Macrophages play an important pathogenic role in immune- mediated glomerulonephritis. These cells are known to be capable of synthesizing a number of biologically active metabolites of arachidonic acid and to be able to influence the proliferation of resident glomerular mesangial cells. Essential fatty acid deficiency (which leads to a lack of arachidonate and an accumulation of the abnormal fatty acid 20:3(n-9)) has been shown to prevent the inflammatory cell infiltrate and glomerular damage in immune-mediated glomerulonephritis. Therefore, the central hypothesis of the proposed project is that arachidonate and its metabolites play a critical role in initiating and perpetuating the injury in glomerulonephritis. To test this hypothesis the changes in glomerular arachidonate metabolism that occur in nephritis will be determined. Immunologic agents (such as nitrogen mustard, radiation, glucan, and endotoxin) will be used to elucidate the relationship between the inflammatory cell infiltrate in nephritis and the observed changes in glomerular arachidonate metabolism. Essential fatty acid deficiency will be utilized to help determine the role of arachidonate and its metabolites in attracting leukocytes into the glomerulus and in the functional deficits of nephritis. The cellular and biochemical mechanisms underlying the changes in glomerular arachidonate metabolism in nephritis will be investigated by determining the effects of macrophages on mesangial cell arachidonate metabolism and proliferation in culture. Pharmacologic manipulations (inhibition of cyclooxygenase of lipoxygenase) will be utilized to establish the role of arachidonate metabolism in the functional deficits of glomerulonephritis. The goal of the proposed study is to develop pharmacologic and/or dietary strategies to prevent the tissue injury and renal dysfunction in glomerulonephritis which avoid the toxicity of present therapeutic modalities. Additionally, understanding the mechamisms by which inflammatory cells interact with resident tissue cells and produce changes in tissue metabolism and function may elucidate the pathogenesis of other inflammatory conditions.
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