The long-term objective of the proposed studies will be to characterize the regulation of the synthesis and release of platelet-activating factor (PAF). From human neutrophilic polymorphonuclear leukocytes (PMN). PAF is a recently described class of lipid mediator which includes the acetylated alkyl phosphoglycerides, acetyl glyceryl ether phosphorylcholine (AGEPC). AGEPC has been shown to be one of the most potent inflammatory mediators thus far described and possesses a remarkable spectrum of platelet dependent and independent inflammatory properties, e.g., platelet, PMN and monocyte stimulation, smooth muscle contraction, and the initiation of increased vascular permeability. Moreover, PAF is synthesized and released by PMN, monocytes, platelets, mast cells, basophils, endothelial cells and likely other cell types strengthening the hypothesis that this lipid autacoid is involved in normal as well as abnormal inflammatory responses. Indeed, PAF is now strongly implicated in mediating a variety of cardiovascular and pulmonary alterations and acute vascular tissue injury. Thus, alterations in the homeostatic mechanisms regulating both the synthesis and release of PAF may be a key factor involved in the pathologic potential of this potent inflammatory mediator. Preliminary evidence now indicates that the amount and duration of PAF synthesis by FMLP-stimulated human PMN is tightly coupled to the ability of the PMN to release the newly-synthesized PAF. However, this hypothesis is based upon the results of experiments utilizing only FMLP-stimulated PMN. Thus, the proposed studies will extend these findings and focus upon several intra-and extracellular factors regulating PAF release from human PMN stimulated with several physiologically relevent soluble secretagogues and phagocytic stimuli. Of major emphasis will be the regulation of PAF metabolism by factors such as divalent cations, albumin and arachidonic acid metabolism. Hopefully, the results of these studies will provide new and valuable information for future studies designed to prevent or treat PAF-mediated inflammatory diseases affecting man.
