Beneficial effects of tempol, a membrane-permeable radical scavenger, on the multiple organ failure induced by zymosan in the rat.
METHODS
We investigated the effects of tempol, a membrane-permeable radical scavenger, on the multiple organ failure (MOF) caused by zymosan in the rat. Zymosan (500 mg/kg, suspended in saline solution, ip) enhances formation of reactive oxygen species, which contribute to the pathophysiology of MOF. After zymosan or saline administration, animals were monitored for 12 days.


RESULTS
Treatment of rats with tempol (10, 30, or 100 mg/kg ip, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan in a dose-dependent fashion. Tempol also attenuated the lung, liver, and intestinal injury (histology) as well as the increase in the concentrations of myeloperoxidase and malondialdehyde caused by zymosan in the lung, liver, and intestine. Immunohistochemical analysis for nitrotyrosine and for poly(adenosine 5'-diphosphate-ribose)synthetase demonstrated a positive staining in lung, liver, and intestine from zymosan-treated rats. The degree of staining for nitrotyrosine and for poly(adenosine 5'-diphosphate-ribose) synthetase was markedly reduced in tissue sections obtained from zymosan-treated rats that had received tempol (100 mg/kg ip). Furthermore, treatment of rats with tempol significantly reduced the following: a) the formation of peroxynitrite, b) the DNA damage, c) the impairment in mitochondrial respiration, and d) the decrease in the cellular concentration of oxidized nicotinamide adenine dinucleotide observed in macrophages harvested from the peritoneal cavity of rats treated with zymosan.


CONCLUSIONS
This study provides the first evidence that tempol, a small molecule that permeates biological membranes and scavenges reactive oxygen species, attenuates the degree of MOF associated with zymosan-induced peritonitis in the rat.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, Univeristy of Messina, Italy.
McDonald
M C
MC
Mazzon
E
E
Filipe
H M
HM
Centorrino
T
T
Lepore
V
V
Terranova
M L
ML
Ciccolo
A
A
Caputi
A P
AP
Thiemermann
C
C
D000704:Analysis of Variance; D000818:Animals; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000188:drug therapy*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D018709:Statistics, Nonparametric; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015054:Zymosan / Q000506:poisoning
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D013113:Spin Labels; C002744:3-nitrotyrosine; D014443:Tyrosine; D015054:Zymosan; D011065:Poly(ADP-ribose) Polymerases; C001803:tempol