PAF is an exceedingly potent phospholipid hormone with key inflammatory and immune activities. PAF receptor antagonists, which are specific for this receptor, block early steps of inflammation, reperfusion injury in a host of tissues, and slow atherogenesis, Unsurprisingly, its synthesis is tightly controlled. We have identified a new class of compounds that activate the PAF receptor. These equally potent compounds arise from uncontrolled oxidation of cellular and lipoprotein phospholipids, and thus are formed under the very conditions found during inflammation and immune responses. These PAF-like lipids stimulate the cloned human PAF receptor, activate inflammatory cells in vitro, and stimulate smooth muscle cell mitogenesis. They, and not PAF, may be the actual mediators in these conditions. The overriding hypothesis to be tested here is PAF-LIKE LIPlDS INAPPROPRIATELY AND EXCESSIVELY INDUCE PATHOLOGIC INFLAMMATORY RESPONSES. The specific hypotheses to be tested in this proposal are: A) PAF-like lipids alter the PAF receptor to an unusual conformation that activates unique intracellular signal transduction pathways B) PAF-like lipids mimic the pathophysiologic roles of PAF C) PAF-like lipids have specific sn-2 arachidonoyl-derived residues that overcome the PAF receptor's requirement for a short sn-2 residue D) Inflammatory conditions produce free radicals that oxidize Low Density Lipoprotein or cellular membrane phospholipids to create PAF-like lipids.
The Specific Aims of this project are: 1) Determine how PAF-like lipids stimulate the PAF receptor 2) Determine if PAF-like lipids are multipotent inflammatory mediators 3) Identify PAF-like lipids and their precursors 4) Determine if PAF-like lipids occur in pathologic states and are pro- inflammatory We anticipate we will define the mechanism of action of this potent class of inflammatory mediators we discovered and described. These are products of uncontrolled free radical reactions so we anticipate these compounds couple the production of free radicals to an immediate inflammatory response and the conversion to a prolonged one. These underlying conditions exist during atherogenesis and reperfusion injury in many tissue beds. PAF antagonists suppress this; we propose the actual mediators are PAF-like lipids. A better understanding of how these interact with the PAF receptor will allow better design of receptor antagonists with the aim of improving their efficacy in models of atherosclerosis, coronary and other vascular diseases.
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