The goal of this study is to better understand the involvement of free radicals in the mechanism of inflammatory responses at all levels from molecular/cellular biology to whole animals and, ultimately, to humans, and to advance both basic and clinical research in free radical-mediated disease processes. Overall this project tested the hypotheses that: 1) free radicals are causative molecules in the complex pathogenesis of diabetes mellitus and inflammation;and 2) specific biochemical pathways are involved in triggering generation of free radicals that may act as mediators and/or modulators of inflammatory reactions associated with human disease. In this study, free radical generation in vivo caused by endotoxin, exotoxin, streptozotocin, acetone and others has been shown in specific disease states of inflammation, pneumonia, diabetes, and ketosis. Research Accomplishments: i) Free Radical Intermediates in Diabetes Mellitus and Ketosis. We have provided ESR and immuno-spin trapping data for in vivo free radical formation as a mechanism that occurs in streptozotocin-induced diabetes and contributes to lipid peroxidation and protein nitration in the liver and kidneys. The studies demonstrated involvement of iNOS in hydroxyl radical-mediated lipid peroxidation since iNOS overexpression correlated with increased free radical production in the organs examined. In addition, we have shown that administration of acetone, a model of ketosis in diabetes, can also lead to protein oxidation and lipid peroxidation through a free radical-dependent mechanism also driven mainly by iNOS overexpression. ii) Free Radical Production in Inflammation. It has been demonstrated that free radical production in superantigen (SEB)-induced interstitial pneumonia (IP) depends on xanthine oxidase, iron and NO induction. It is concluded that macrophage toxicants, xanthine oxidase inhibitors, iron chelators, or inducible nitric oxide synthase inhibitors may be potential therapeutic agents against alveolitis and fibrosis in interstitial pneumonia iii)Free Radical Generation by Metals and Toxic Chemicals. Wide use of flame retardants can pose an environmental hazard so it is of interest to determine the mechanism of their toxicity. Of all the BFRs, 3,3',5,5'-tetrabromobisphenol A (TBBPA) is produced in the largest volume. The hydroxyl radical generated via the Fenton reaction from hydrogen peroxide reacts in vivo with DMSO to give the methyl radical, which is trapped by POBN. These observations suggest that the hepatotoxicity of TBBPA in rats may be due to the in vivo generation of the hydroxyl radical as a result of redox reactions involving the TBBPA metabolite 2,6-dibromohydroquinone and its corresponding semiquinone radical.
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