The lifelong physical health and intellectual development of an individual is often determined substantially during pregnancy and parturition. Lack of normal physiological adaptations with pregnancy, specific diseases of pregnancy e.g. pregnancy-induced hypertension (PIH), preterm labor and abnormalities of the labor process all contribute greatly to perinatal mortality, morbidity and subsequent developmental disorders. Products of arachidonic acid metabolism are intimately involved both in the normal regulatory events of pregnancy and in the aforementioned disorders of pregnancy. The overall objective of this proposal is an evaluation of the biosynthesis and functions of arachidonate lipoxygenase metabolites during human pregnancy and parturition. These products of arachidonic acid metabolism have potent biological activities that include actions on vascular tone and myometrial contractility, modulation of prostaglandin biosynthesis, mediation of inflammatory processes and regulation of immune function. The metabolism of arachidonic acid will be investigated by use of homogenates and minces of fresh tissues and by use of cells prepared from tissues and maintained in monolayer culture. Individual metabolites of arachidonic acid will be separated, identified and quantified by high-performance liquid chromatography and specific radioimmunoassays. The effects of gestational age, labor at term, preterm labor, infections and pregnancy-induced hypertension, both qualitatively and quantitatively, on the metabolism of arachidonic acid by way of lipoxygenase pathways in fresh tissues, will be evaluated. The effects of hormones, bacterial products, monokines and other substances in amniotic fluid from control, and complicated (e.g. PIH, infection etc.) pregnancies on arachidonate lipoxygenase activities in uterine tissues and in cells derived from such tissues will be determined. Additionally serum and amniotic fluid from normal and complicated pregnancies will be tested for actions on functions of lymphocytes from normal and complicated pregnancies and associated alterations in arachidonic acid metabolism. The results of the studies proposed will provide insights into the mechanisms that regulate the onset of labor at term, preterm labor and labor associated with infections as well as the pathogenesis of PIH. Hence, more effective approaches to the management of such pregnancies may be developed.
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