PHAGOCYTE RESOLVING METABOLISM

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Inflammation is usually self-limited and when "uncontrolled" leads to tissue damage and organ dysfunction. The resolution phase is a series of essential cellular processes that lead from acute inflammation to homeostasis, namely catabasis that has been widely believed to be a passive process 1, 2, 3. In this laboratory, new evidence has emerged indicating that resolution is an active process with the identification of novel specialized lipid-derived mediators (LM) we termed resolvins and docosatrienes (protectins) that limit key events in inflammation and tissue injury. It is now clear that the balance of novel LM within resolution is critical. The focus of this project is the systematic elucidation of further metabolic (likely inactivation) routes within resolution using mediator-lipidomics and in vivo models. In work in progress, we found that resolvins, namely, RvE1 and the docosatriene 10,17-DT, actively counter-regulate murine and human neutrophils (PMN). We will focus on the pathways that metabolically transform these LM and test the hypothesis that: Resolution requires timely metabolic breakdown of pro-resolving lipid mediators. Resolvins and docosatrienes are endogenous anti-inflammatory signals that temporally counter-regulate proinflammatory circuits and govern PMN traffic toward resolution. Local inactivation of these novel endogenous antiinflammatory mediators is essential for catabasis. To this end, four specific aims are proposed, which include: Aim 1. Establishing the structures and pathways of Rv and DT-derived metabolites in resolution in vivo and human PMN; 2. Identify the resolution interval(s) when Rv & DT transformation pathways are operative; 3. Determine the actions of the new RvE1 and 10,17-DT-derived metabolites with human PMN; 4. Renal transplant rejection and protection studies. Long-term goals for this project are 2-fold: a) to elucidate the inactivation pathways for LM involved in resolution-inflammation and b) to provide biochemical map(s) of these essential resolution pathways to clinicians, knowledge of which can improve current treatments.