Proliferation of synovial cells is a hallmark of rheumatoid arthritis and is a central event in the process leading to joint tissue injury in rheumatoid arthritis patients. Little is known about why these cells proliferate or how abnormal cell growth can be regulated. Certain fatty acids and their oxidative metabolites, termed eicosanoids, are capable of influencing cell proliferation. The major eicosanoid precursor in mammalian cells is arachidonic acid (AA), precursor to dienoic prostaglandins. The generation and activities of eicosanoids can be modified by adding to cells in vitro or to diets in vivo, substrates other than AA for oxidative metabolism. The goals of this proposal are to determine the effects of eicosapentaenoic acid (EPA), an omega-3 fatty acid (FA) prominent in fish lipid and precursor to trienoic prostaglandins, on proliferation of human synovial cells in tissue culture. The effect on cell growth of another novel omega 3-FA found in high concentration in fish oil - docosahexaenoic acid (DCHA) will also be determined. DCHA is not a prostaglandin precursor, but FA themselves have important effects on cell function and can influence metabolism of other FA. The metabolism of EPA (uptake by cells, distribution into phospholipids including a poorly understood but potentially important phospholipid termed plasmalogen, conversion to trienoic prostaglandins) will be studied. The influence of DCHA and other FA on EPA metabolism and action on cell proliferation will be investigated. The potential effects of dietary fish oil supplements on synovial cell proliferation and function and peripheral blood monocyte function (mediator release, plasmalogen formation) will be studied. A unique animal model of inflammation, the dorsal subcutaneous air pouch in the rat, will be utilized to determine the effect of diets enriched in omega-3 FA on acute and chronic inflammation and on growth of the synovial-like cells which line the pouch. Further understanding of synovial cell proliferation and of inexpensive nontoxic means to control it should be useful in the search for agents which will be beneficial to patients with diseases characterized by chronic inflammation and abnormal cell growth.
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