A cascade of linoleic acid metabolites has recently been identified, and its involvement in the pathogenesis of diseases related to over- stimulation of inflammation, such as Adult Respiratory Distress Syndrome (ARDS) has been suggested. ARDS occurs in 150,000 patients annually in the U.S. and causes greater than 50% mortality, but the underlying cause of pulmonary damage remains poorly understood. It is known that leukotoxin (9,10-epoxy-12-octadecanoate) is present in large quantities in these patients and consequently, it has been proposed as a causative agent for ARDS. Leukotoxin is produced from linoleic acid in neutrophils. Leukotoxin appears to be a pro-toxin; only leukotoxin diol, and not the parent epoxide, is toxic in a variety of systems. These diverse systems include HeLa cells, bronchiolar epithelium and cardiac muscle. The central hypothesis of this application is that the biosynthesis of linoleate oxylipins by neutrophils and pulmonary macrophages causes the pulmonary epithelial damage associated with ARDS and with severe burns.
Three specific aims will be pursued to test this hypothesis. First, the mechanism of production of linoleate oxylipins by human and rat neutrophils and macrophages will be characterized, and the plasma and bronchoalveolar concentrations of linoleate oxylipins in ARDS patients will be measured. Second, in order to establish an immune function for these oxylipins, the toxicity of leukotoxin and leukotoxin diol to microorganisms and mammalian cells will be compared. Finally, the effect of dietary linoleic acid content on the production of linoleate oxylipins will be assessed. As a part of this third study, the pulmonary pathology resulting from the inflammation response elucidated in animals consuming various amounts of linoleic acid will be evaluated relative to linoleate oxylipins production. A clear understanding of the mechanisms responsible for production and release of cytotoxic linoleate oxylipins by inflammatory cells may allow the design of new therapeutic interventions for burn and ARDS patients.
| Yu, Z; Xu, F; Huse, L M et al. (2000) Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res 87:992-8 |
