It is probable that prostaglandins that are formed by the action of fatty acid cyclooxygenase on the substrate, arachidonic acid, are of signal importance in the control of utero-placental blood flow and in the biochemical mechanisms that eventuate in parturition in women. Arachidonic acid also is metabolized by way of lipoxygenase enzyme pathways into substances with potent biological activities that include the modulation of prostaglandin biosynthesis. We propose to evaluate the metabolism of arachidonic acid, by way of the lipoxygenase pathways, in uterine and intrauterine tissues of pregnant women. The metabolism of arachidonic acid in such tissues will be investigated by use of homogenates of fresh tissues and by use of cells prepared from the tissues and maintained in monolayer culture. Arachidonate lipoxygenase activities in tissues will be evaluated by use of radiometric thin-layer chromatography; the individual metabolites of arachidonic acid formed by the tissues will be separated, identified, and quantified by high-performance liquid chromatography. The rate of formation of arachidonate lipoxygenase products by uterine and intrauterine tissues will be determined. The effect of gestational age, labor at term, preterm labor, and pregnancy-induced hypertension on the metabolism of arachidonic acid by way of lipoxygenase pathways in fresh tissue also will be evaluated. The effect(s) of hormones, and other substances, in plasma and amniotic fluid on arachidonate lipoxygenase acvtivities in uterine and intrauterine tissues and in cells prepared from such tissues and maintained in monolayer culture will be investigated. Substances in plasma and amniotic fluid that inhibit and stimulate arachidonate lipoxygenase activities will be isolated and characterized by use of techniques that include salt precipitation, ion-exchange chromatography, and preparative isoelectric focusing. We are of the view that the findings of the studies proposed will provide insight into the mechanisms that lead to the timely onset of parturition as well as preterm labor and also insights into the pathogenesis of pregnancy-induced hypertension. Such knowledge should enable us to develop more effective approaches to the prevention or arrest of preterm labor and to the management of pregnancy-induced hypertension.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD020747-02
Application #
3319122
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1984-12-01
Project End
1987-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Mitchell, M D; Trautman, M S; Dudley, D J (1993) Immunoendocrinology of preterm labour and delivery. Baillieres Clin Obstet Gynaecol 7:553-75
Mitchell, M D; Dudley, D J; Edwin, S S et al. (1991) Interleukin-6 stimulates prostaglandin production by human amnion and decidual cells. Eur J Pharmacol 192:189-91
Mitchell, M D (1991) Current topic: the regulation of placental eicosanoid biosynthesis. Placenta 12:557-72
Mitchell, M D; Branch, D W; Lundin-Schiller, S et al. (1991) Immunologic aspects of preterm labor. Semin Perinatol 15:210-24
Mitchell, M D; Romero, R J; Avila, C et al. (1991) Prostaglandin production by amnion and decidual cells in response to bacterial products. Prostaglandins Leukot Essent Fatty Acids 42:167-9
Liechty, K W; Koenig, J M; Mitchell, M D et al. (1991) Production of interleukin-6 by fetal and maternal cells in vivo during intraamniotic infection and in vitro after stimulation with interleukin-1. Pediatr Res 29:1-4
Mitchell, M D; Koenig, J M (1991) Increased production of 15-hydroxyeicosatetraenoic acid by placentae from pregnancies complicated by pregnancy-induced hypertension. Prostaglandins Leukot Essent Fatty Acids 43:61-2
Romero, R; Wu, Y K; Mazor, M et al. (1989) Amniotic fluid arachidonate lipoxygenase metabolites in preterm labor. Prostaglandins Leukot Essent Fatty Acids 36:69-75
Romero, R; Wu, Y K; Oyarzun, E et al. (1989) A potential role for epidermal growth factor/alpha-transforming growth factor in human parturition. Eur J Obstet Gynecol Reprod Biol 33:55-60

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