Peroxynitrite, a potent cytotoxic
oxidant formed by the reaction of NO with
superoxide anion, has been proposed to have major pathogenetic role in inflammatory process. Here we have investigated the therapeutic efficacy of Mn(III)tetrakis (4-benzoic acid)
porphyrin (
MnTBAP), a novel
superoxide dismutase mimetic that possesses
peroxynitrite scavenging effect, in rats subjected to
carrageenan-induced
pleurisy. In vivo treatment with
MnTBAP (3 and 10 mg/kg 5 min before
carrageenan) prevented in a dose-dependent manner the
carrageenan-induced the degree of pleural exudation, polymorphonuclear migration in rats subjected to
carrageenan-induced
pleurisy. Lung
myeloperoxidase (MPO) activity and histological organ injury was significantly reduced by
MnTBAP. However,
MnTBAP did not inhibit the inducible
NO synthase in lung samples. Immunohistochemical analysis for
nitrotyrosine, a footprint of
peroxynitrite, revealed a positive staining in lungs from
carrageenan-treated rats. No positive
nitrotyrosine staining was found in the lungs of the
carrageenan-treated rats that received
MnTBAP (10 mg/kg) treatment. In addition, in vivo
MnTBAP treatment significantly reduced in a dose-dependent manner
peroxynitrite formation as measured by the oxidation of the
fluorescent dye dihydrorhodamine 123, prevented the appearance of DNA damage, the decrease in mitochondrial respiration and partially restored the cellular level of NAD+ in ex vivo macrophages harvested from the pleural cavity of rats subjected to
carrageenan-induced
pleurisy. Our study demonstrates that the
MnTBAP exerts multiple protective effects in
carrageenan-induced
pleurisy. We suggest
peroxynitrite produced during the inflammatory process trigger
DNA strand breakage and subsequent cellular dysfunction. Part of these anti-inflammatory effects may be related to: (1) reduction of
superoxide formation due to the
superoxide dismutase-like activity of the compound and (2) scavenging of
peroxynitrite.