MULTIPLE ORGAN FAILURE FOLLOWING ZYMOSAN-INDUCED PERITONITIS IS MEDIATED BY NITRIC-OXIDE

In the present study we tested the hypothesis that nitric oxide may pl ay a role in the pathogenesis of multiple organ failure induced by per itoneal injection of zymosan in the rat. A severe inflammatory respons e characterized by peritoneal exudation, high plasma and peritoneal le vels of nitrate/nitrite (breakdown products of nitric oxide), prostagl andin E-2 and leukocyte infiltration into peritoneal exudate was induc ed by zymosan administration. This inflammatory process started within 3 h of administration and onset occurred at 18 h, coinciding with dam age of lung, small intestine and liver, as assessed by histological ex amination and by increase of myeloperoxidase activity, indicative of n eutrophil infiltration. Furthermore, at 18 h after zymosan-induced per itonitis, expression of inducible nitric oxide synthase enzyme was fou nd mainly in the macrophages of inflamed lungs. Subcutaneously adminis tration of a nonisoform selective nitric oxide synthase inhibitor, N-G -nitro-L-arginine methyl ester, reduced formation of peritoneal exudat e fluid, blocked plasma and peritoneal nitrate/nitrite accumulation, a nd attenuated the elevated release of peritoneal prostaglandin E-2. In addition, nitric oxide synthase inhibition was effective in preventin g the development of organ failure since tissue injury and neutrophil infiltration, by myeloperoxidase evaluation, was reduced in lung, smal l intestine, and liver. In conclusion, major findings of our study are that nitric oxide exerts a proinflammatory role in the development of multiple organ failure and nitric oxide synthase inhibition is an eff ective antiinflammatory therapeutic tool, since inhibits not only nitr ic oxide but also prostaglandin production and cellular infiltration i n inflamed organs.