The broad long-term objectives of this proposal are two-fold: 1) to elucidate novel endogenous pathways for antiinflammatory lipid mediators (LM) and 2) assess their contributions to human health and disease. Oxidized lipids that act on human neutrophils (PMN) are generally considered as """"""""proinflammatory mediators"""""""".1""""""""3 In this project, we found that certain mediators such as lipoxins (LX) possess down-regulatory actions in key events in inflammation and reperfusion injury. Aspirin (ASA) treatment actually triggers formation of 15-epimeric lipoxins(ATL) that may underlie some of ASA's beneficial effects in vascular disease and cancer by piratingLX signaling.In work in progress, we found that ASA also triggers two novel pathways from eicosapentanoic acid (EPA, a major fish oil). Since ASA and dietary supplements of EPA are widely used in the U.S., it is important to elucidate anti-inflammatoryactions on PMN. We propose the following novel hypothesis: Aspirin piratesformation of natural counterregulatory lipid mediators during PMN interactions with inflamed and hypoxic endothelial cells. These local mediators mimic native LXat their PMN receptors, and other new compounds we isolated antagonize proinflammatory leukotriene receptors. They down-regulate PMN and mimic novel endogenous """"""""anti-inflammatory"""""""" lipid mediator circuits. To test this, four specific aims are proposed:
Aim 1 will elucidate the novel aspirin-triggered lipid mediators (ATLM) derived from EPA during endothelial-PMN interactions and their routes of formation.A second series examines formation by hypoxic cells. The ability of ATLM to block PMN will be established and ranked.
Aim 2 addresses the recognition of novel ATLM and LX stable analogs by LXA4 and leukotriene B4 (LTB4) receptors using recombinant as well as receptor chimeras to determine mimetic/antagonist- properties, and Aim 3 focuses on activation of these receptors by ATLM and other novel ligands.
Aim 4 will focus on the impact of ATLM in inflammation and reperfusion injury using transgenic mice overexpressing LXA4 receptors or LTB4 receptors to determine whetherthese circuits are responsible for the anti- inflammation. ATLM generation will be examined in these mice given EPA and ASA treatment. Completion of these aims will provide a new paradigm to address inflammatory diseases, namely by elucidating endogenous lipid mediators of antiinflammation.
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