Protective effects of a superoxide dismutase mimetic and peroxynitrite decomposition catalysts in endotoxin-induced intestinal damage.
1. The relative contributions of superoxide anion (O2-) and peroxynitrite (PN) were evaluated in the pathogenesis of intestinal microvascular damage caused by the intravenous injection of E. coli lipopolysaccharide (LPS) in rats. The superoxide dismutase mimetic (SODm) SC-55858 and the active peroxynitrite decomposition catalysts 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-disulphonatophenyl)-por phyrinato iron (III) and 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)-porphyrinato iron (III) (FeTMPS, FeTMPyP respectively) were used to assess the roles of O2- and PN respectively. 2. The intravenous injection of LPS elicited an inflammatory response that was characterized by a time-dependent infiltration of neutrophils, lipid peroxidation, microvascular leakage (indicative of microvascular damage), and epithelial cell injury in both the duodenum and jejunum. 3. Administration of the SODm SC-55858, FeTMPS or FeTMPyP at 3 h post LPS reduced the subsequent increase in microvascular leakage, lipid peroxidation and epithelial cell injury. Inactive peroxynitrite decomposition catalysts exhibited no protective effects. Only, SC-55858 inhibited neutrophil infiltration. 4. Our results suggest that O2 and peroxynitrite play a significant role in the pathogenesis of duodenal and intestinal injury during endotoxaemia and that their remoyal by SODm and peroxynitrite decomposition catalysts offers a novel approach to the treatment of septic shock or clinical conditions of gastrointestinal inflammation. Furthermore, the remarkable protection of the intestinal epithelium by these agents suggests their use during chemo- and radiation therapy, cancer treatments characterized by gastrointestinal damage. Potential mechanisms through which these radicals evoke damage are discussed.
Discovery Pharmacology, G.D. Searle, Monsanto Co, St. Louis, MO 63167, USA.
D
D
Salvemini
D P
DP
Riley
P J
PJ
Lennon
Z Q
ZQ
Wang
M G
MG
Currie
H
H
Macarthur
T P
TP
Misko
D000818:Animals; D002384:Catalysis; D003078:Colchicine / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000378:metabolism / Q000633:toxicity*; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*; D016877:Oxidants / Q000378:metabolism / Q000633:toxicity*; D011166:Porphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
C112917:5,10,15,20-tetrakis(2,4,6-trimethyl-3,3-disulfonatophenyl)porphyrinato iron(III); D005290:Ferric Compounds; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D009566:Nitrates; D009942:Organometallic Compounds; D016877:Oxidants; D011166:Porphyrins; C092399:meso-tetrakis(1-methyl-4-pyridiniumyl)porphyrin; D013481:Superoxides; C103720:SC 55858; C039642:peroxynitric acid; D013482:Superoxide Dismutase; D003078:Colchicine