Protective effects of n-acetylcysteine on lung injury and red blood cell modification induced by carrageenan in the rat.
Oxidative stress has been suggested as a potential mechanism in the pathogenesis of lung inflammation. The pharmacological profile of n-acetylcysteine (NAC), a free radical scavenger, was evaluated in an experimental model of lung injury (carrageenan-induced pleurisy). Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity that contained many neutrophils (PMNs), an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate, tumor necrosis factor alpha, and interleukin 1beta. All parameters of inflammation were attenuated by NAC treatment. Furthermore, carrageenan induced an up-regulation of the adhesion molecules ICAM-1 and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS), as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine, and PARS was reduced by NAC. In vivo NAC treatment significantly reduced peroxynitrite formation as measured by the oxidation of the fluorescent dihydrorhodamine-123, prevented the appearance of DNA damage, an 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. A significant alteration in the morphology of red blood cells was observed 24 h after carrageenan administration. NAC treatment has the ability to significantly diminish the red blood cell alteration. Our results clearly demonstrate that NAC treatment exerts a protective effect and clearly indicate that NAC offers a novel therapeutic approach for the management of lung injury where radicals have been postulated to play a role.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Italy. salvator@www.unime.it
Mazzon
E
E
Dugo
L
L
Serraino
I
I
Ciccolo
A
A
Centorrino
T
T
De Sarro
A
A
Caputi
A P
AP
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002351:Carrageenan / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects / Q000648:ultrastructure; D016166:Free Radical Scavengers / Q000494:pharmacology*; D020672:I-kappa B Proteins; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009504:Neutrophils / Q000502:physiology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D020672:I-kappa B Proteins; C000606206:Nfkbia protein, rat; D009566:Nitrates; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; C039642:peroxynitric acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D002351:Carrageenan; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases; D000111:Acetylcysteine