Protective effect of N-acetylcysteine on multiple organ failure induced byzymosan in the rat

Background and Methods: In the present study, we evaluated the effect of N- acetylcysteine treatment in a nonseptic shock model induced by zymosan in t he 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. 9% 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-acetylcystei ne (40 mg/kg; 1 and 6 hrs after administration of zymosan or saline). In th e fifth and sixth groups, rats received ip administration of N-acetylcystei ne (20 mg/kg; 1 and 6 hrs after zymosan or saline administration). In the s eventh and eighth groups, rats received ip administration of N-acetylcystei ne (10 mg/kg; 1 and 6 hrs after zymosan or saline administration). After zymosan or saline injection, animals were monitored for the evaluatio n of systemic toxicity (conjunctivitis, ruffled fur, diarrhea, and lethargy ), loss of body weight, and mortality for 72 hrs. Exudate formation, leukoc yte infiltration, nitrate/nitrite production, lung and intestine myeloperox idase activity and lipid peroxidation, and histologic examination were eval uated 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 we ll as by an increase in the exudate nitrate/nitrite concentration. Lung and intestine myeloperoxidase activity and lipid peroxidation was significantl y increased in zymosan-treated rats. This inflammatory process coincided wi th 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 oxidati on of the fluorescent dihydrorhodamine 123 at 18 hrs after zymosan challeng e. Immunohistochemical examination demonstrated a marked increase in the im munoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, i n the lung of zymosan-shocked rats. Pretreatment of zymosan-shocked rats wi th ip administration of N-acetylcysteine (40, 20, and 10 mg/kg, 1 and 6 hrs after zymosan) prevented the development of peritonitis and reduced peroxy nitrite formation in a dose-dependent manner. In addition, ip administratio n of N-acetylcysteine (40 mg/kg, 1 and 6 hrs after zymosan) was effective i n preventing the development of lung and intestine injury and neutrophil in filtration, as determined by myeloperoxidase evaluation. Conclusions: Taken together, the present results demonstrate that N-acetylc ysteine exerts potent anti-inflammatory effects.