BIOTRANSFORMATION OF PLATELET ACTIVATING FACTOR

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An influx of neutrophils and macrophages characterizes the inflammatory process. These cells respond to phagocytic and soluble stimuli by producing inflammatory mediators including the arachidonic acid metabolites and platelet activating factor (PAF). The production of PAF and the arachidonic acid derived mediators is thought to be very closely related to the availability of 1-O-alkyl-2-arachidonoyl-sn-glycerol-3-phosphocholine. This study addresses the contribution made by ether phospholipid catabolism in the regulation of PAF precursors. The long term objectives of this proposal are to determine: 1) If the composition and level of ether phospholipids is regulated, 2) what the functional significance of this class of phospholipids might be and 3) elucidate the mechanism of ether phospholipid regulation if such regulation is found. The current studies on the metabolism of 1-O-[3H]alkyl-2-acety- GPC has defined two alternate pathways of PAF metabolism. A pathway found in several cell types but represented in this proposal by either bone marrow derived macrophages or a clonal macrophage-like cell line in which ethanolamine phospholipids are metabolites of PAF. The second pathway found in PC-12 cells (a clonal line derived from rat pheochromocytoma) and splenic T cells, is characterized by 1-O-alkyl-2-acyl-sn-glycero-3- phosphoglycerol (1-O-alkyl-2-acyl-GPG) as the primary metabolite. Surprisingly, the ether linkage of 1-O-alkyl-2-acyl-GPG does not to be susceptible to hydrolysis. Studies of PAF metabolism in macrophages demonstrated that label which originated in the alkyl moiety of 1-O- [3H]alkyl-2-acetyl-GPC appeared in the following species; 1-O-[3H]alkyl-2- acetyl-GPC, 1-O-[3H]alkyl-2-acyl-GPC, 1-O-[3H]alkyl-2-acyl-GPE and 1-O-alk- 1'-enyl-2-acyl-GPE after incubations of one hour or less. After extended incubation periods (2 to 6 hours) a significant portion of the label was present in the acyl linkage of diacyl phospholipids and acyl linkage of neutral lipids indicating then the ether linkage had been cleaved. A phsopholilpid base exchange reaction is proposed for the synthesis of 1-O- alkyl-2-acyl-GPE from 1-O-alkyl-2-acyl-GPC. The cleavage of the alk-1'- enyl group of ethanolamine plasmalogen is considered as the means of releasing the sn-1 group of the ether lipid.