The experimental model of renal allograft rejection is not only an excellent example of cell mediated glomerular destruction, but also cell mediated tubular dysfunction and damage. While other projects in this Center Grant are directed at defining the role of potent biological mediators on glomerular dysfunction and destruction, this project will be concerned with the tubular portion of the nephron. The effects of three categories of substances will be examined. First, the effects of lipid derived mediators and monokines from inflammatory cells will be determined. In addition the effects of supernatants from cultured activated mononuclear cells on the function of selected nephron segments will be examined. These include the sulfidopeptide leukotrienes LTC4 and LTD4, platelet activating factor, interleukin 1, and gamma interferon. The second category includes the important mitogen epidermal growth factor. The third category is represented not by an endogenously derived substance, but by the critically important immunosuppressive agent cyclosporin A. While it is well appreciated that this compound has contributed significantly to the clinical success of renal transplantation, the rationale for studying its effects is based on its well known toxicity. All studies will utilize the general technique of in vitro microperfusion and are designed to test specific transport processes in defined nephron segments likely to be affected by these classes of molecules. The results of these studies should contribute significantly to our understanding of tubular function derangements observed during inflammatory cell mediated destruction of nephrons.
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