It is well established, but not generally appreciated, that perinatal serum concentrations of non-esterified docosahexaenoic acid (22:6 n-3) are approximately 5-50 times higher than that in normal adult serum. Such high concentrations support the growth and development of the brain which is rich in this omega-3 fatty acid. Recent data from this laboratory indicate that such high concentrations of docosahexaenoic acid, but not arachidonic acid, have profound inhibitory effects on macrophage activation in vitro. This may contribute to the increased susceptibility of fetuses and neonates to infection. Such perinatal infections remain a major clinical problem causing, not only acute mortality and morbidity, but also long-lasting sequelae such as birth defects and mental retardation. A difficulty in treating such infections is the well- documented immaturity of the host system during intrauterine and neonatal life. The overall goal of this proposal is to understand how docosahexaenoic acid inhibits macrophage function - and thus, the pathogenesis of perinatal infections. The proposed experiments focus on the effects of DHX on additional macrophage functions important in fetal host-defenses. These include a) Inhibition of macrophage Ia-expression. Cell-surface expression of these molecules is known to be impaired in the fetus, and this results in the inability of fetal macrophages to active T-lymphocytes. b) Inhibition of the ability of macrophages to kill intracellular pathogens. c) Alteration of prostaglandin and leukotriene production by macrophages. Docosahexaenoic acid alters the secretion of these important molecules by other cell types. Further experiments will examine the mechanisms of docosahexaenoic acid-inhibition of macrophage activation. Docosahexaenoic acid is an omega-3 fatty acid which is a major component of fish oil diets. Such diets have been used in the therapy of certain autoimmune diseases, atherosclerosis, and cancer. Given the important role of macrophage activation in these diseases, the proposed experiments may aide our understanding of the beneficial effects of such diets.
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