Multiple organ failure following zymosan-induced peritonitis is mediated by nitric oxide.
In the present study we tested the hypothesis that nitric oxide may play a role in the pathogenesis of multiple organ failure induced by peritoneal injection of zymosan in the rat. A severe inflammatory response characterized by peritoneal exudation, high plasma and peritoneal levels of nitrate/ nitrite (breakdown products of nitric oxide), prostaglandin E2 and leukocyte infiltration into peritoneal exudate was induced by zymosan administration. This inflammatory process started within 3 h of administration and onset occurred at 18 h, coinciding with damage of lung, small intestine and liver, as assessed by histological examination and by increase of myeloperoxidase activity, indicative of neutrophil infiltration. Furthermore, at 18 h after zymosan-induced peritonitis, expression of inducible nitric oxide synthase enzyme was found mainly in the macrophages of inflamed lungs. Subcutaneously administration of a nonisoform selective nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, reduced formation of peritoneal exudate fluid, blocked plasma and peritoneal nitrate/nitrite accumulation, and attenuated the elevated release of peritoneal prostaglandin E2. In addition, nitric oxide synthase inhibition was effective in preventing the development of organ failure since tissue injury and neutrophil infiltration, by myeloperoxidase evaluation, was reduced in lung, small 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 effective antiinflammatory therapeutic tool, since inhibits not only nitric oxide but also prostaglandin production and cellular infiltration in inflamed organs.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Zingarelli
B
B
Sautebin
L
L
Rizzo
A
A
Crisafulli
C
C
Campo
G M
GM
Costantino
G
G
Calapai
G
G
Nava
F
F
Di Rosa
M
M
Caputi
A P
AP
D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D009102:Multiple Organ Failure / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects; D010538:Peritonitis / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015054:Zymosan / Q000008:administration & dosage / Q000633:toxicity*
D009569:Nitric Oxide; D015054:Zymosan; D019001:Nitric Oxide Synthase