Effects of tempol, a membrane-permeable radical scavenger, in a rodent model of carrageenan-induced pleurisy.
Carrageenan causes enhanced formation of reactive oxygen species, which contribute to the pathophysiology of inflammation. We have investigated the effects of tempol, a membrane-permeable radical scavenger, in rats subjected to carrageenan-induced pleurisy. Treatment of rats with tempol (10, 30, or 100 mg/kg 15 min prior to carrageenan) attenuated the pleural exudation and the migration of polymorphonuclear cells caused by carrageenan dose dependently. Tempol also attenuated the lung injury (histology) as well as the increase in the tissue levels of myeloperoxidase and malondialdehyde caused by carrageenan in the lung. However, tempol did not inhibit the activity of inducible nitric oxide synthase in the lungs. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenan-treated rats. Lung tissue sections from carrageenan-treated rats also showed positive staining for poly-(ADP-ribose) synthetase (PARS). The degree of staining for nitrotyrosine and PARS was markedly reduced in tissue sections obtained from carrageenan-treated rats, which had received tempol (100 mg/kg). Furthermore, treatment of rats with tempol significantly reduced (i) the formation of peroxynitrite, (ii) the DNA damage, (iii) the impairment in mitochondrial respiration, and (iv) the fall in the cellular level of NAD(+) observed in macrophages harvested from the pleural cavity of rats treated with carrageenan. Tempol also attenuated the cell injury caused by hydrogen peroxide (1 mM) in cultured human endothelial cells. This study provides the first evidence that tempol, a small molecule which permeates biological membranes and scavenges ROS, attenuates the degree of inflammation and tissue damage associated with carageenan-induced pleurisy in the rat. The mechanisms of the anti-inflammatory effect of tempol are discussed.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi 98100, Messina, Italy. salvator@www.unime.it
McDonald
M C
MC
Filipe
H M
HM
Costantino
G
G
Mazzon
E
E
Santagati
S
S
Caputi
A P
AP
Thiemermann
C
C
D000818:Animals; D002351:Carrageenan; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004249:DNA Damage; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D016877:Oxidants / Q000633:toxicity; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D009566:Nitrates; D016877:Oxidants; D013113:Spin Labels; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D002351:Carrageenan; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011065:Poly(ADP-ribose) Polymerases; C001803:tempol