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Reproductive Endocrinology |
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
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.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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 NAD+-dependent 15-hydroxyprostaglandin 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 myometrium (10, 11, 12, 13, 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.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Placentas and fetal membranes were collected from singleton pregnancies ending at term (37–41 weeks gestation; n = 26) or preterm (23–35 weeks gestation; n = 27). The term group consisted of spontaneous vaginal delivery (n = 8), cesarean section in labor (n = 8), or cesarean section not in labor (n = 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 -80 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 ice (-80 C) and stored at -80 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 clinical signs of infection including fever. A comprehensive medical history was established for each of the women. Chorioamnionitis was not diagnosed in any of the placentas from term deliveries.
Assay of NAD+-dependent PGDH
The activity of NAD+-dependent PGDH was
determined as described by Keirse et al. (11). Conversion of
PGF2
to its metabolites, 15-keto-PGF2 and
13,14-dihydro-15-keto-PGF2, was determined under
conditions of zero order reaction kinetics, and the results were
expressed as nanomoles of PGF2 metabolized per mg
protein (Pierce protein assay, Pierce Chemical Co., Rockford, IL)/min
to account for differences in the water content of villous tissue at
different stages of gestation (12). The lower limit of reliable
quantitation was 0.1 nmol PGF2/mg protein·min.
Immunohistochemistry
Immunohistochemistry was conducted on 5-µm sections of placentas and fetal membranes using the avidin-biotin-peroxidase technique (Vectastain ABC kits, Vector Laboratories, Burlingame, CA) and diaminobenzidine substrate as described previously (13, 14). The polyclonal primary antibody to PGDH was raised in rabbits against purified human placental type 1 PGDH (15) and was used at dilutions of 1:2000 for placental sections and 1:3000 for fetal membranes. Sections were stained for cytokeratin to identify trophoblast cells using a polyclonal primary antibody raised in rabbits against bovine epidermal keratin. Negative controls included sections incubated with nonimmune rabbit serum (diluted similarly to the PGDH antibody), antibody dilution buffer alone, or primary antibody that had been preabsorbed with 1.5 µmol/L type 1 PGDH (15).
All experimental sections were processed simultaneously to allow direct comparison between groups. All sections were examined by light microscopy. The amount of immunoreactive (ir-) PGDH present in the chorion was analyzed in noncounterstained sections using computerized image analysis (Imaging Research, St. Catharines, Canada). A background value was obtained from the area in between amnion and chorion. This was subtracted, and the results were expressed as relative optical density. Comparison between patients was performed using the values from at least eight areas per section.
In situ hybridization
In situ hybridization for PGDH mRNA was conducted on placentas and fetal membranes from term (n = 4) and preterm (n = 6; three without infection and three with infection) women in labor, using techniques described previously (16). Briefly, 15-µm cryosections were incubated overnight with radiolabeled PGDH oligonucleotide probe, washed, exposed to x-ray film (XAR 5, Eastman Kodak, Rochester, NY), then dipped in Ilford K5 liquid emulsion (Ilford, Mobberley, Cheshire, UK) and developed using standard procedures (16, 17). The sections were counterstained with Carazzi’s hematoxylin to permit identification of nuclei.
The oligonucleotide probe for PGDH was 45 bases long; it was made by solid phase synthesis using an Applied Biosystem DNA synthesizer (Foster City, CA) and purified on an 8% polyacrylamide-8 mol/L urea preparative sequencing gel. The PGDH probe was complementary to bases 659–704 of the human gene (18). A control 45-mer oligonucleotide was constructed randomly. Northern blot analysis of total RNA extracted from placenta tissue was performed to verify the specificity of the probe. The controls and experimental sections were processed simultaneously to allow direct comparison between groups. The sections were exposed to x-ray film together with 14C-labeled standards (American Radiochemical, St. Louis, MO). The optical density of the chorion on the autoradiographic film was quantified using computerized image analysis. The results are expressed as relative optical density (ROD) after subtraction of background values for absorbance.
Statistical analyses
Results are expressed as the mean ± SEM for the numbers of samples (patients) stated. Comparison between groups was performed using nonparametric one-way ANOVA or Wilcoxon’s rank sum test. Statistical significance was set at P < 0.05.
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Results |
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Placentas and chorions showed wide variation in PGDH activity
within all patient categories. Mean PGDH activity in chorion in term
labor [1.16 ± 0.24 nmol/mg protein·min (±SE);
n = 16] was lower than that in the term, not in labor, group
(1.78 ± 0.32 nmol/mg protein; n = 10), although the
differences were not significant (Fig. 1a
). PGDH
activity was much lower in chorion from patients in PTL than in that
from patients in term labor. Three of the 14 chorions from patients in
PTL without inflammation had undetectable PGDH activity, whereas PGDH
was undetectable in 6 of the 10 chorions with signs of inflammation.
PGDH activity in both preterm groups was significantly different from
that in the term, not in labor, group (Fig. 1a; P <
0.01 to <0.002, by Wilcoxon rank sum test), but only the activity in
the group with PTL associated with inflammation was significantly
different from that in the term, in labor, group (P <
0.005). The PGDH activity in PTL combined with inflammation was lower
than that in PTL without inflammation (P < 0.05). In
contrast to the pattern in chorion, the mean PGDH activities in the
placentas were not significantly different between any of the patient
groups (Fig. 1b).
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). There was a higher percentage of PROM
in the infected group (n = 7 of 10) compared to that in the group
at PTL without infection (Table 1). No PGDH activity was
detectable in the chorions of the four women with clinical signs of
infection, all of whom also had PROM for longer than 24 h.
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Immunoreactive PGDH was present in the placental
syncytiotrophoblast and in the extravillous trophoblast, but was absent
from Langhans cytotrophoblast cells in all sections (13, 14). In the
membranes, ir-PGDH was undetectable in the amnion epithelial and
subepithelial layers and in the decidual layer, but was localized to
the trophoblast layer of chorion (Fig. 3A). ir-PGDH
staining of the chorion after PTL in the absence of inflammation
indicated a decrease (Fig. 3B) in the number of positive cells and the
intensity (ROD) of the staining in the trophoblast layer compared with
those in sections from patients at term. In PTL with infection, the
chorion was invaded by polymorphonuclear leukocytes, and there was a
further reduction in ir-PGDH (Fig. 3, C and D). This was particularly
marked in stage III chorioamnionitis and was associated with loss of
trophoblast cells. The amount of ir-cytokeratin staining in chorion was
similar in PTL patients without infection and patients at term, but was
less in women with PTL and infection (data not shown).
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P < 0.05). In 5 of 11 chorions from patients in PTL
with infection, there was no PGDH immunoreactivity, whereas all
chorions from patients in PTL without infection had some positive
staining. When PTL was associated with PROM lasting for more than
24 h, ir-PGDH in chorion was reduced significantly (Fig. 5). In the placenta, no difference in ir-PGDH was
observed between term and preterm groups. In general, there was a
similar pattern between patient groups in PGDH activities in the
chorion and ir-PGDH intensity. Preabsorption of the PGDH antibody with
purified type 1 NAD+-dependent PGDH completely eliminated
staining, confirming the specificity of the response.
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PGDH mRNA was localized to the human placenta and fetal membranes
(Fig. 6). In the fetal membranes, PGDH mRNA was present
primarily in the extravillous trophoblast of chorion (Fig. 6, A–F).
The epithelial layer and subepithelial layer of the amnion and the
decidua showed very low expression of PGDH mRNA in all groups (Fig. 6, C and D). In PTL (Fig. 6, B, D, and F), there was less expression of
PGDH mRNA in the chorion than at term (Fig. 6, A, C, and E). Expression
of PGDH was further reduced in membranes from women in PTL with
underlying infection (Fig. 7). In the placenta, low
levels of PGDH mRNA were present in the syncytiotrophoblast (Fig. 6G)
and extravillous trophoblast (not shown). No signal was observed when
the control probe was hybridized with a section of membranes adjacent
to one known to contain PGDH mRNA (Fig. 6H).
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), but did not reach statistical significance.
No significant differences were observed in PGDH mRNA levels in the
placentas between patient groups. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previously, we found that PGDH expression was reduced in a subset of patients presenting in PTL in the absence of infection (14). It was suggested that a lowering of PGDH might allow PGs generated in amnion or chorion (19, 20) to pass in increased amounts to decidua and myometrium, thereby contributing to the stimulus that leads to preterm delivery. Subsequently, we showed that PGDH activity and mRNA were diminished in the chorion of a small set of patients in PTL with infection compared to those in women in idiopathic PTL without infection (21). It was reported that loss of extravillous trophoblast in the chorion of these patients might be responsible for the loss of PGDH (22).
The present report is the first to use in situ hybridization to localize PGDH mRNA principally to the extravillous trophoblast of human fetal membranes and to show the reduction of PGDH mRNA in these cells in patients with idiopathic PTL. The gradation of PGDH between term and PTL is apparent. Further, within the PTL group we report the association between diminution of PGDH activity and immunoreactivity with PROM for more than 24 h. Seventy-five percent of these patients had an underlying inflammatory process, and in the majority of these, no PGDH activity was present. These effects were restricted to the fetal membranes, and there were no significant differences in PGDH activities in placentas from the four groups of patients. This finding supports our previous demonstration that the reduced PGDH mRNA and ir-PGDH protein of chorion in patients with PTL are not reflected in comparable changes in placental tissue from the same patients (14, 20).
PGDH is present in high amounts in the placenta and fetal membranes
from early in human gestation (23). The enzyme is thought to provide a
protective mechanism by which PGs generated in amnion or chorion are
metabolized and prevented from reaching the decidua or myometrium (13, 24, 25, 26). It remains unclear whether a fall in PGDH in chorion
contributes to the mechanisms of parturition at term. Although there
was a slight decrease in PGDH activity and immunoactivity in chorion
laeve collected after spontaneous labor compared to those after term
elective cesarean section in the absence of labor, these differences
were not significant. Similar results were reported by Germain et
al. (24). Sangha et al. (14) found by Northern blotting
that PGDH mRNA was reduced in chorionic membranes collected after
labor, but others have reported higher PGDH activity in chorion at term
labor (26). Thus, it seems unlikely that a fall in chorionic PGDH
activity is a major contributing factor to the increase in PG output
that occurs at term (19, 24). Serial samples of amniotic fluid
collected from rhesus monkeys during late gestation contained similar
increases in concentrations of PGF2 and
13,14-dihydro-15-keto-PGF2 in association with
spontaneous parturition (27). Thus, in this subhuman primate species,
it was also concluded that increased PG output at term probably
occurred more in response to an increase in PG biosynthesis than to a
fall in primary PG metabolism.
However, our study suggests that reductions in PGDH mRNA, activity, and ir-PGDH-positive extravillous trophoblast cells of chorion occur in a subset of patients in PTL, even without infection. The histological integrity of the trophoblast cell appears to be maintained, at least at the light microscopic level, and the cells continue to be immunopositive for cytokeratin, a marker of epithelial-derived cells. At present it is not clear why PGDH activity is diminished in these patients. The enzyme is regulated by progesterone (28, 29), and administration of the progesterone antagonist RU486 results in loss of PGDH, reduced levels of PG metabolites, and increased concentrations of PGE2 in decidual blood vessels and stromal cells from patients in early gestation. Chorionic trophoblast cells express 3ß-hydroxysteroid dehydrogenase enzyme (30) and are capable of synthesizing progesterone from pregnenolone (31). However, the effects of progesterone or other steroids on PGDH expression and activity have not been established for trophoblast cells obtained in late gestation.
When PTL was associated with an inflammatory response, there was extensive infiltration of leukocytes to the chorionic trophoblast interface and then throughout the membranes. The integrity and structure of the trophoblast cells are lost by a process of suppurative necrosis, and PGDH activity of the membranes decreases dramatically. Thus, different mechanisms are likely to cause reductions in PGDH expression in PTL with or without inflammatory responses. We accept that the inflammatory process that accompanies membrane rupture does not allow us to distinguish between processes that antecede PTL and processes that result from it. Certainly the role of infection, and indeed that of PGs, in the etiology of PTL have been questioned (32), but at this time this does not appear to constitute a majority opinion (33, 34, 35, 36, 37). Further, in the absence of markers of "silent" infection, we cannot exclude the possibility that patients described as being without inflammation may have had an undocumented infective process.
The link between inflammation and preterm PROM is evident. Almost 75% of our preterm group with inflammation had preterm PROM, and in all but one of them, PROM had lasted longer than 24 h. Fifty percent of the preterm group without inflammation was combined with PROM; in the two women in whom PROM was longer than 24 h, no PGDH activity was present. A localized infection or bacterial proteases and/or host products secreted in response to bacterial infection may lead to weakening and rupture of the membranes (33, 34). Romero et al. (35) found that 55% of women with preterm PROM have a positive amniotic fluid culture at the time of the onset of parturition and that most of these patients will have increased levels of PGs in their amniotic fluid (37). We suggest that inflammation mediates a decrease in chorionic PGDH, whereas bacterial products and inflammatory mediators, such as interleukins, stimulate PG synthesis (9, 38, 39). This combination results in increased PG concentrations with the potential to affect myometrial contractility and preterm birth.
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Acknowledgments |
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Footnotes |
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Received February 15, 1996.
Revised October 2, 1996.
Accepted November 15, 1996.
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References |
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5
4 isomerase in human
placenta and fetal membranes throughout gestation. J Clin
Endocrinol Metab. 75:956–961.[Abstract]
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