Protective effect of N-acetylcysteine on multiple organ failure induced by zymosan in the rat.
METHODS
In the present study, we evaluated the effect of N-acetylcysteine treatment in a nonseptic shock model induced by zymosan in the rat. Animals were randomly divided into eight groups (ten animals in each group). The first group was treated with ip administration of saline solution (0.90% NaCl) and served as the sham group. The second group was treated with ip administration of zymosan (500 mg/kg suspended in saline solution). In the third and fourth groups, rats received ip administration of N-acetylcysteine (40 mg/kg; 1 and 6 hrs after administration of zymosan or saline). In the fifth and sixth groups, rats received ip administration of N-acetylcysteine (20 mg/kg; 1 and 6 hrs after zymosan or saline administration). In the seventh and eighth groups, rats received ip administration of N-acetylcysteine (10 mg/kg; 1 and 6 hrs after zymosan or saline administration). After zymosan or saline injection, animals were monitored for the evaluation of systemic toxicity (conjunctivitis, ruffled fur, diarrhea, and lethargy), loss of body weight, and mortality for 72 hrs. Exudate formation, leukocyte infiltration, nitrate/nitrite production, lung and intestine myeloperoxidase activity and lipid peroxidation, and histologic examination were evaluated at 18 hrs after zymosan administration.


RESULTS
Administration of zymosan in the rat induced acute peritonitis, as assessed by a marked increase in the leukocyte count in the exudate, as well as by an increase in the exudate nitrate/nitrite concentration. Lung and intestine myeloperoxidase activity and lipid peroxidation was significantly increased in zymosan-treated rats. This inflammatory process coincided with the damage of lung and small intestine. Peritoneal administration of zymosan in the rat also induced a significant increase in the plasma levels of nitrite and nitrate and stable metabolites of nitric oxide and in levels of peroxynitrite, as measured by the oxidation of the fluorescent dihydrorhodamine 123 at 18 hrs after zymosan challenge. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, in the lung of zymosan-shocked rats. Pretreatment of zymosan-shocked rats with ip administration of N-acetylcysteine (40, 20, and 10 mg/kg, 1 and 6 hrs after zymosan) prevented the development of peritonitis and reduced peroxynitrite formation in a dose-dependent manner. In addition, ip administration of N-acetylcysteine (40 mg/kg, 1 and 6 hrs after zymosan) was effective in preventing the development of lung and intestine injury and neutrophil infiltration, as determined by myeloperoxidase evaluation.


CONCLUSIONS
Taken together, the present results demonstrate that N-acetylcysteine exerts potent anti-inflammatory effects.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Italy. salvator@imeuniv.unime.it
Costantino
G
G
Mazzon
E
E
Caputi
A P
AP
D000111:Acetylcysteine / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000276:immunology / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis; D013997:Time Factors; D015054:Zymosan
D016166:Free Radical Scavengers; D009566:Nitrates; C039642:peroxynitric acid; D009569:Nitric Oxide; D015054:Zymosan; D000111:Acetylcysteine