ANTIINFLAMMATORY AND ANTISECRETORY POTENTIAL OF HISTIDINE IN SALMONELLA-CHALLENGED MOUSE SMALL-INTESTINE

Challenge of mouse small intestinal loops with Salmonella typhimurium invoked the accumulation of luminal fluid, acute inflammation, and ext ensive structural damage to the small intestinal mucosa, as determined by histology and electron microscopy. Intraperitoneal and intestinal luminal injection of L-histidine, a known antioxidant, reduced the amo unt of fluid accumulating in the intestinal lumen and protected the in testinal tissue from S. typhimurium-induced damage. The reduction in S . typhimurium-induced fluid accumulation by L-histidine was specific f or the L-enantiomer because D-histidine had no significant protective effect. Efficacy of L-histidine in protecting the infected intestinal tissue was attributed to the capacity of the imidazole ring to scaveng e reactive oxygen species (ROS) generated by cells in the intestine du ring the acute inflammatory response. Glutathione levels were markedly reduced in S. typhimurium-challenged, inflamed intestinal tissues as a result of ROS generation. importantly, after dosing the S. typhimuri um-challenged mice with L-histidine, the glutathione content of the sm all intestinal tissue was not significantly different from mock-challe nged controls. Further evidence favoring this mechanism included the c apacity of L-histidine to scavenge ROS produced as a result of lipopol ysaccharide (LPS) exposure of mononuclear cells (U937), as demonstrate d with a redox-sensitive fluorescent dye (2'7'-dichlorodihydrofluoresc ein [DCF]). Addition of L-histidine, and to a lesser extent D-histidin e, to the culture media of U937 cells before LPS exposure, resulted in a significant dose-dependent reduction in LPS-induced intracellular D CF fluorescence, as measured quantitatively by flow cytometry. The pot ential therapeutic value of anti-inflammatory drugs containing an L-hi stidine-like structure could protect infected mucosal tissues irrespec tive of microbial etiology.