Free Radical Production and Production Mechanism in the Early and Advanced Stages of Gastrointestinal Lesions

Abstract

Disruption of redox balance due to the overproduction of free radicals and reactive oxygen species (ROS) could cause protein denaturation, lipid peroxidation, and DNA mutation. These lead to an induction of gastrointestinal diseases such as gastric ulcers induced by long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) and ulcerative colitis. Magnetic resonance technique, which is non-invasive and free of radiation exposure, is a promising tool for evaluating redox status in the living body. This study investigated ROS production in rats with gastric ulcers induced by a typical NSAIDs indomethacin using in vivo ESR/spin probe technique. The ESR signal intensity of membrane-permeable nitroxyl probe in the indomethacin group showed enhanced decay compared with the vehicle group, but the enhancement was not observed in the presence of a membrane-permeable ROS scavenger, suggesting the intracellular ROS production. The imaging analysis using Overhauser-enhanced MRI (OMRI) with dual probes labeled with 14N and 15N enabled visualization of ROS production in the glandular stomach of rat with indomethacin-induced gastric ulcers. The intracellular ROS production in the distal and proximal colon in the initiation stage and intra- and extra-cellular ROS production of the advanced stage of colitis induced by dextran sodium sulfate (DSS) using the OMRI/dual-probe technique was observed. Furthermore, nitration of src homology protein tyrosine phosphatase 2 in macrophages might be involved in the activation of Toll-like receptor 4 and NF-κB, inducing infiltration of activated neutrophils into colonic mucosa to produce ROS in DSS-induced colitis mice.