15-Hydroxyprostaglandin Dehydrogenase: Implications in Preterm Labor with and without Ascending Infection

0021-972X/97/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1997 by The Endocrine Society Vol. 82, No. 3 Printed in U.S.A. 15-Hydroxyprostaglandin Dehydrogenase: Implications in Preterm Labor with and without Ascending Infection* CLAUDIA A. VAN MEIR, STEPHEN G. MATTHEWS, MARC J. N. C. KEIRSE, MILDRED M. RAMIREZ, ALAN BOCKING, AND JOHN R. G. CHALLIS Department of Obstetrics and Gynecology, Leiden University Hospital (C.A.V.M., M.J.N.C.K.), Leiden, The Netherlands; and the Department of Obstetrics and Gynecology, Medical Research Council Group in Fetal and Neonatal Health and Development, Lawson Research Institute, St. Joseph’s Health Center, University of Western Ontario (S.G.M., M.M.R., A.B., J.R.G.C.), London; and the Department of Physiology, University of Toronto (S.G.M., J.R.G.C.), Toronto, Ontario, Canada ABSTRACT There is evidence that intrauterine infection, which stimulates PG synthesis may play a role in the pathogenesis of some preterm labor. Local tissue concentrations of PGs are controlled not only by the rate of synthesis, but also by catabolism, which is regulated by 15-hydroxyprostaglandin dehydrogenase (PGDH). We hypothesized that a decrease of PGDH activity could contribute to an increase in PG output at the time of preterm labor (PTL) especially in association with infection. We measured PGDH activity with a zero order kinetic enzymatic assay, PGDH messenger ribonucleic acid by in situ hybridization and PGDH distribution and localization with immunohistochemistry in human placenta and fetal membranes from women at term before (n 5 10) or after (n 5 16) labor compared to preterm labor at less than 36 weeks without (n 5 16) and with (n 5 11) chorioamnionitis. PGDH activity in chorion was significantly lower in PTL than at term and was further reduced when PTL was associated with inflammation. Immunoreactive PGDH and PGDH messenger ribonucleic acid localized predominantly to chorionic trophoblasts at term and were reduced in PTL women with or without infection. These effects were not observed in the placenta. Loss of PGDH with infection was associated with infiltration of chorion by polymorphonuclear leukocytes, resulting in a compromised structural integrity, although the amniotic epithelium was generally intact. We conclude that a reduction in PGDH in the human fetal membranes may occur in some cases of preterm labor and may contribute to an increase in net PG accumulation and drive to myometrial contractility. (J Clin Endocrinol Metab 82: 969 –976, 1997) P myometrium (10 –14). The purpose of the present study was to localize PGDH messenger ribonucleic acid (mRNA) in human fetal membranes and to establish whether a change in PGDH expression occurred at the time of PTL with or without infection. To examine this hypothesis, we determined PGDH activity, immunoreactivity, and PGDH mRNA levels in the placenta and fetal membranes from women at term with or without labor and from patients in PTL with or without infection. RETERM LABOR (PTL) continues to be a major problem in obstetrics, contributing to perinatal mortality, morbidity, and impaired long term development of the newborn (1–3). Many researchers have related the presence of intrauterine infection to preterm birth, and in some populations, approximately 40% of PTL patients may have an underlying infective process (4, 5). Increased output of cytokines and uterotonins, including oxytocin and PGs, have been implicated in the onset and progression of PTL in the absence or presence of infection, and similar changes may occur in labor at term (6 –9). At term, PG synthesis occurs mainly in the amnion and decidua. The chorion has a very high capacity to catabolize PGs, due to the presence of type 1 NAD1-dependent 15hydroxyprostaglandin dehydrogenase (PGDH), which catalyzes transformation of PGs into their 15-keto derivatives, the initial step in inactivating primary PGs. Throughout pregnancy, chorionic PGDH appears to form an effective metabolic barrier that minimizes the passage of bioactive PGs, originating in the amnion or chorion to the decidua and Materials and Methods Tissue collection Placentas and fetal membranes were collected from singleton pregnancies ending at term (37– 41 weeks gestation; n 5 26) or preterm (23–35 weeks gestation; n 5 27). The term group consisted of spontaneous vaginal delivery (n 5 8), cesarean section in labor (n 5 8), or cesarean section not in labor (n 5 10), performed for reasons such as breech, previous cesarean section, or fetal distress. Four patients in the preterm group had a cesarean section in labor because of fetal distress or breech delivery; none had an elective cesarean section. For all deliveries, the duration of the first stage of labor was no longer than 16 h. Sixteen of 27 patients in the PTL group started with rupture of membranes before the spontaneous onset of labor (prelabor rupture of the membranes; PROM). Immediately after delivery, the placenta was placed on ice. For activity measurements, the maternal and fetal surfaces of the placenta were dissected off, and villous tissue was removed. The chorion was sampled by gently peeling it away from the amnion. Tissues were washed in ice-cold saline (0.9%), frozen in liquid nitrogen, and stored at 280 C. Pieces of placenta and full thickness membranes (amnion, chorion, and decidua) were washed in saline and either fixed in 4% paraformaldehyde-0.2% glutaraldehyde for immunohistochemistry or frozen on dry Received February 15, 1996. Revision received October 2, 1996. Accepted November 15, 1996. Address all correspondence and requests for reprints to: Dr. J. R. G. Challis, Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. * This work was supported by the Medical Research Council of Canada (Group Grant in Fetal and Neonatal Health and Development) and fellowships from the Lawson Research Institute (to C.A.V.M. and M.M.R.). 969 970 JCE & M • 1997 Vol 82 • No 3 VAN MEIR ET AL. ice (280 C) and stored at 280 C for in situ hybridization histochemistry. Tissues for immunohistochemistry were washed in phosphate-buffered saline (0.01 mol/L; pH 7.5) and stored in ethanol (70%) before being embedded in paraffin wax for sectioning. The remainder of all preterm placentas were subjected to conventional pathological examination. The pathologist determined the definition and stage of inflammation of acute chorioamnionitis as described by Blanc (10). This diagnosis of acute chorioamnionitis relies primarily on establishing the presence of polymorphonuclear leukocytes in the area of the placental chorionic plate. Inflammation was present in 11 of the 27 preterm placentas. Of these, there was 1 with intervillositis (minimal inflammation; stage I), 4 with moderate inflammation (chorionitis; stage II), and 6 with severe inflammation, (chorioamnionitis; stage III). Four of these 11 women had (...truncated)