Patrick J. Lennon

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

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)‐porphyrinato 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. 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. 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. Our results suggest that O2− 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 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.

New conformationally constrained polyaza macrocycles prepared via the bis(chloroacetamide) method

Abstract The synthesis of two new series of conformationally constrained polyazamacrocycles featuring polysubstitution at macrocycle ring carbons is described.