Protective effects of a superoxide dismutase mimetic and peroxynitrite decomposition catalysts in endotoxin-induced intestinal damage

1 The relative contributions of superoxide anion (O-2(-)) 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 pero xynitrite decomposition catalysts 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-d isulphonatophenyl)-porphyrinato iron (III) and 5,10,15,20-tetrakis(N-methyl -4'-pyridyl)-porphyrinato iron (III) (FeTMPS, FeTMPyP respectively) were us ed to assess the roles of O-2(-) and PN respectively. 2 The intravenous injection of LPS elicited an inflammatory response that w as characterized by a time-dependent infiltration of neutrophils, lipid per oxidation, 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 re duced 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 infilt ration. 4 Our results suggest that O-2(-) and peroxynitrite play a significant role in the pathogenesis of duodenal and intestinal injury during endotoxaemia and that their removal by SODm and peroxynitrite decomposition catalysts of fers a novel approach to the treatment of septic shock or clinical conditio ns of gastrointestinal inflammation. Furthermore, the remarkable protection of the intestinal epithelium by these agents suggests their use during che mo- and radiation therapy, cancer treatments characterized by gastrointesti nal damage. Potential mechanisms through which these radicals evoke damage are discussed.