Rheumatoid arthritis (RA) is a disabling disease of joint inflammation affecting about 2% of adult Americans. Polymorphonuclear leukocytes (PMN) and monocytes present in the synovial fluid of rheumatoid joints generate reduced oxygen species and release proteases which contribute to the destruction of articular cartilage. The 5-lipoxygenase (5-LO) pathway of arachidonic acid (AA) metabolism leads to the production of leukotriene (LT) B4 in PMN and monocytes, and LTC4, LTD4 and LTE4 in monocytes and eosinophils. LTB4 is chemotactic for PMN and monocytes and can also cause granule and superoxide release from these cells. LTC4, LTD4 and LTE4 cause arteriorlar constriction and contraction of epithelial cells leading to fluid transudation and accumulation of proteins in extravascular compartments. Decreasing the production of LTs or substituting the production of the biologically less active pentaene analog, LTB5, could be a useful, specific, and potentially non-toxic mechanism of controlling joint inflammation.
Our aim i s to identify the role of a Omega-3 fatty acids (Omega-3FA) in altering the clinical course of RA, and to seek relationships with alterations in the cell biology and biochemistry of the 5-LO pathway of AA metabolism and of platelet activating factor (PAF) generation in leukocytes. The first goal will be to determine the effect of ingestion of Omega-3FA on the clinical course of RA and to seek relationships between clinical effects with the net production of 5-LO products and production of PAF in response to calcium ionophore A23187, generation of pentaene 5-LO products, and changes in chemotaxis by peripheral blood PMN, and to correlate changes with the lipid composition of these cells. 5-LO products will be analyzed by radioimmunoassay and high performance liquid chromatography. The second goal will be to examine the effect of incorporation of Omega-3FA on the ability of monocytes, PMN, and eosinophils to produce 5-LO products in response to the transmembrane stimulus zymosan for PMN and monocytes, and formyl-methionyl-leucyl-phenylalanine for eosinophils. The third goal is to determine the mechanism by which incorporation of Omega-3FA into cell membranes alters release of AA from the cell membranes of PMN of normal volunteers; by examining the controls and properties of PMN phospholipase A2 function and by purification of the enzyme beginning with fast protein liquid chromatography ion exchange and gel filtration techniques. The fourth goal is to identify specific differences in the enzymatic metabolism of LTB4 and LTB5 and their 20-PH derivatives.
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