The long term goal of this project is to obtain a further understanding of the biochemical interactions between the mother and the fetus with regards to platelet-activating factor (PAF) and arachidonic acid metabolism release and the relationships of these autacoids with initiation and maintenance of parturition. Efforts will be directed to elucidate the catabolism of PAF and its relationship to ethanolamine plasmalogens as metabolic products. The activity of the enzymes involve in this metabolic conversion will be determined in a cell line derived from human amnion (WISH). Studies will be carried out i order to determine the cellular origin and regulation of the plasma PAF-acetylhydrolase (PAF-AH)_, the enzyme responsible for PAF inactivation. The role of various steroid hormones in the regulation of the plasma PAF-AH will be investigated. Macrophages obtained from several sources (lung, decidua) and from the differentiated form of two established cell lines (HL-60 and U937) will be employed to investigate the mechanisms operative in the regulation of PAF-AH, since these cells are known to secrete the enzyme into the culture medium. The effects of estrogens, glucocorticoids, and progestins in the regulation of the PAF- acetyltransferases that are involved in PAF biosynthesis will also be analyzed. The plasma type PAF-AH will be purified and the regulation of its genetic expression by steroid hormones will be characterized. Using the techniques of molecular biology, the MRNA for this enzyme will be isolated and employed for the preparation of specific probes; these probes will then be used for determining the effects of the steroids in the expression of PAF-AH. Similar studies will be carried out for the enzyme lysoPAF:acetyl-CoA acetyltransferase. The role of PAF in certain complications of pregnancy will be further investigated, with emphasis on the function this potent hypotensive agent may play in women with pregnancy-induced hypertension/preeclampsia. The molecular species and concentration of PAF in the various compartments of human amniotic fluid will be characterized. The investigations proposed should provide important information related to the initiation and maintenance of parturition and the participation of PAF, particularly in terms of the relationships between the fetus and the maternal compartment. The role of the hormonal environment in the regulation of the key enzymes involved in regulating the steady-state concentration of PAF will provide insights into the function of this autacoid in gestation and parturition.
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