Biomedical subjects

M D Mitchell

Publications and source records attributed to M D Mitchell.

At least 73 records · Page 4Linked to original sources

PubMed1997

Amniotic fluid interleukin-10 (IL-10) concentrations during pregnancy and with labor.

To determine if amniotic fluid interleukin-10 (IL-10) concentrations are elevated in women with labor, either at term or preterm, and in the setting of infection-associated preterm labor, amniotic fluid samples were collected from women: (1) at term, not in labor (n = 42); at term, in labor (n = 56), preterm contractions, undelivered within 1 week (n = 22), and preterm labor, delivered within 1 week (n = 31). IL-10 concentrations were assayed in each sample via ELISA (Pharmingen, San Diego, CA). In a subsequent analysis, 8 women with preterm labor associated with chorioamnionitis were matched for gestational age with women experiencing preterm contractions (undelivered within 7 days) and preterm labor (delivered within 7 days) and amniotic fluid IL-10 concentrations compared. Approximately 40-70% of amniotic fluid samples obtained from women in each group had detectable IL-10. However, there were no significant differences in amniotic fluid IL-10 concentrations among the patients. While 1 of 8 patients with chorioamnionitis had amniotic fluid IL-10 concentrations greater than 300 pg/ml, there were no statistically significant differences among the matched samples. Amniotic fluid IL-10 concentrations were not elevated in women with term labor, preterm labor, or chorioamnionitis. This finding contrasts with the elevated concentrations of pro-inflammatory cytokines and chemokines such as interleukin-1, tumor necrosis factor-alpha, IL-6, IL-8, MIP-1 alpha, and GRO alpha reported in previous studies. Because we did not detect elevations of the key anti-inflammatory cytokine IL-10 in amniotic fluid of women with infection-associated preterm labor, we suggest that anti-inflammatory processes in this setting may be attenuated.

Adult↗

PubMed1997

Interleukin (IL)-6 and IL-8 production by human amnion: regulation by cytokines, growth factors, glucocorticoids, phorbol esters, and bacterial lipopolysaccharide.

Amniotic fluid at term contains high concentrations of interleukin (IL)-6 and IL-8. The source of these cytokines has not been identified, although the fetal membranes (amnion and chorion) are likely contributors. Amnion cytokine production was investigated by using amnion cells isolated by enzymatic digestion (from placentas delivered at term before labor) and cultured in vitro. IL-6 and IL-8 were measured in conditioned media by ELISA. Amnion cells produced detectable amounts of both IL-6 and IL-8 throughout the 7-day culture period. The ratio of IL-8 to IL-6 was approximately 5:1, similar to the ratio found in amniotic fluid. Production of both IL-6 and IL-8 was stimulated in a concentration-dependent fashion by interleukin-1beta (0.1-10 ng/ml), tumor necrosis factor-alpha (1-100 ng/ml), and bacterial lipopolysaccharide (0.1-10 microg/ml), and also by 100 nM phorbol 12-myristate 13-acetate. Epidermal growth factor (1-25 ng/ml) had only minimal effects on amnion cytokine production. Dexamethasone (10 nM) inhibited IL-6/-8 production by approximately 50% throughout the culture period. Production of IL-6/-8 by cultured amniotic fibroblasts, which under basal conditions was much lower than that by epithelial cells, was regulated by all the agents tested in a fashion similar to that of the epithelial cells. These findings suggest that the amnion contributes to the pool of IL-6 and IL-8 in amniotic fluid. We speculate that amnion-derived cytokines might have functions during normal human parturition that are distinct from their conventional roles as inflammatory mediators.

Amnion↗

PubMed1997

The molecular mechanisms of term and preterm labor: recent progress and clinical implications.

Current tocolytic protocols rely largely on the use of beta-mimetics to induce myometrial quiescence and delay delivery. Unfortunately, the rapid transplacental passage and poor receptor specificity of the commonly used beta-mimetics results in widespread activation of intrauterine and extrauterine beta 1 and beta 2 receptors. The use of beta-mimetics is associated with a range of well-recognized and potentially dangerous side effects for mother and fetus. The value of continued use of beta-agonists after obtaining uterine quiescence also has been the subject of recent debate. In this article we have attempted to explore the biochemical and molecular rationale for the use of alternative therapeutic modalities in the treatment and prevention of PTL. In the light of the current view that the term "preterm labor" covers a considerable diversity of causes, we propose that a range of treatment regimes should be chosen on the basis of the diagnosis and classification of the patient according to the their particular condition. Although the measurement of several biochemical parameters have been suggested to be of use in predicting PTL, we believe that a panel of diagnostic indicators (e.g., free or total CRH, IL-6, extracellular matrix proteases, fetal fibronectin) is more likely to provide useful diagnostic information on which appropriate treatment modalities can be selected (Table 1). Because of the complex and interactive nature of the mechanisms operating within the intrauterine environment to regulate myometrial activation and uterotonin production, we speculate that a combination of tocolytics, anti-inflammatory agents, uterotonic antagonists, and receptor blockers is likely to be more effective than a monotherapeutic approach, which focuses on only one facet of the process of uterine activation for pharmacologic intervention. For example, the use of antibiotics, PGHS inhibitors, and/or beta-mimetics might be an appropriate first line of treatment for infection-associated PTL in extreme prematurity. If it is successful, this treatment might be followed by longer term use of a progestagen and/or NO donor to maintain myometrial quiescence until closer to term. Alternatively, use of progesterone or oxytocin antagonists may be effective in augmenting the actions of beta-mimetics while reducing their side effects, whereas other combinations may be useful as long-term prophylactics in women with a high risk of developing PTL. Improvements continue in our diagnostic ability to correctly identify the different causes of preterm labor. We anticipate that careful selection of differing combinations of therapeutic options will result in significant reductions in the morbidity, mortality, and healthcare costs associated with preterm birth.

Female↗

PubMed1997

The effect of 3-aminobenzamide on thymidine incorporation in ultra-violet irradiated chick pigment epithelium cells.

The addition of 3-aminobenzamide (3-AB) to cultures of chick embryo pigmented epithelium rescues these cells after high doses of ultraviolet treatment. The addition of 3-AB prevents cells from losing pre-formed protein and DNA and stimulates thymidine incorporation by the cells after ultraviolet irradiation. Since 3-AB is an inhibitor of poly (ADP) ribosylation, these observations support the conclusion that death of these cells after ultra-violet irradiation depends upon poly (ADP) ribosylation and may be an apoptotic response.

Animals↗

PubMed1997

Regulation of interleukin (IL)-6 and IL-8 production in an amnion-derived cell line by cytokines, growth factors, glucocorticoids, and phorbol esters.

PROBLEM: To determine whether amnion cells produce interleukin (IL)-6 and -8 and thus may contribute to the high concentrations of these cytokines in amniotic fluid at term. METHOD OF STUDY: Amnion-derived WISH cells were treated in culture with stimuli over 16 hr, and IL-6 and IL-8 concentrations in the conditioned media were measured by enzyme-linked immunosorbent assay or bioassay (IL-6 only). RESULTS: IL-8 production was approximately 5-fold higher than that of IL-6 under basal and stimulated conditions. Significant (by Dunnett's test after analysis of variance) stimulation of production of both cytokines was achieved by IL-1 beta (> 0.2 ng/ml), TNF alpha (> 10 ng/ml), and the phorbol ester, phorbol 12-myristate 13-acetate (> 2 nM), over a 16-hr culture period. Epidermal growth factor at 10 ng/ml induced a small increase in production of IL-8, but not of IL-6, whereas bacterial lipopolysaccharide had minimal effects on production of either cytokine. Basal and cytokine-stimulated IL-6 and IL-8 production was inhibited by dexamethasone at concentrations equal to or greater than 1 nM. CONCLUSION: These findings suggest that amnion may be a significant contributor to the IL-6 and IL-8 content of amniotic fluid, and that WISH cells may be a suitable model for the study of cytokine production by amnion epithelial cells.

Amnion↗

PubMed1996

Elevations of amniotic fluid macrophage inflammatory protein-1 alpha concentrations in women during term and preterm labor.

OBJECTIVE: To determine whether elevated concentrations of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in amniotic fluid (AF) are related to term and preterm labor. METHODS: Amniotic fluid was obtained from women from five different clinical situations: 1) term cesarean delivery, no labor (n = 29); 2) normal term labor, no infection (n = 36); 3) preterm labor, delivery more than 1 week from sampling, no infection (n = 19); 4) preterm labor, delivery within 1 week from sampling, no infection (n = 18); and 5) preterm chorioamnionitis (n = 8). Amniotic fluid was collected aseptically at the time of amniocentesis, amniotomy, or hysterotomy. Concentrations of MIP-1 alpha were determined by enzyme-linked immunosorbent assay. Statistical analysis was by Wilcoxon rank-sum test, Kruskal-Wallis test, and unpaired t test. RESULTS: Women in normal term labor had significant elevations of AF MIP-1 alpha concentrations when compared with women at term undergoing repeat cesarean delivery (P < .001). In women with term gestation, AF MIP-1 alpha correlated well with cervical dilation (r2 = 0.479, P < .001). In women with preterm labor who later delivered within 1 week of presentation, AF MIP-1 alpha concentrations were higher than those from women who did not deliver within 1 week. Women who presented with clinically evident chorioamnionitis had the highest concentrations of AF MIP-1 alpha (P = .001). CONCLUSION: Women in labor have significantly elevated AF concentrations of MIP-1 alpha, particularly if labor is associated with intrauterine infection. We suggest that MIP-1 alpha is involved in the physiology of normal labor and in the pathogenesis of infection-associated preterm labor.

Amniotic Fluid↗

PubMed1996

Dose-related effects of low dose aspirin on hemostasis parameters and prostacyclin/thromboxane ratios in late pregnancy.

BACKGROUND: The purpose of this study was to determine which low dose of low dose aspirin (LDA) optimized the urinary prostacyclin (PGI2)/thromboxane (TXA2) ratio and minimized evidence of platelet aggregation during normal late pregnancy. METHODS: Twelve women with uncomplicated singleton pregnancies between 28 and 34 weeks gestation participated in a randomized blinded study. Blood samples for salicylate levels were obtained pretreatment, 4 hours and 7 days after administration of placebo, 20mg, 40mg or 80mg of aspirin. Twenty-four hour urine specimens collected at the same intervals were assayed for PGI2 and TXA2 metabolites. In addition, bleeding time and platelet aggregation studies were performed prior to and after 7 days of LDA or placebo. RESULTS: A dose-related increase in bleeding time occurred with 40 mg and 80 mg of LDA, but not with the 20 mg dose or placebo. Platelet aggregation studies changed progressively from a normal baseline to abnormal with an increasing dose of LDA. The PGI2/TXA2 ratio increased with aspirin doses as low as 20mg, with a decrease in TXA2 metabolites but not in PGI2 metabolites. Serum salicylate was not detectable in any sample from any patient. CONCLUSION: There are dose-related changes in platelet aggregation and bleeding times with progressively increasing doses of LDA. A lower dose of LDA, such as 20-40 mg per day, may be as efficacious as higher doses in the prophylaxis of pre-eclampsia in high risk populations.

Adolescent↗

PubMed1996

5-Hydroxyeicosatetraenoic acid and human parturition.

5-Hydroxyeicosatetraenoic acid (5-HETE) is an arachidonic acid (AA) metabolite derived from the lipoxygenase pathway which is capable of inducing uterine contractions. The purpose of this study was to determine a). whether 5-HETE concentrations in amniotic fluid increase before or after the onset of labor and b). whether acetylsalicylic acid (ASA) could modulate the production of 5-HETE by human amnion cells. 5-HETE concentrations are increased in amniotic fluid before the onset of labor. Furthermore, ASA treatment as expected inhibited PGE2, but also significantly increased 5-HETE production by amnion cells. 5-HETE concentrations on average increased by greater than 2.5 fold (p < 0.001) in amniotic fluid prior to spontaneous labor when compared with samples obtained from the same patients earlier in gestation and therefore may be important in mechanisms regulating the onset of labor. ASA provokes an increase in 5-HETE biosynthesis by amnion cells: control media 2.60 +/- 1.5, ASA treatment alone 5.17 +/- 0.20, IL-1 beta alone 6.39 +/- 2.1, and ASA + IL-1 beta 8.95 +/- 1.2 (mean +/- SEM) picograms per microgram protein per 16 hours. These findings may explain in part why cyclooxygenase inhibitors are not always successful in treating women with preterm labor.

Amniocentesis↗

PubMed1996

Cyclosporin A inhibits prostaglandin E2 production by fetal amnion cells in response to various stimuli.

Use of cyclosporin A as part of an immunosuppressive regimen in pregnant transplant patients is not uncommon. Although successful pregnancies have been reported with the use of various immunosuppressive agents including cyclosporin A, the concern for fetal outcome still remains. Our purpose was to evaluate the effects of immunosuppressive cyclosporin A on prostaglandin E2 (PGE2) production by human fetal amnion. Amnion cells were isolated from term placentae obtained at elective cesarean section before the onset of labor. Cells were grown to confluence and then incubated for 16 hours with cyclosporin A (1-1000 ng/ml) in the presence and absence of interleukin 1 beta (IL-1 beta, 1 ng/ml), phorbol 12-myristate 13-acetate (PMA, 10(-7) M) and ionomycin (0.5 microM). PGE2 was measured by radioimmunoassay and cellular protein determined. IL-1 beta, PMA and ionomycin all stimulated amnion cell PGE2 production as expected. However, these stimulatory actions were attenuated by at least 50% when cells were co-incubated with cyclosporin A (1000 ng/ml). Concentrations of cyclosporin A tested included the therapeutic range (250-1000 ng/ml). Our results indicate that cyclosporin A does not stimulate amnion cell PGE2 production and is probably unrelated to preterm labor and delivery in allograft recipients.

Amnion↗

PubMed1996

Elevations of serum interleukin-12 concentrations in women with severe pre-eclampsia and HELLP syndrome.

The objective is to test the hypothesis that serum IL-12 concentrations would be elevated in women with severe pre-eclampsia and HELLP syndrome. The Methods used were as follows: Serum was obtained from women admitted to our Labor and Delivery unit diagnosed with severe pre-eclampsia or HELLP syndrome and normal control patients. IL-12 concentrations in these samples were determined by the use of two different and specific enzyme-linked immunosorbent assays for the p40 subunit and the intact p75 dimer. It was found that serum IL-12 (p40 subunit) concentrations were elevated in women with both severe pre-eclampsia (p = 0.011) or HELLP syndrome (= 0.004). Similar findings were noted for these patients when matched with control patients for maternal age, gestational age, and parity. Eleven women had elevations of serum IL-12 p75 dimer, and 10 of these 11 patients had severe pre-eclampsia or HELLP syndrome. In conclusion, we found that women with severe pre-eclampsia and HELLP syndrome commonly have detectable concentrations of the IL-12 p40 monomer and were more likely than normal control women to have detectable serum IL-12 p75 dimer. While the exact role of IL-12 in hypertensive disease during pregnancy is unclear, our data support the hypothesis that the regulation of IL-12 production and metabolism is abnormal in women with pre-eclampsia and HELLP syndrome, perhaps contributing to the immunologic alterations characteristic of these disorders.

Adult↗

PubMed1996

Intrauterine infection and the effects of inflammatory mediators on prostaglandin production by myometrial cells from pregnant women.

OBJECTIVE: Our purpose was to evaluate the effects of known stimulants of prostaglandin production on cultured myometrial cells from women in labor with and without intrauterine infection. STUDY DESIGN: Myometrial segments were obtained from 16 patients between 33 and 40 weeks' gestation who had been in labor for > or = 8 hours at cesarean delivery; 8 patients had clinical chorioamnionitis and 8 did not. Myometrial cells were isolated and grown in culture. Incubations were conducted with interleukin-1 beta, tumor necrosis factor-alpha, or epidermal growth factor. Prostaglandin E2, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin) were measured by radioimmunoassay, and cellular protein was determined. RESULTS: Cultured human myometrial cells from patients with and without prior intrauterine infection produced prostaglandins in response to interleukin-1 beta, tumor necrosis factor-alpha, and epidermal growth factor at a significantly increased rate (p<0.05 vs controls at and above 10 ng/ml of interleukin-1 beta, tumor necrosis factor-alpha, and epidermal growth factor). The major prostaglandin produced in response to each stimulant was 6-keto-prostaglandin F1 alpha; however, this response was attenuated in cells from patients with intrauterine infection. CONCLUSIONS: Cultured human myometrial cells from patients with and without prior intrauterine infection respond to known stimulants of prostaglandin production. Prior intrauterine infection has no effect on baseline prostaglandin production, but the amount of prostacyclin produced as a response to cellular stimulants is decreased with prior intrauterine infection. This effect may have a role in regulating myometrial function in intrauterine infection.

6-Ketoprostaglandin F1 alpha↗

PubMed1996

Prostaglandin H synthase-2 in human gestational tissues: regulation in amnion.

Using reverse transcriptase-polymerase chain reaction we have established that mRNAs for prostaglandin H synthases 1 and 2 (PGHS-1 and PGHS-2) are present in amnion, chorion and decidua from women both at term before and after the onset of labour and from women at 28-35 weeks of gestation before the onset of labour. By Western blot analyses we have demonstrated that epidermal growth factor, interleukin 1 beta and phorbol 12-myristate 13-acetate all increase PGHS-2 amounts in amnion cells. The degree of stimulation caused by these substances (218-311 per cent) is less than the increase in prostaglandin production usually generated (five- to 10-fold). Hence we believe that these substances may have multiple sites of action in the pathways of arachidonic acid metabolism.

Amnion↗

PubMed1996

Regulation of prostaglandin H synthase-2 in chorion and decidual cells.

The regulation of chorio-decidual prostaglandin biosynthesis has important implications for our understanding of the mechanisms of human parturition. It has been known for many years that prostaglandin H synthase (PGHS) is a key enzyme in prostaglandin biosynthesis but recently an inducible form (PGHS-2) has been identified that is separate from the constitutive form (PGHS-1). We have evaluated whether substances known to stimulate prostaglandin biosynthesis in chorio-decidua act via PGHS-2. Human chorion and decidual cells were grown to confluence and treated for up to 16 h with interleukin 1 beta 10 ng/ml), epidermal growth factor (EGF) (10 ng/ml) or phorbol 12-myristate 13-acetate (PMA) (10(-7) M). Microsomal protein was isolated, separated by gel electrophoresis and PGHS-2 amounts determined using an antibody specific for PGHS-2. All three test agents caused an increase in PGHS-2 levels in chorion cells (189%-288%) and decidual cells (153%-541%). Hence, induction of PGHS-2 is one of the mechanisms by which several substances can elevate the rate of prostaglandin biosynthesis.

Blotting, Western↗

PubMed1996

Increase in prostaglandin bioavailability precedes the onset of human parturition.

The traditional paradigm that prostaglandins (PGS) are of central importance in the initiation of labor has been challenged. A group of investigators has recently reported that the amniotic fluid concentrations of PGE(2) and PGF(2 alpha) increase only late in the course of labor implying that "the accumulation of prostaglandins in amniotic fluid is an after-effect of labor and not indicative of a role of these compounds in the initiation of human parturition." The present study was conducted to determine whether amniotic fluid prostaglandin concentrations increase prior to the onset of human labor, the central question in this controversy. Three amniocenteses were performed in 17 women with intrahepatic cholestasis of pregnancy -- the first two prior to the onset of labor and the third during early spontaneous labor. PGE(2) and PGF(2 alpha) were measured with sensitive and specific radioimmunoassays. Amniotic fluid concentrations of PGE(2) and PGF(2 alpha) increased prior to the onset of spontaneous labor. An additional increase in the concentrations of PGE(2) and PGF(2 alpha) was found in samples obtained in early labor. We conclude that an increase in prostaglandin bioavailability precedes the onset of spontaneous human parturition.

Amniocentesis↗

PubMed1996

Elevation of amniotic fluid interleukin-4 concentrations in women with preterm labor and chorioamnionitis.

Preterm labor associated with intrauterine infection is characterized by increased amniotic fluid concentrations of various proinflammatory cytokines, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, IL-8, and macrophage inflammatory protein-1alpha (MIP-1alpha). The purpose of this study was to determine if preterm labor in women with clinically evident chorioamnionitis is marked by elevations of the anti-inflammatory cytokine interleukin-4 (IL-4) and the T cell growth factor IL-2. Amniotic fluid samples were obtained from (1) women at term, not in labor (n = 10); (2) women at term, in labor (n = 10); (3) women with preterm contractions but undelivered within 1 week of amniotic fluid collection (n = 10); (4) women with preterm labor and delivery without clinically evident chorioamnionitis (n = 10); (5) women with preterm labor associated with chorioamnionitis (n = 8); and (6) women with preterm labor and delivery without infection matched with patients with chorioamnionitis (n = 8). Amniotic fluid concentrations of IL-4 and IL-2 were determined for each sample with a specific and sensitive enzyme-linked immunoassay. We found that women with infection-associated preterm labor and delivery had significantly higher concentrations of IL-4 when compared to appropriately matched controls (p < 0.05). Additionally, women with preterm labor and delivery not associated with infection had higher amniotic fluid IL-4 concentrations than women with preterm contractions but no labor (p < 0.05). Women with term labor had rare modest elevations of amniotic fluid IL-4. No IL-2 was detected in any sample. Our data indicate that amniotic fluid IL-4 is elevated in women with preterm labor and delivery, particularly in association with chorioamnionitis. We suggest that IL-4, although previously considered an anti-inflammatory agent, may have a paradoxical proinflammatory role in the pathogenesis of infection-associated preterm labor.

Adult↗

PubMed1996

Significant decrease in parathyroid hormone-related protein concentrations in amniotic fluid with labour at term but not preterm.

It has been determined whether amniotic fluid concentrations of parathyroid hormone-related protein (PTHrP) change with labour. An evaluation of which cells from intrauterine tissues might produce PTHrP has also been conducted. Amniotic fluid was obtained by amniocentesis from women: (1) at term, not in labour; (2) in normal term labour; (3) in preterm labour, undelivered within one week; (4) in preterm labour, delivered within one week; (5) in preterm labour associated with clinical chorioamnionitis; and (6) who were gestation-matched controls for chorioamnionitis patients-women in this group were similar to those in Group 4 but were different patients. Amnion, chorion, and decidual cells were grown by standard techniques and incubated with interleukin-1 beta (IL-1 beta). PTHrP was assayed in duplicate samples of amniotic fluid or tissue culture media using an immunoradiometric assay. There was a significant reduction in amniotic fluid concentrations of PTHrP during labour at term. Preterm labour was not associated with significant changes in amniotic fluid concentrations of PTHrP although a trend for reduced concentrations was observed. Amnion and chorion produced measurable quantities of PTHrP and rates of production were increased by treatment with IL-1 beta. Decidual cells did not produce detectable amounts of PTHrP. Hence, labour at term is associated with a decrease in amniotic fluid PTHrP concentrations that may reflect reduced amnion production, which in turn may play a permissive or active role in the mechanism(s) of parturition. These data support the view that the mechanisms that control term and preterm labour may be regulated differently.

Amniocentesis↗

PubMed1996

Characterization of porcine endometrial, myometrial, and mammary oxytocin binding sites during gestation and labor.

Changes in oxytocin (OT) receptor expression have been found to be an important determinant of the physiological effect of OT in several species. To date there are no published studies of OT binding sites during pregnancy in the pig. The purpose of the present study is to improve understanding of the role of OT in porcine parturition. The concentration and affinity of OT binding sites were determined for myometrium and endometrium from pregnant and postpartum gilts. Tissues were obtained after slaughter from 7 animals in each of four groups: 1) 90 days gestation, 2) 112 days gestation, 3) term after milk letdown (before delivery), and 4) within 1-3 h after farrowing. Mammary tissues were obtained for some animals in each group (n = 3-5/group). Before slaughter, blood was collected from each animal and assayed for estradiol-17 beta, progesterone, 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM), and OT. Binding of 3H-OT in the three tissues was concentration- and time-dependent. Sites of 3H-OT binding (fmol/mg protein +/- SEM) increased toward term for each tissue and remained elevated in the postpartum group. Endometrial and mammary tissues displayed the most acute increases in OT binding site concentrations while myometrial tissues displayed a more gradual increase in OT binding sites over the times studied. The binding sites displayed high affinity for 3H-OT and were characterized by linear Scatchard plots. Concentrations of estradiol-17 beta, PGFM, and OT (pg/ml +/- SEM) were positively correlated with 3H-OT binding site concentrations, whereas progestrone concentrations (ng/ml +/- SEM) were negatively correlated with binding site concentration, as determined by Pearson's Correlation Analysis. The data represent the first account of changes in the expression of OT binding sites on porcine tissues during gestation and labor.

Animals↗

PubMed1996

Induction of preterm birth in mice by RU486.

We hypothesized that treatment of pregnant mice with the progesterone receptor antagonist RU486 might cause preterm labor and result in the delivery of live pups. We also hypothesized that RU486 administration would alter prostaglandin production by decidual explants taken from these pregnancies. C3H/HeN females mated with C57BI/6 males were injected with a single s.c. dose of RU486 on Days 12-14 of gestation. Three doses were tested (50 micrograms, 150 micrograms, and 250 micrograms), and the mice were observed for evidence of delivery. The time course of delivery was determined in a second experiment using 150 micrograms of RU486, and care was taken to observe the condition of the delivered pups. In a third experiment, mice were killed when delivery commenced after injection with 150 micrograms of RU486, and decidual explants were prepared. Controls that had received injections of vehicle were killed at the same time, and decidual explants were established. Media were removed after 24 h and analyzed for prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) by RIA and for interleukin 6 (IL-6) by ELISA. Two of 3 mice given 50 micrograms of RU486 delivered 16 pups prematurely. All 3 mice given 150 micrograms of RU486 delivered 22 pups prematurely, and 2 of 3 given 250 micrograms of RU486 delivered 12 pups prematurely. Of mice treated with 150 micrograms of RU486, none delivered within 12 h; 2 of 7 delivered within 15 h; and 6 of 7 delivered within 22 h. All pups appeared to be healthy, with no evidence of placental infarction or death. PGE2, PGF2 alpha, and IL-6 production by decidual explants was significantly greater in tissues taken from RU486-treated mice (n = 6) than in controls (n = 3). In summary, RU486 reliably induced preterm birth of the mice within 24 h after s.c. injection. This was associated with increased decidual prostaglandin and cytokine production and thus may mediate preterm labor. Inducing preterm birth with RU486 in a mouse model may be useful in investigations of the mechanism(s) of preterm labor.

Abortifacient Agents, Steroidal↗