may improve cellular energy homeostasis in pathophysiologic conditions associated with peroxynitrite generation.

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