The long term objective of the proposed research will be to characterize the biological roles of 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (also called Acetyl Glyceryl Ether Phosphorylcholine or AGEPC) as a mediator of inflammation. The specifically proposed studies will focus upon elucidating the potent vasoactive properties of AGEPC, and upon its production during acute inflammation in vivo. Recently it has been documented that 1.0 picomole or less of AGEPC induces increased vascular permeability and vascular labeling as well as leukocyte emigration in the skin of experimental animals. Since 1 million neutrophils stimulated in vitro synthesize a product physicochemically and biologically identical to 1-5 picomoles of AGEPC (also, other cells including monocytes, macrophages, basophils, and platelets release AGEPC-like products), it is likely that cellular infiltrates of various inflammatory processes produce sufficient AGEPC to initiate both the vasoactive and leukotactic aspects of acute inflammation. However, vasoactive effects of locally secreted AGEPC may be influenced by a complex set of conditions including the pathophysiologic character of the microvascular response to AGEPC, the mediation or modulation of the microvascular response to AGEPC by other vasoactive molecules which may be derived from stimulated inflammatory cells, the degradation of AGEPC in tissue by plasma or cell derived enzymes, and the abundance and kinetics of AGEPC synthesis during inflammation. Therefore, the proposed studies will utilize both histologic and a combination of specialized biochemical and physiologic observations in the rat to accomplish the following: 1) characterize both the immediate and prolonged vasoactive effects of AGEPC in skin, cremaster muscle, and ileal mesentry; 2) investigate the possible roles of mast cells, neutrophils, and arachidonic acid metabolites in mediating or modulating the vasoactivity of AGEPC; 3) explore the possibility of metabolic alteration of AGEPC in skin; 4) document the synthesis of AGEPC in specific types of inflammatory skin lesions. It is hoped that these investigations will provide new information regarding the role of AGEPC as mediator of acute inflammation.
