Leukotrienes (LTs) have been implicated in the regulation of immune responses, including inflammation and allograft rejection. These molecules belong to a family of biologically active lipids called eicosanoids that are derived from arachidonic acid (AA). The eicasanoids include both the cylooxygenase products(prostaglandins and thromboxanes) and the 5-lipoxygenase (5lo) products, the leukotrienes. The conversion of AA to leukotriene A4 (LTA4) by the enzyme 5lo is the first step in the synthesis of all leukotrienes. LTA4 can either be converted to leukotriene B4 by LTA4 hydrolase or be conjugated with reduced glutathione by LTC4 synthase to form the peptidyl leukotrienes, LTC4 and LTD4. We have generated mouse lines deficient in the synthesis of all leukotrienes and a line defective in the production of only LBT4. We have used these mice to define the contribution of lipids to various acute and chronic inflammatory responses including allograft rejection. We have found that this role can differ significantly depending on the sex of the mice and on the strain of the animals. One or more of these factors could be shown to be variables in both acute and chronic inflammatory responses. Initial studies suggest that the contribution of leukotrienes to allograft rejection may also be dependent on the strain combination examined. The overall aim of this proposal is to define the mechanism(s) by which the genetic background of host and graft determine the contribution of leukotrienes to inflammatory responses including acute and chronic allograft rejection. We will do this by testing the following possible hypotheses. a. Leukotriene synthesis by either the infiltrating leukocytes or the somatic cells of the graft is higher in strains in which ablation of this pathway has the greatest impact. b. Expression of leukotriene receptors is qualitatively or quantitatively different in these strains. c. Related pathways such as the cyclooxygenase pathway or lipoxin pathway are differentially modulated in various strains when 5lo pathway is blocked.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Duke University
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