(Taken directly from the application): Leukotrienes (LTs), potent lipid mediators derived from arachidonic acid (AA), can be isolated from virtually all inflammatory lesions and thus have been implicated in the pathogenesis of both acute and chronic inflammatory diseases, including allograft rejection. However, as response to inflammatory stimuli results in the activation of numerous mediators with overlapping activities, defining the role of LTs in the initiation, perpetuation and resolution of a particular inflammatory lesion in vivo has been difficult. To address this question directly we have generated mice deficient in the synthesis of these lipid. Specifically we have generated mice deficient in 5-lipoxygenase (5LO) and 5-lipoxygenase activating protein (FLAP) proteins essential for the production of all biologically active LTS, and in LTA4hydrolase, an enzyme required for the synthesis of LTB4-Using these mouse lines we have defined a role for these lipids in models of acute inflammation. These models provide simple in vivo systems for defining the contribution of these lipid mediators to inflammatory responses. In addition they provide systems for; identification of specific cell types that produce and are affected by these lipids, for the study of the regulation of the LT pathway in vivo, and for defining the interaction of LTS with other inflammatory mediators. Using these models, studies completed during the preceding grant period have identified powerful effects of background genes on the relative contributions of LTS to inflammation. Based on these data, we hypothesize that genetic factors have a profound influence on the actions of LTS in inflammatory responses including allograft rejection. In this application we will define the mechanisms by which genetic factors modify the role of leukotrienes in acute inflammation. In addition we will determine whether these same genetic factors determine the contribution of LTS to the initiation and progression of allograft destruction. Finally, we will determine the relative anti-inflammatory effects of ablating LT receptor signaling compared to inhibition of LT synthesis in both acute inflammation and in allograft rejection. We will determine whether, similar to the effects of inhibition of LT synthesis, the impact of this lesion can also be altered by modifier genes.
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