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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2909-2915
Copyright © 2004 by The Endocrine Society

15-Hydroxyprostaglandin Dehydrogenase and Cyclooxygenase 2 Messenger Ribonucleic Acid Expression and Immunohistochemical Localization in Human Cervical Tissue during Term and Preterm Labor

Susanne Abelin Törnblom, Falguni A. Patel, Birgitta Byström, Diana Giannoulias, Anders Malmström, Maria Sennström, Stephen J. Lye, John R. G. Challis and Gunvor Ekman

Department of Obstetrics and Gynecology (S.A.T., B.B., M.S., G.E.), Karolinska Hospital and Karolinska Institute, SE-171 76 Stockholm, Sweden; Departments of Physiology and Obstetrics and Gynecology (F.A.P., D.G., S.J.L., J.R.G.C.), University of Toronto, Toronto, Ontario, Canada M5S 1A1; and Department of Cell and Molecular Biology (A.M.), University of Lund, SE 22184 Lund, Sweden

Address all correspondence and requests for reprints to: Susanne Abelin Törnblom, Department of Obstetrics and Gynecology, Karolinska Hospital/Karolinska Institute, SE-171 76 Stockholm, Sweden. E-mail: susanne.abelin{at}kbh.ki.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Here we have examined the enzymes cyclooxygenase (COX)-2 and 15-hydroxyprostaglandin dehydrogenase (15-OH PGDH) in pregnant human cervix. In biopsies taken transvaginally after preterm and term elective cesarean sections and vaginal deliveries, the levels of mRNA coding for COX-2 and 15-OH PGDH were assessed by Northern blotting. The cellular localization of the COX-2 and 15-OH PGDH proteins was determined by immunohistochemical analysis.

COX-2 and 15-OH PGDH mRNAs were expressed at detectable levels in the cervical biopsies from all four groups of subjects. At cesarean sections (unripe cervix), the level of 15-OH PGDH mRNA was significantly higher than the level in the ripe cervix at the time of partus, irrespective of the gestational length. In contrast, the level of COX-2 mRNA was similar in all subjects. Immunoreactivity of COX-2 and 15-OH PGDH was expressed by activated fibroblasts. The present investigation documents the expression and cellular localization of COX-2 and 15-OH PGDH in the preterm and term pregnant human cervix. This observation indicates that both preterm and term cervical ripening is associated with decreased degradation of prostaglandins.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PREMATURE BIRTH CONTINUES to be the leading cause of infant mortality and morbidity, accounting for as much as 70% of perinatal mortality (1). The frequency of premature birth varies from 5–10% in the developed regions of the world and can be as high as 40% in certain very poor areas (2). The frequency of premature birth has not changed significantly during the past two decades, and the basic mechanisms underlying the initiation of both preterm and term cervical ripening and labor remain largely unknown. Few reliable methods exist to predict which groups of women are at an increased risk of premature labor (PTL), and current therapeutic approaches have not been successful in reducing the frequency of PTL (3, 4, 5, 6). Infection has been suggested as being one important factor involved in the pathophysiology of PTL, but in the majority of cases, PTL must be regarded as idiopathic (7, 8).

PTL involves a softening of the cervix and the occurrence of regular myometrial contractions, both of which are necessary for vaginal delivery. Cervical ripening detected clinically as softening, reflects a pronounced remodeling of the extracellular matrix (ECM), which in humans consists primarily of fibrils of collagen I and III (9). During term cervical ripening, the turnover and degradation of collagen is increased, resulting in a lower concentration of collagen containing fewer cross-links (9). Decorin, the major proteoglycan in the human cervix, influences collagen fibrillation and, thus, the stiffness of the nonpregnant cervix (10). During the final stages of term cervical ripening, the cervical mRNA level for decorin is reduced, with concomitant increases of 14% in the mRNA levels and protein concentrations of the large proteoglycan versican (11). Versican has the capacity to attract water and bind hyaluronan, resulting in disintegration of the collagen bundles and a change in the physical properties to produce a soft and elastic tissue, thus facilitating dilation of the cervix.

The preterm cervical ripening in humans has not been extensively investigated. Rechberger et al. (12) found a significant lower collagen cross-linking in cervical biopsies obtained from women with cervical insufficiency. Further studies on preterm cervical ripening are in progress.

Several hormones, including estrogen, progesterone, and prostaglandins, are involved in the term cervical ripening process (13, 14). Furthermore, this process can be regarded as an inflammatory reaction because the levels of mRNA encoding IL-6, IL-8, and granulocyte colony-stimulation factor, as well as the corresponding protein levels, are increased 100-fold during cervical ripening (15). It is well known that cytokines recruit activated cells, in particular neutrophils, but also macrophages and mast cells, which can produce degradative enzymes such as metalloproteinases (MMPs). Thus, increased secretion of MMP-1, -2, -3, and especially -8 has been observed in the human cervix during the final stages of ripening (16, 17). Most research concerning preterm labor and delivery has been focused on the hormones involved in the initiation of labor and on tocolytic agents, which reduce myometrial contractility. However, painful strong contractions do not result in a preterm delivery because the cervix is stiff and closed. A preterm delivery requires both a cervical ripening and strong myometrial contractions. Therefore, it is also of major importance to improve our understanding of the physiology of preterm cervical ripening. Studies in humans suggest that prostaglandins, notably prostaglandin (PG) E2, play a major role in cervical ripening and the onset of labor (18). Indeed today, local application of PGE2 in a gel is considered to be the gold standard procedure for inducing cervical ripening and labor (18, 19, 20, 21, 22). Prostaglandins are derived by the release of arachidonic acid from membrane phospholipids and the subsequent conversion of this precursor through several well-regulated steps to the final products. Three different enzymes are of primary significance in regulating the levels of biologically active prostaglandins in tissues. Of the two synthetic enzymes, cyclooxygenase (COX)-1 appears to be constitutively expressed, whereas COX-2 is up-regulated by certain cytokines (e.g. IL-1, TNF-{alpha}, IL-8), other growth factors, and glucocorticoids and repressed by progesterone (18, 23). Earlier studies have revealed a significantly higher level of COX-2 mRNA in the amnion of patients who gave birth prematurely (24). Furthermore, this mRNA and the corresponding protein levels are higher in the amnion of women during spontaneous term labor than in the amnion of women not in spontaneous labor (25, 26, 27, 28).

In addition, the nicotinamide adenine dinucleotide- positive-dependent catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-OH PGDH) metabolizes PGE2 and PGF2-{alpha} to their biologically inactive 15-keto derivatives. The level of 15-OH PGDH mRNA in the chorio-decidua of women undergoing spontaneous term or preterm labor is significantly lower than in that of women undergoing elective cesarean section after term pregnancy (27). Indeed, 15-OH PGDH deficiency has been proposed to be a potential causative factor in connection with the preterm labor syndrome (29).

Therefore, our present hypothesis is that cervical ripening and labor are associated with an increased expression of COX-2 and decreased expression of 15-OH PGDH, resulting in increased levels of active prostaglandins in cervical ECM. In this case, premature changes in these enzymes might induce premature cervical ripening and labor. Accordingly, the levels of mRNA coding for COX-2 and 15-OH PGDH in relationship to cervical ripening and gestational age at the time of preterm and term parturition have been investigated here.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A total of 46 women undergoing singleton pregnancies were included in the present study. The two preterm groups included women undergoing spontaneous vaginal delivery (n = 16) or elective cesarean section (n = 8). The women in the two control term groups also underwent vaginal delivery (n = 11) or elective cesarean section (n = 11). The women who delivered by cesarean section demonstrated unripe cervices and had not entered into labor (Table 1Go). Clinical signs of infection, such as fever, elevated white blood cell count, a positive C-reactive protein reaction, or a positive urine/cervical culture, were absent. 15-OH PGDH mRNA was analyzed in all of the women, whereas in the case of COX-2 mRNA, fewer patients could be analyzed due to the limited amount of material available (Table 1Go). Immunohistochemistry and the dual immunofluorescence analysis could only be performed on two cervical samples obtained from women who delivered vaginally at term due to the limited amount of available material.


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  		TABLE 1. Pertinent patient data

 
This study was performed after receiving the approval of the local Ethics Committee of the Karolinska Institute and the informed consent of each subject.

Collection of cervical tissue samples

Immediately after parturition, a biopsy from the anterior cervical lip of each woman was taken transvaginally (at the 12 o’clock position). These samples were immediately frozen in liquid nitrogen and stored thereafter at –70 C.

Northern blot hybridization

Twenty micrograms of total cellular RNA (extracted using Trizol), together with an RNA ladder (Life Technologies Inc., Gaithersburg, MD), were first fractionated on the basis of size by horizontal electrophoresis (Horizon 20 x 25; Life Technologies) in a 1% agarose gel containing 37% deionized formaldehyde and, thereafter, transferred to a nylon membrane (Zeta Probe GT Blotting Membrane; Bio-Rad Laboratories Inc., Mississauga, Ontario, Canada). The subsequent blotting involved hybridization with an 800-bp fragment of 15-OH PGDH cDNA and a 1.9-kb fragment of COX-2 cDNA as probes (28, 29). These fragments were labeled with {alpha}-[32P] deoxy-CTP (Amersham Life Science, Buckinghamshire, UK) using the random priming procedure (Ready to Go; Pharmacia Bio Process Technology, Uppsala, Sweden) and then separated from remaining unincorporated [32P] CTP by passage through a nick column (Pharmacia). Hybridization was carried out for 24 h, followed by washing three times for 15 min in 150 mM sodium phosphate/0.1% sodium dodecyl sulfate and then for 15 min in 30 mM sodiumphosphate/0.1% sodium dodecyl sulfate. The blots obtained were exposed to Kodak X-AR film (Kodak, Rochester, NY) with an intensifying screen for 5–7 d.

After this autoradiographic exposure, the blots were stripped and reprobed with cDNA for mouse 18S rRNA, which was used as an internal standard to allow correction for variations in gel loading and transfer efficiency. Using computerized image analysis (MCID; Imaging Research, Inc., St. Catherine’s, Ontario, Canada), the relative optical densities were determined after different periods of exposure to ensure that the values obtained were within the linear range of the autoradiographic film and of the densitometry. The results are expressed as the ratio of the relative optical densities of the hybridization signals for 15-OH PGDH mRNA/18S rRNA.

Immunohistochemistry

The cervical tissue samples were embedded in Tissue-Tek (Mites, Elkhart, IN). Frozen sections, 8-µm thick, were mounted onto gel chromatin-coated glass slides. These sections were then fixed in 2% paraformaldehyde in PBS (pH 7.4), air dried, and stored at –20 C until analysis. Endogenous peroxidase activity was eliminated by pretreatment with 0.3% hydrogen peroxide in PBS. The 15-OH PGDH protein was localized using a polyclonal antibody raised in rabbits against purified type I placental 15-OH PGDH (1:3000; generously donated by Dr. H.H. Tai, Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY) and diluted in PBS (150 mM NaCl, 10 mM Na2HPO4, 1.5 mM NaH2PO4, pH 7.5; containing 1% BSA). Antibody binding was visualized with the Vectastain ABC kit (Vector Laboratories, Burlingame, CA) using 3,3-diaminobenzidine (Sigma Chemical Co., St. Louis, MO) as the chromagen.

The tissue sections were first incubated with normal goat immune serum as a blocking agent to eliminate nonspecific binding. Next, these sections were exposed to the primary antibody at 4 C for 18–24 h, followed by washing in PBS, incubation with a biotinylated secondary antibody for 2 h, a second wash in PBS, and incubation with an avidin-biotin peroxidase complex for 2 h (30). After final washing with PBS, the immunoreactive proteins were visualized by adding diaminobenzidine (diaminobenzidine powder; Sigma) for 3 min and using counterstaining with Carazzi’s hematoxylin, dehydrated in ethanol (50%, 70%, 90%, and 100%), and then placed in xylene for three washes. Negative control sections were treated in an identical manner, except that the primary antibodies were omitted from the initial incubation medium.

Dual immunofluorescence

After blocking nonspecific binding of antibodies by incubation in PBS containing 1% BSA for 2 h at room temperature, tissue sections (prepared as described earlier) were exposed to primary antibodies against smooth muscle {alpha}-actin (a monoclonal mouse anti-smooth muscle {alpha}-actin antibody, A2547, diluted at 1:3000; Sigma) together with either rabbit anti-human COX-2 (1:200, PG27B; Oxford Biomedical Research, Oxford, MI) or rabbit antihuman 15-OH PGDH (1:3000). This incubation was performed in a 1% BSA solution containing 0.3% Triton X-100 overnight (18–24 h) at 4 C. Subsequently, the sections were washed three times in 0.1 M PBS and then incubated with the secondary antibodies at 37 C for 45 min. The secondary antibodies used in this case were fluorescein isothiocyanate-conjugated sheep antimouse IgG (at 1:50 dilution; Amersham Pharmacia Biotech, Baie d’Urfe, Quebec, Canada) for covisualization of {alpha}-actin and COX-2 and CY3-conjugated sheep antirabbit IgG (at a 1:1000 dilution) for 15-OH PGDH (both in 1% BSA) (30). Thereafter, the samples were washed again in PBS, an antifading reagent (1 mg p-phenylendiamine, 1 ml in 50% glycerol/50% PBS) was added, and coverslips were applied for subsequent analysis.

Microscopic analysis

Tissue sections were analyzed under a fluorescent Optiphot-2 microscope (Nikon, Tokyo, Japan) using a green filter to visualize fluorescein isothiocyanate and a red filter to visualize CY3. Digital photographs of the sections were taken with a 128-bit, cooled Sensicam imaging camera (Cooke Inc., Auburn Hills, MI) using Sensicontrol 4.02 software (Cooke Inc.) and subsequently visualized on a computer. These images were then transferred into the CorelDraw program (Corel Corp., Ottawa, Ontario, Canada) and superimposed to compare the pattern of localization of COX-2 or 15-OH PGDH with that of {alpha}-actin. If the two patterns are identical, it can be concluded that the enzyme of interest is present in the same cell type that expresses {alpha}-actin.

Statistical analysis

Data are presented as the mean ± SEM for the number of observations indicated. Relative OD values were analyzed using the Student’s t test, and the level of significance was set at P < 0.05. Calculations were performed using the Sigma Stat program (Jandel Scientific Software, San Rafael, CA).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Levels of 15-OH PGDH and COX-2 mRNA in the cervix of women giving term and preterm birth involving or not involving labor

The cDNA probe for human placental 15-OH PGDH hybridized with two mRNA transcripts with sizes of 3.4 and 2.0 kb in the human cervix. Some variability in the abundance of these transcripts was observed within each group of women (Fig. 1Go, A and B). The cDNA probe for COX-2 hybridized with one mRNA transcript with a size of 1.9 kb in the human cervix. 15-OH PGDH and COX-2 mRNAs were detectable in all of the samples examined.



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  		FIG. 1. A and B, Northern blotting of 15-OH PGDH mRNA in the human cervix. A, Samples associated with preterm elective cesarean section (C/S; n = 8) and preterm spontaneous vaginal delivery (S.V.D.; n = 16). B, Term elective cesarean section (C/S; n = 11) and term S.V.D. (n = 11). The top panel depicts the autoradiograph of the blot probed with [32P]-labeled 15-OH PGDH cDNA; whereas, in the middle panel, [32P]-labeled cDNA for mouse 18S rRNA was used as the probe. The bottom histogram illustrates the ratio (mean ± SEM) of the relative OD (R.O.D.) of the hybridization signals for 15-OH PGDH mRNA and 18s rRNA. *, P < 0.05.

 
15-OH PGDH mRNA

The expression of cervical 15-OH PGDH mRNA (relative to that of 18S rRNA) was 40% lower (P < 0.05) in women who underwent spontaneous vaginal delivery, preterm as well as at term, compared with women with unripe cervix who delivered by elective cesarean sections, preterm as well as term.

Approximately the same 40% lower relative expression of 15-OH PGDH mRNA was observed when comparing cervical samples associated with preterm spontaneous vaginal delivery with preterm elective cesarean section and when comparing term spontaneous vaginal delivery with term cesarean section. Thus, there were no significant differences in this parameter between the term and preterm cesarean section samples or between term and preterm spontaneous labor (Fig. 1Go, A and B).

COX-2 mRNA

Cox-2 mRNA was present in all four groups of cervical samples, although without any differences in the level relative to 18S rRNA. Thus, no significant changes in this parameter were associated with cervical status (ripe or unripe) or gestational age (data not shown).

Localization of the 15-OH PGDH and COX-2 proteins in the human cervix

Positive staining for the immunoreactive 15-OH PGDH protein was observed in the cells of the ECM of the human cervix, which is the major tissue in this organ. The most common cells in this ECM are fibroblasts, and a considerable portion of these fibroblasts stained for {alpha}-actin, indicating an activated myofibroblastic state. In the distal portion of the cervix, from which our biopsies were taken, smooth muscle cells are scarce (2–4%) (31).

Using dual immunofluorescence, the pattern of localization of immunoreactive 15-OH PGDH was compared with that of {alpha}-actin, a putative fibroblast activity marker (Fig. 2AGo, in green). {alpha}-actin is expressed by both activated fibroblasts and smooth muscle cells (32, 33). In both tissue samples examined, positive staining for PGDH in the ECM (in red) was found to be more widespread than the staining for {alpha}-actin (Fig. 2Go, B–D). Although it seems likely that the {alpha}-actin-positive cells are activated fibroblasts (i.e. myofibroblasts) because muscle cells are so very scarce in the distal portion of the cervix, further investigations are required to identify the different cell types in this sections (31). Staining for COX-2 and {alpha}-actin colocalized, indicating the expression of COX-2 by activated fibroblasts (Fig. 3Go).



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  		FIG. 2. Immunofluorescent comparison of the localization of 15-OH PGDH and {alpha}-actin proteins in the human pregnant cervix. A, Immunohistochemical labeling of actin with fluorescein isothiocyanate (green). B, Immunohistochemical labeling of PGDH with CY3 (red). C, Labeling for both {alpha}-actin and 15-OH PGDH. D, Immunohistochemical localization of 15-OH PGDH. E, Hematoxylin and eosin staining of the human pregnant cervix. All photographs were taken at a magnification of x200. The black or white bar delineates a distance of 25 µm.

 


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  		FIG. 3. Immunofluorescent colocalization of COX-2 and {alpha}-actin proteins in the human pregnant cervix. A, Immunohistochemical labeling of {alpha}-actin with fluorescein isothiocyanate (green). B, Immunohistochemical labeling of COX-2 with CY3 (red). C, Colocalization of {alpha}-actin and COX-2. D, Hematoxylin and eosin staining of the human cervix. All photographs were taken at a magnification of x200. The black or white bar delineates a distance of 25 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present investigation demonstrates the expressions of 15-OH PGDH and COX-2 mRNAs and the localizations of their proteins in the human preterm and term cervix. The observation of significantly lower levels of 15-OH PGDH mRNA in the ripe cervix of women undergoing spontaneous vaginal delivery, irrespective of the infant’s gestational age, supports the hypothesis that prostaglandins play a role in both preterm and term cervical ripening and the onset of labor. In contrast, the cervical levels of COX-2 mRNA were similar in all four groups of subjects.

This latter observation is in agreement with the reports of Sparey et al. (34) and Moore et al. (35), which demonstrate a lack of any significant changes in the expression of the COX-2 protein or corresponding mRNA in the myometrium in relationship to gestational age or to the onset of labor. In contrast, Zuo et al. (36) observed decreased COX-2 expression in the myometrium in association with vaginal delivery. Hirst et al. (25) have detected elevated levels of COX-2 mRNA in amnion in connection with preterm labor and term vaginal delivery compared with parturition by cesarean section. Furthermore, studies on the human endometrium also indicate an up-regulation of COX-2 (37, 38).

In the present study, the ratio of the levels of 15-OH PGDH mRNA to 18S rRNA was reduced in the subjects exhibiting ripe cervices and undergoing vaginal delivery compared with women with unripe cervices who delivered by cesarean section. This observation is in agreement with a study published recently by Giannoulias et al. (30), which reports a decrease in the level of PGDH protein expression in the human myometrium in association with both preterm and term labor. Earlier findings by Sangha et al. (27) revealed attenuated expression of 15-OH PGDH mRNA in the chorio-decidua associated with term spontaneous labor compared with term elective cesarean section. However, these findings are discrepant with those of van Meir et al. (28), which documented lower chorionic levels of 15-OH PGDH activity in association with preterm labor compared with term labor and even lower activity in the case of preterm labor complicated by infection. Nevertheless, the significant decrease in the level of 15-OH PGDH mRNA during cervical ripening observed here supports an important involvement of 15-OH PGDH in the cervical extracellular remodeling process, which occurs at the onset of labor.

Furthermore, expression of the 15-OH PGDH protein was found here to demonstrate a widespread distribution among the cells in cervical tissue. On the other hand, COX-2 appears to be expressed only by cells that also contain {alpha}-actin (i.e. most probably myofibroblasts). These patterns of localization correspond well to those of 15-OH PGDH and COX-2 in the myometrium that were observed by Giannoulias et al. (30).

Prostaglandins are one of many important factors involved in the onset of human parturition (18). PGE2 induces a remodeling of the cervical ECM, in part by elevating collagenolytic activity, which results in a breakdown of this tissue. This process also involves cytokines, nitric oxide, and MMPs and can be regarded as an inflammatory reaction. Our present findings indicate that local synthesis of PGE2 (which plays a pivotal role in the synthesis of cytokines) in cervical tissue is accompanied by a decrease in 15-OH PGDH activity.

PGE2 is the natural initiator of the cervical ripening process and facilitates spontaneous labor. Local application of PGE2 remains the most common clinical strategy for inducing cervical ripening and labor (18, 19, 20, 21, 22). In a recently published investigation, we reported that application of PGE2 is as effective in inducing cervical ripening and labor at preterm as it is at term and post term (39).

The final cervical ripening and onset of labor involves increased levels of granulocyte colony-stimulating factor, IL-6, and IL-8, which result in recruitment and activation of neutrophils (15, 40). Thus, cervical ripening must be regarded as an inflammatory reaction, which is probably hormonally regulated (13, 14, 18). To improve our understanding of preterm cervical remodeling, the involvement of different cytokines must be analyzed.

It has been suggested that preterm labor and reduced degradation of prostaglandins may be caused by an exogenous infection (7). However, it does not seem likely that the normal onset of term labor is the result of such infection. Fetal and/or maternal hormonal alterations resulting in an inflammatory reaction are more likely to be involved here (13, 14, 18).

Finally, the role of the fetus in onset of labor has also been considered. It is well known that in connection with this onset the levels of placental hormones, including estrogen and progesterone, increase 100-fold until term pregnancy. Both the mRNA levels and the protein concentrations of estrogen receptor {alpha} are significantly increased in the ripe cervix at partus compared with term (14). On the contrary, the mRNA levels and the protein concentrations of estrogen receptor ß reached the highest levels in the unripe cervix at term pregnancy (14). These observations support estrogen receptor {alpha} dominance during term cervical ripening (14).

Moreover, other investigators have maintained that corticotrophin-releasing hormone (CRH) is involved in the process of labor. Indeed, elevated plasma levels of CRH have been observed in women undergoing preterm labor, which is of particular interest because CRH stimulates prostaglandin production (41).

It is well known that women who have undergone a preterm delivery run the highest risk of having another preterm birth. Thus, questions concerning the involvement of genetic and immunological factors must also be raised. New techniques, such as proteomics and microarray analysis, may provide some insight in this context (42).

The influence of the fetus on the onset of labor may also involve fetal fibronectin. Thus, increased levels of this protein in cervical mucus are associated with cervical ripening and onset of labor (43).

This observation is of considerable interest because fetal fibronectin can interact with various membrane receptors, e.g. integrins and heparan sulfates, which initiate signaling pathways. Further studies are necessary to elucidate the possible role of fetal fibronectin as a signaling molecule involved in cervical ripening and the onset of labor.

In summary, the findings of this first study on the expression and localization of 15-OH PGDH and COX-2 mRNAs in the human cervix during cervical ripening and labor emphasize the important role played by prostaglandins in the cervical ripening process even in connection with preterm labor. However, no differences between preterm and term labor with respect to these parameters were observed.


   Footnotes
 
This work was supported by grants from the Swedish Research Council (Grant GEO 349-2002-7189, AM 7479), the Karolinska Institute Funds, and the Swedish Society of Medicine.

Abbreviations: COX, Cyclooxygenase; ECM, extracellular matrix; MMP, metalloproteinase; 15-OH PGDH, 15-hydroxyprostaglandin dehydrogenase; PG, prostaglandin; PTL, premature labor.

Received July 6, 2003.

Accepted March 4, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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