Inflammatory cells play an important pathogenic role in immune-mediated glomerulonephritis and vascular disease. These cells are known to be capable of synthesizing a variety of biologically active metabolites of arachidonic acid. Essential fatty acid deficiency (which leads to a lack of arachidonate) and a diet enriched in eicosapentaenoic acid (which substitutes for arachidonate) have been shown to prevent the inflammatory cell infiltrate and glomerular damage in the glomerulonephritis seen in a murine model of human systemic lupus erythematosus. The central hypothesis of the proposed research is that metabolites of arachidonic acid may initiate and perpetuate the injury in glomerulonephritis and vasculitis. To test this hypothesis changes in histology (i.e., the invasion of inflammatory cells) during the development of glomerulonephritis and vasculitis will be correlated with changes in arachidonate metabolism. Pharmacologic manipulations (inhibition of cyclooxygenase or lipoxygenase) and essential fatty acid deficiency will be utilized to elucidate the role of arachidonate metabolites in these disorders. Immunologic tools (such as nitrogen mustard, glucan, and monoclonal antibodies against leukocyte classes) will be used to gain an understanding of the relationship between the inflammatory cells in these disorders and changes in arachidonate metabolism. The long-term objective is to develop new strategies for ameliorating the glomerular or vascular injury in immunemediated glomerulonephritis and vasculitis in man.
