The long-term objective of this research project is to determine the toxicological and clinical significance of a unique class of cytotoxic compounds, namely, the diol metabolites of monoepoxides of linoleic acid (leukotoxin and isoleukotoxin). These monoepoxides are found at high levels in the serum of patients with severe burns and acute respiratory distress syndrome (ARDS) and was shown to cause coronary cardiac arrest and severe lung edema in experimental animals. Recent results by the investigator, however, show that leukotoxin and isoleukotoxin are toxic only in cells which contain epoxide hydrolase. This suggests that the pathological effects previously attributed to the epoxides are actually due to the diol metabolites. Based on these results, the specific aims of this application are to: (1) Chemically synthesize the monoepoxides and corresponding diol isomers of linoleic acid, (2) Analyze the biological activity of these synthesized compounds using in vitro (cardiac myocytes) and transgenic mouse models, (3) Use a heterologous expression system to identify human enzyme pathways which lead to the production of these compounds, and (4) Identify and quantify these compounds in the serum of patients with acute respiratory distress syndrome.
These specific aims are designed to test the hypothesis that linoleic acid diols directly cause or mediate effects that were previously attributed to the parent epoxides and that enzymatically catalyzed diol formation is the rate limiting step. This work will provide a basis for developing specific inhibitors of epoxide hydrolases in order to prevent the formation of these compounds during acute inflammation in humans.
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