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Original Articles |
Perinatal Research Centre, Departments of Physiology, Obstetrics and Gynaecology, and Pediatrics, University of Alberta, Edmonton, Alberta T6G 2S2 Canada
Address all correspondence and requests for reprints to: Jane E. Mijovic, Perinatal Research Centre, University of Alberta, 220 Heritage Medical Research Centre, Edmonton, AB, Canada T6G 2S2.
Abstract
Term and preterm parturition is associated with elevated intrauterine PG production. Although an increase of PG synthesis by the fetal membranes during term labor is well documented, there is little data available regarding the prostanoid production of these tissues at term, before the spontaneous onset of labor. In the present study, we determined the expression of PG H2 synthase (PGHS), the committing and rate-limiting enzyme of prostanoid biosynthesis, in the chorion laeve during gestation. Tissues were collected from 18 patients at term (37–41 weeks of gestation) and from 13 patients between 17 and 35 weeks of pregnancy. None of the patients were in labor. PGHS-specific activity and the abundance of messenger RNAs (mRNAs) encoding the two PGHS isoenzymes (the constitutive PGHS-1 and the inducible PGHS-2) were measured by a cell-free enzyme assay and specific ribonuclease protection assays, respectively. PGHS-specific activity as well as PGHS-1 and -2 mRNA levels were significantly (P < 0.01) higher at term before labor than earlier during gestation. Furthermore, PGHS activity at term exhibited significant positive correlation with PGHS-2 mRNA levels, but not with PGHS-1 mRNA levels. In situ hybridization indicated that the expression of both PGHS mRNAs increased in the epithelial and the mesenchymal cells of the amnion and the chorion laeve at term. Additionally, PGHS activity and mRNA levels were determined in the chorion laeve of a group of patients who gave birth spontaneously before term (30.6 ± 1 weeks, mean ± SEM, n = 5), and the values were compared with a group who delivered by cesarean section before labor at a similar gestational age (31.9 ± 1.4 weeks, n = 5, P > 0,05 vs. the preterm labor group). None of the patients exhibited signs of genital tract infection. PGHS-specific activity and PGHS-1 and -2 mRNA levels were significantly higher in the preterm labor group than in the group who delivered preterm without labor. In situ hybridization suggested that the enhanced PGHS-1 and -2 mRNA expression occurred predominantly in the mesenchymal cells of the fetal membranes at preterm labor. Thus, PGHS-1 and -2 expression increases in the chorion laeve at term before labor, with PGHS-2 as the functionally prevalent isoform. This supports the possibility that PGs originating in the fetal membranes promote the onset of normal labor. Furthermore, preterm labor is associated with the elevated expression of the two PGHS isoenzymes in the chorion laeve. The maturation of the fetal membranes in preparation for term labor involves both the epithelial and the mesenchymal cells, whereas preterm labor is accompanied by the maturation of the mesenchymal tissue components, as reflected by PGHS expression. This difference may have implications in the early recognition of preterm labor.
PGs HAVE long been implicated in the process of human parturition. It has been observed that the administration of PG synthesis inhibitors to pregnant women significantly prolonged gestation, reduced uterine contractions, and lengthened the duration of labor (1, 2). Also, labor is induced by the administration of PGs at midpregnancy and at term (3). The concentration of endogenous PGs and their metabolites rises in the amniotic fluid and maternal plasma as labor progresses (4, 5, 6, 7, 8). This increased PG production was proposed to be the consequence of labor, caused by tissue trauma and the exposure of the gestational tissues to proinflammatory factors in the vaginal fluids through the dilating cervix (7). The PGs produced may function by augmenting or facilitating labor. However, it is well documented that amniotic fluid PG levels rise at late gestation even before the onset of clinical labor (5, 9, 10, 11). Therefore, the possibility exists that an induction of PG synthesis occurs in the gestational tissues before labor, as part of the process leading to labor initiation.
The principal sites of PG synthesis in the pregnant human uterus are the amnion, the chorion laeve, and the decidua (12). The rate-limiting, and committing step of PG biosynthesis is the conversion of the precursor, arachidonic acid, to PG H2. The reaction is catalyzed by PG endoperoxide H synthase, which has two isoforms referred to as PGHS-1 and PGHS-2. PGHS-1 is constitutively expressed in many cells, whereas PGHS-2 may be induced by agonists such as growth factors, cytokines, and endotoxin (13). Most pharmacological inhibitors of PG synthesis act by blocking PGHS activity.
It has been shown that the activity of PGHS and the abundance of PGHS-2 messenger RNA (mRNA), but not of PGHS-1 mRNA, are elevated in both the amnion and the chorion laeve after spontaneous term labor as compared with tissues collected before labor onset at term (14, 15, 16, 17). These observations indicate that the expression of PGHS-2 increases in these tissues during term labor, enhancing their capacity to produce PGs.
Further, it has been demonstrated that PGHS-specific activity rises in the amnion in late gestation before labor (16). This suggests that PGHS induction in the fetal membranes may contribute to the increased intrauterine PG production observed before the onset of labor at term. In the present study, we explored further this possibility by examining the expression of the PGHS isoenzymes in the chorion laeve during the course of gestation and before term labor. The chorion laeve is juxtaposed to the amnion membrane, is also of fetal origin, and, as mentioned above, shows an increase of PGHS expression with term labor that is analogous to changes in the amnion. We also examined the expression of PGHS in the chorion laeve at spontaneous preterm birth to establish changes associated with this pathological condition. Further, we determined the localization of PGHS-1 and -2 mRNAs among the various cell types of the fetal membranes during gestation and after preterm labor by in situ hybridization. The results implicate the stimulated expression of PGHS in the fetal membranes as a major factor contributing to the increase of intrauterine PG production before labor onset at term and at preterm birth.
Materials and Methods
Materials
Leupeptin, phenylmethylsulfonylfluoride, diethyldithiocarbamic
acid, tryptophan (Try), 1,4-piperazine-diethanesulfonic acid (PIPES),
Ficoll-400, diethylpyrocarbonate (DEPC), Denhardt’s solution, and
cytokeratin immunohistochemical detection kits were purchased from
Sigma Chemical Co. (St. Louis, MO). [5, 6, 8, 11, 12, 14,
15-N-3H]PG E2 (PGE2) (SA, 140
Ci/mmol) was obtained from Amersham Canada (Oakville, Canada), and
[
-32P]cytidine 5'-triphosphate was purchased from
DuPont Canada (Mississauga, Canada). Arachidonic acid was obtained from
NuChek Preparations (Elysian, MN). Reduced glutathione, proteinase-K,
ribonuclease-A, ribonuclease-T1, ribonuclease (RNase)-free
DNase 1, and Digoxigenin (DIG) nucleic acid labeling and detection kits
were purchased from Boehringer Mannheim Canada (Laval, Canada).
Vasoactive intestinal peptide (VIP) substrate kit for peroxidase was
bought from Vector Labs. (Burlingame, CA). T7 and T3 RNA polymerase was
obtained from BRL (Gaithersburg, MD). Sep-Pak C18
cartridges were products of Waters-Millipore (Milford, MA). All other
chemicals were of analytical (ACS) purity.
Tissue collection
Placentas with attached fetal membranes were obtained from a total of 36 uncomplicated singleton pregnancies. Of these, 18 were collected at term (18) (after 37 and before 41 completed weeks of gestation; mean ± SE = 38.3 ± 0.6 weeks) elective cesarean section (CS) in the absence of labor, 5 were collected following preterm CS (<37 completed weeks) in the absence of labor, and 5 were collected following spontaneous preterm labor (<37 completed weeks). Preterm CSs were performed because of pregnancy-induced hypertension, placenta previa, or fetal distress. Eight samples were collected by the Central Laboratory for Human Embryology, University of Washington, following elective abortion before 20 weeks of pregnancy. Absence of labor was defined as less than one uterine contraction per 10 min, less than 2 cm cervical dilatation (determined by pelvic examination), and intact membranes. Gestational age was calculated from the first day of the last menstrual period. All placentas were processed within 20–30 min of delivery. Women with clinical signs of inflammation or genital infection (fever, foul vaginal discharge) or bacterial vaginosis were excluded from the study. Patients in preterm labor presented with intact membranes, and delivered spontaneously within 72 h following admission. All patients were routinely tested for the presence of group B streptococcus in the vaginal flora, and those found positive were not included in the study. The use of these tissues was approved by the University of Alberta ethical review committee.
The placenta was separated from the fetal membranes immediately after
delivery by cutting around the placental margins. Membranes were washed
in physiological saline to remove excess blood. Small pieces of the
full-thickness membrane were rolled and fixed in 10% formalin in PBS
for 24–48 h at room temperature. The amnion was separated from the
chorio-decidua by blunt dissection, and decidual tissue was dissected
from the chorion laeve using a blade. The removal of decidual tissue
from the chorion was monitored by histological examination indicating
that it was near complete. The isolated chorion membranes were cut into
strips (10 x 20 mm), washed repeatedly with physiological saline,
and snap-frozen in liquid nitrogen. The effects of the trauma of
isolation on tissue PG production were minimized by limiting
preparation time to 
20 min. The frozen tissue was then
pulverized using a dry ice-cooled pestle and mortar and separated into
batches for RNA extraction and enzyme activity assay.
The formalin-fixed tissue samples were processed for in situ hybridization and histological analysis by dehydration and embedding in paraffin blocks. Five-micrometer-thick sections were cut and collected on ribonuclease-free, 3-aminopropylethoxysilane-coated slides. All samples of full-thickness membranes were examined for neutrophil invasion as a histological sign of inflammation; only tissues that were shown to be negative were used.
PGHS-specific activity determination
The PGHS enzyme activity assay was developed in our laboratory (16, 19). This assay determines the sum of the activities of the two PGHS isoenzymes in microsomal preparations. Microsomes were isolated from chorion tissue homogenates as described previously (15).
All microsomal incubations were carried out in a 37 C water bath for 4 min in the presence of optimal cofactor concentrations (1 mmol/L tryptophan and 1 mmol/L reduced glutathione). The specific activity of the enzyme at 20 µM arachidonate produces a value statistically equal to the maximum velocity (Vmax) of the enzyme (19). Therefore, an incubation system using 20 µM arachidonate was employed to quantitate PGHS enzyme activity. Each microsomal preparation was assayed in triplicate, at three different protein concentrations, to ascertain whether a linear relationship existed between enzyme activity and the protein content of the reaction mixture. Linearity was achieved with all enzyme preparations. PG produced during the incubations was extracted using Sep-Pak C18 cartridges (20), and correction was made for extraction losses in each sample. The recovery of PGs after extraction was in the range of 84–97%. Because the cofactor conditions used during the incubations favored PGE2 production (19), PGE2 was quantitated in the extracts by RIA. The protein content of the microsomal fraction was determined by the Bradford technique (21). Enzyme activity was expressed as picograms of PGE2 produced per microgram microsomal protein per minute.
RNA preparation and ribonuclease protection assays
Total RNA was extracted from tissues using the acid guanidinium thiocyanate-phenol-chloroform method (22). The RNA concentration of each sample was determined by absorbance at 260 nm.
Human PGHS-1 (23) and PGHS-2 cDNAs (24) were used for the development of complementary RNA (cRNA) probes for the ribonuclease protection assay (14). Total tissue RNA (40 µg) was hybridized in solution with either the PGHS-1 or PGHS-2 probe generated by in vitro transcription and digested with a mixture of ribonuclease A and ribonuclease T1 as previously described (14). The protected RNA fragments were separated in 6% polyacrylamide denaturing gels and subjected to autoradiographic analysis.
To verify loading of RNA, the level of the constitutively expressed
-actin was also determined using ribonuclease protection assays. The
human -actin probe was generated from a 270 nucleotide sequence of
the C-terminal amino acid coding region (25). Total RNA (40 µg) from
the same samples used for PGHS-1 and -2 mRNA determination was
hybridized with the -actin probe under identical conditions to those
described above. In each assay, probes were hybridized to yeast
transfer RNA (tRNA) to monitor nonspecific background hybridization. No
probe protection was seen in these samples. Undigested probe was also
electrophoresed in each assay to further verify specific
protection.
PGHS mRNA in situ hybridization
Sections were dewaxed and rehydrated by passing the slides through a graded series of xylenes and ethanols and then DEPC treated water. Slides were placed in 0.2 M hydrochloric acid for 30 min at room temperature, followed by 3% Triton-X 100 for 15 min at room temperature. The sections were then treated with 0.1 mol/L Tris-HCl, pH 7.5, 0.5 mmol/L EDTA containing 100 µg/mL proteinase K for 30 min at 37 C. Following this, they were rinsed in 0.1 mol/L Tris-HCl, 0.1 mol/L sodium chloride containing 0.2% glycine; postfixed for 5 min with 10% formalin in PBS; acetylated for 10 min with 0.25% acetic anhydride containing 0.1 mol/L triethanolamine at room temperature; and prehybridized for 60 min at 37 C in solution containing 50% formamide, 2 x SSC (3 mol/L NaCl, 0.34 mol/L sodium citrate, pH 7.0), 1 x Denhardt’s solution [0.02% (wt/vol) each of BSA, Ficoll 400 and polyvinylpyrrolidone], 1 µg/mL tRNA, 50 mmol/L PBS, 1 mmol/L EDTA, and 5% dextran sulfate.
Digoxigenin-labeled sense and antisense probes were synthesized by in vitro transcription from the same human PGHS-1 and -2 cDNA templates used in the ribonuclease protection assays (15).
The tissue sections were hybridized overnight at 37 C in the presence of 500 ng/ml probe dissolved in 50% formamide, 2 x SSC, 1 x Denhardt’s solution, 1 µg/mL tRNA, 50 mM PBS, 1 mM EDTA, and 5% dextran sulfate. The unhybridized probe was removed with 2 x 15-min washes in 2 x SSC, 1 x 10-min wash in 1 x SSC at room temperature, and 1 x 10-min wash in 0.1 x SSC at 37 C. The hybrids were then visualized by enzyme-linked immunoassay using the DIG nucleic acid detection kit (Boehringer Mannheim). Sections from each tissue preparation were also hybridized with sense probes as negative controls. Epithelial cells were identified by counterstaining for cytokeratin using a commercial kit (Sigma). Slides were examined by lightfield microscopy and photographed.
Six sections from membranes from all the first and second trimester patients and preterm CS and SL patients were examined by in situ hybridization; this yielded 5–10 fields of view per section (30–60 fields of view per patient). Six sections from eight patients in the term not in labor group were also analyzed in this way. The results described were obtained from a representative patient from each group.
Data assessment and statistical analysis
PGHS-1 and -2 mRNA levels in tissue samples were evaluated by
quantification of the protected bands on autoradiographs using
densitometry with a GS-670 Bio-Rad imaging densitometer (Bio-Rad,
Hercules, CA). Peaks corresponding to protected bands were integrated
with a software package supplied by the manufacturer. In all sets of
hybridization reactions, 40 µg RNA from a pooled tissue RNA
preparation was included as PGHS-1, PGHS-2, or -actin standards. The
standards were assigned a densitometric value of 1 on the
autoradiograms, and PGHS-1, PGHS-2, and -actin mRNA densitometric
intensities were normalized to that value. The PGHS densitometric
values were then divided by the -actin mRNA densitometric values
measured in the same RNA preparations. The resultant ratio is referred
to as PGHS mRNA band intensity, and is interpreted as representing
PGHS-1 and PGHS-2 mRNA levels corrected for variations between
individual ribonuclease protection assays and RNA sample quality.
Enzyme activity and mRNA levels were compared between the two groups of patients who delivered in the absence of labor at term and before term, respectively. Statistical comparisons were performed using the nonparametric Wilcoxon’s signed rank test, because the data were not normally distributed.
Polynomial regression was used for longitudinal analysis of changes in PGHS activity and PGHS-1 and -2 mRNA levels as functions of gestational age.
PGHS mRNA expression in chorion collected at term was compared with enzyme activity in the same tissues by simple linear regression. Correlational analysis using untransformed and reciprocally transformed data gave consistent results. In all statistical analyses, significance was achieved at P < 0.05.
Results
Gestational age-dependent changes in PGHS activity in the human
chorion laeve were investigated by measuring enzyme activity levels
following the elective termination of pregnancy at various times during
gestation. Eighteen tissue samples obtained after elective CS at term
(37–41 completed weeks), 5 tissues collected after elective CS
preterm, and 8 tissues obtained following elective early termination of
pregnancy (<20 weeks of gestation) were included in the analysis. None
of the patients were in labor. The mean and range of the gestational
ages in the two groups of patients who delivered at term and before
term, respectively, are presented in Table 1
. PGHS-specific activity in the chorion
laeve from patients who delivered at term was significantly higher than
in patients whose pregnancies were terminated before term (Table 1).
Figure 1 shows enzyme activity levels in
the individual tissues as a function of gestational age. The polynomial
curve fitted to the data points predicts an increase of PGHS activity
following 35–37 weeks of pregnancy.
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demonstrates the
expression of PGHS-1 and -2 mRNAs in a representative group of these
patients. Forty micrograms of total chorion RNA was hybridized with the
PGHS-1 or -2 cRNA probe and produced single protected bands of the
expected sizes (309 bp for PGHS-1 mRNA and 400 bp for PGHS-2 mRNA). The
PGHS-1 and -2 mRNA autoradiographic signals were quantified by
densitometry and normalized to -actin mRNA levels. As shown in Table 1
, PGHS-1 as well as PGHS-2 mRNA levels were significantly higher in
the chorion laeve of patients at term not in labor than in the chorion
laeve of patients who delivered earlier also in the absence of labor.
The gestational age-dependent pattern of mRNA abundance in the
individual tissues indicated an increase of PGHS-1 mRNA expression, and
a sharp rise of PGHS-2 mRNA expression after 35–37 weeks of gestation
(Fig. 3, A and B, respectively).
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). This suggested that
the increase of PGHS activity at term was predominantly the consequence
of PGHS-2 induction.
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As shown in Fig. 5, cytokeratin-positive
chorion and amnion epithelial cells were essentially devoid of PGHS-1
and -2 mRNA before term (A and B on the upper and lower parts of the
figure). Low-intensity, sporadic staining was observed in the
cytokeratin-negative (mesenchymal) cells of the fetal membranes for
PGHS-1 mRNA during this period and for PGHS-2 mRNA close to term. In
tissues collected at term (Fig. 5C), PGHS-1 and -2 expression was
pervasive throughout the epithelial and mesenchymal components of the
membranes. However, the pattern of staining appeared markedly
heterogeneous, because some cells exhibited strong hybridization
whereas others, often adjacent, showed low levels of hybridizing
material. Decidua cells exhibited variable intensity of staining for
both mRNAs throughout gestation. Figure 5D are negative controls,
hybridized with PGHS-1 mRNA (upper) or -2 mRNA (lower) sense cRNA
probes. Very weak nonspecific hybridization was detected with both
sense probes.
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, PGHS-specific activity after spontaneous preterm labor was
significantly higher than after elective CS in the absence labor at the
same gestational age. Figure 7 shows the
results of ribonuclease protection assays to measure chorion laeve
PGHS-1 and -2 mRNA levels in the two groups of patients examined for
PGHS activity. Densitometric quantification and statistical analysis
demonstrated (Fig. 8) that the abundance
of PGHS-1 as well as PGHS-2 mRNAs was significantly higher after
spontaneous preterm labor than following preterm delivery without
labor.
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, the localization of PGHS-1
and -2 mRNAs in membranes collected at preterm CS in the absence of
labor and in membranes obtained after spontaneous preterm delivery are
presented. Figure 9, C and D are negative controls hybridized with the
corresponding sense probes. In situ hybridization patterns
in Fig. 9, A and B (upper section) clearly indicate a marked increase
in the abundance of PGHS-1 mRNA in the cytokeratin-negative cells of
the chorion laeve and the amnion after spontaneous preterm labor.
Hybridization patterns in the lower section of Fig. 9, A and B,
indicate an increase in abundance of PGHS-2 mRNA with preterm labor,
which was also localized to the cytokeratin-negative cells of the
chorion laeve and amnion mesoderm. The cytokeratin-positive chorion
laeve trophoblasts and amnion epithelium exhibited little or no
increase of either PGHS-1 or -2 mRNA hybridization with preterm labor.
Cells in the decidua stained positive for PGHS-2 mRNA after preterm
labor.
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In the present investigation, we explored the changes of PGHS
expression in the human chorion laeve during gestation before the onset
of labor. The tissues were collected from patients who underwent
elective termination of pregnancy in the absence of labor at various
gestational ages. The results show that the expression of both PGHS
isoenzymes is increased at term as compared with earlier during
gestation. The distribution of PGHS activity and PGHS-1 and -2 mRNA
levels vs. gestational age was consistent with a sharp
increase of enzyme expression between the 36th and 41st weeks of
pregnancy. Furthermore, PGHS-2 mRNA abundance, but not PGHS-1 mRNA
abundance, showed significant positive correlation with PGHS activity
levels in the tissues, suggesting that the inducible PGHS-2 isoenzyme
was expressed in a functionally predominant and increasing manner
during the last weeks of gestation. A similar pattern of gestational
age-dependent expression of PGHS activity (16) and PGHS-2 mRNA (26) has
been reported in the amnion of patients who, like those in the present
study, had their pregnancies interrupted in the absence of labor. In
agreement with these changing patterns of enzyme expression,
PGE2 and PGF2 concentrations have been found
to rise severalfold in the amniotic fluid at late gestation before
labor onset (5, 9, 10, 11). Taken together, these observations strongly
suggest that an induction of PGHS (with PGHS-2 as the functionally
dominant isoform) occurs in the fetal membranes shortly before labor
and is likely responsible, at least partially, for an increase of
intrauterine PG production at this time. The resulting rise in PG
concentrations may have a pivotal influence on the timing of labor.
It is well documented that PGs accumulate in the amniotic fluid during labor (5, 7, 8). Elevated PG production by explants or cells from fetal membranes obtained after spontaneous labor, as compared with tissues collected before labor, has also been reported in several studies (27, 28, 29, 30). PGHS activity and PGHS-2 mRNA levels are higher in the amnion and chorion laeve following spontaneous delivery than before labor at term (14, 15, 16, 31). The increase of intrauterine PG production associated with term labor is often considered a consequence of labor, caused mainly by tissue trauma and the exposure of the fetal membranes and the decidua to stimulating factors in the vaginal fluids via the opening cervix (7). However, the increased expression of PG biosynthetic enzymes before labor is evidently not attributable to factors and conditions brought about by the process of labor itself. It is therefore reasonable to suggest that the induction of PGHS in the fetal membranes at term, as demonstrated in the present and previous investigations, is part of the process that leads to labor, possibly in a causative fashion.
The chorion is known to have a considerable capacity to inactivate PGs mainly by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH). The mean level of PGDH activity and mRNA in the chorion laeve is lower in patients after spontaneous labor compared with that before labor at term and is also reduced in idiopathic preterm labor (32, 33). The gestational age-dependent expression of chorion laeve PGDH during normal pregnancy has not been investigated in sufficient detail yet to permit the assessment of the net contribution of this tissue or other adjacent tissues to the level of biologically active PGs in the uterus at term or before. Expectedly, a more comprehensive characterization of PG biosynthesis and metabolism by all the gestational tissues will improve our understanding of the control of intrauterine PG concentrations during pregnancy and in the context of parturition.
Localization of PGHS-1 and -2 mRNAs by in situ hybridization confirmed that both were expressed in the cytokeratin-positive and -negative cells of the chorion laeve and the amnion (34), and revealed that expression levels increased with advancing gestation. Considering that the two PGHS genes are subject to different types of regulation (13, 35), these data indicate that both tissues undergo maturation at term before the onset of labor, resulting in the enhanced expression of a constitutive, developmentally controlled gene (i.e. PGHS-1), and the inducible, agonist-controlled gene (PGHS-2). Furthermore, the maturational process involves both the cytokeratin-positive epithelial and the cytokeratin-negative mesenchymal cell types in the fetal membranes. During term labor, however, only the inducible PGHS-2 is expressed in an increasing manner, predominantly in the epithelial cells of the amnion and the chorion laeve (15).
PGHS expression patterns at preterm labor were substantially different from those seen with labor at term. Preterm labor was associated with increases in the levels of both PGHS mRNA isoforms, and the increases were localized predominantly to the mesenchymal cells of the amnion and the chorion laeve. The available data did not allow the determination of whether the increases occurred shortly before or during preterm labor, but the virtual absence of epithelial cell involvement in PGHS-1 and -2 induction clearly distinguishes preterm labor from labor at term and from tissue maturation at term before labor. It is therefore reasonable to suggest that preterm labor is characterized by the preterm maturation of the mesenchymal components of the fetal membranes (as indicated by enhanced PGHS-1 mRNA expression), accompanied by a preterm induction of PGHS-2, also in the mesenchymal cells. Notably, the stimulation by glucocorticoids of PGHS-2 expression in cultured amniotic fibroblasts has been reported recently (36), thus further studies may be warranted to explore the significance of this phenomenon in the context of preterm labor.
The factors and control mechanisms that influence the structural integrity and functional properties of the gestational tissues before term and preterm labor are largely undefined. The existence of a "placental clock" has been proposed recently, with the purported function of determining the pace of maturation of the placenta and the membranes as gestation progresses (37). Numerous agonists have been found to stimulate PG production and PGHS expression in various in vitro models derived from fetal membranes (38). Infection (nonsymptomatic, subclinical, or manifest) and the resulting host response in the genitourinary tract may often play a role in the early onset of labor, as suggested by accumulating evidence (39). In the present study, however, we selected patients who were devoid of genital tract infection and inflammation, as defined by the usual clinical, histological, and bacteriological criteria, because the majority of the preterm labor cases occurs in this group. The evidence presented strongly suggests that the fetal membranes mature at term in preparation for labor, and that the process includes the enhanced expression of both PGHS isoenzymes, with PGHS-2 being functionally predominant. PGHS expression in preterm labor appears to be limited to the mesenchymal cells of the membranes, indicating that tissue regulation in this condition is different from that in normal term labor. The implications of this difference may be important regarding the need for early diagnosis and treatment of idiopathic preterm labor.
Footnotes
1 This work was supported by the Medical Research Council of Canada,
the Alberta Heritage Foundation for Medical Research, and the
University of Alberta Hospitals Special Services Research
Council. 
Received January 23, 1997.
Revised July 31, 1997.
Revised December 22, 1997.
Accepted December 24, 1997.
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J. McLaren, D.J. Taylor, and S.C. Bell Prostaglandin E2-dependent production of latent matrix metalloproteinase-9 in cultures of human fetal membranes Mol. Hum. Reprod., November 1, 2000; 6(11): 1033 - 1040. [Abstract] [Full Text] [PDF]
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 J. R.G. Challis, S. G. Matthews, W. Gibb, and S. J. Lye Endocrine and Paracrine Regulation of Birth at Term and Preterm Endocr. Rev., October 1, 2000; 21(5): 514 - 550. [Abstract] [Full Text]
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 J. Reese, B. C. Paria, N. Brown, X. Zhao, J. D. Morrow, and S. K. Dey Coordinated regulation of fetal and maternal prostaglandins directs successful birth and postnatal adaptation in the mouse PNAS, August 15, 2000; 97(17): 9759 - 9764. [Abstract] [Full Text] [PDF]
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 G. Gross, T. Imamura, S. K. Vogt, D. F. Wozniak, D. M. Nelson, Y. Sadovsky, and L. J. Muglia Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1415 - R1423. [Abstract] [Full Text] [PDF]
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 J. L. Cook, D. B. Zaragoza, D. H. Sung, and D. M. Olson Expression of Myometrial Activation and Stimulation Genes in a Mouse Model of Preterm Labor: Myometrial Activation, Stimulation, and Preterm Labor Endocrinology, May 1, 2000; 141(5): 1718 - 1728. [Abstract] [Full Text] [PDF]
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S. Gyomorey, S.J. Lye, W. Gibb, and J.R.G. Challis Fetal-to-Maternal Progression of Prostaglandin H2 Synthase-2 Expression in Ovine Intrauterine Tissues During the Course of Labor Biol Reprod, March 1, 2000; 62(3): 797 - 805. [Abstract] [Full Text]
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J. E. Mijovic, T. Zakar, J. Angelova, and D. M. Olson Prostaglandin endoperoxide H synthase mRNA expression in the human amnion and decidua during pregnancy and in the amnion at preterm labour Mol. Hum. Reprod., February 1, 1999; 5(2): 182 - 187. [Abstract] [Full Text] [PDF]
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