RETRACTED: Peroxynitrite‐mediated DNA strand breakage activates poly (ADP‐ribose) synthetase and causes cellular energy depletion in carrageenan‐induced pleurisy

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Abstract
The aim of the present study was to investigate the role of poly (ADP‐ribose) synthetase in acute local inflammation (carrageenan‐induced pleurisy), where oxyradicals, nitric oxide and peroxynitrite are known to play a crucial role in the inflammatory process. DNA single‐strand breakage and activation of the nuclear enzyme poly (ADP‐ribose) synthetase (PARS) triggers an energy‐consuming, inefficient repair cycle, which contributes to peroxynitrite‐induced cellular injury. Here we investigated whether peroxynitrite production and PARS activation are involved in cytotoxicity in macrophages collected from rats subjected to carrageenan‐induced pleurisy. Macrophages harvested from the pleural cavity exhibited a significant production of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, and by nitrotyrosine Western blotting at 4 hr after carrageenan injection. Furthermore, carrageenan‐induced pleurisy caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, activation of PARS and reduction of NAD+ cellular levels. In vivo treatment with 3‐aminobenzamide (10 mg/kg intraperitoneally, 1 hr after carrageenin injection) significantly inhibited the decrease in mitochondrial respiration and the activation of PARS and partially restored the cellular level of NAD+. In a separate group of experiments, in vivo pretreatment with NG‐nitro‐L‐arginine methyl ester, a non‐selective inhibitor of nitric oxide (NO) synthesis (10 mg/kg intraperitoneally, 15 min before carrageenan administration), reduced peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration and the loss of cellular levels of NAD+. Our study suggests that formation of peroxynitrite and subsequent activation of PARS may alter macrophage function in inflammatory processes and inhibition of NO and PARS may be a novel pharmacological approach to prevent cell injury in inflammation.

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