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D J Dudley

Publications and source records attributed to D J Dudley.

At least 19 recordsLinked to original sources
PubMed1999

Immunoendocrinology of preterm labor: the link between corticotropin-releasing hormone and inflammation.

Preterm labor is the final common pathway after several potential insults to the uterus or fetus. The preterm labor syndrome may be precipitated by several different pathophysiologic events, including intrauterine infection, uterine ischemia, uterine overdistention, hormonal disturbances, and other problems. Intrauterine infections (both clinically evident and subclinical) are associated with increased amniotic fluid concentrations of proinflammatory cytokines, and gestational tissues and the fetus are potential sources of these cytokines. In addition to culture-proven intrauterine infection, there may be an "intrauterine inflammatory response syndrome" that could account for cases of preterm labor in which no infectious organism can be identified. Because the immunologic and endocrinologic systems regulate each other extensively, there is potential for corticotropin-releasing hormone to regulate inflammatory responses and vice versa. The cytokine interleukin 1 stimulates production of corticotropin-releasing hormone, and corticotropin-releasing hormone in turn regulates cytokine production by immune effector cells. Because maternal stress is associated with preterm birth, abnormalities in the regulation of corticotropin-releasing hormone and the production of inflammatory cytokines may be a mechanism that could form the pathophysiologic basis for this association.

Corticotropin-Releasing Hormone↗
PubMed1998

Endocrine assays to predict preterm delivery.

Advances in the understanding of the endocrine and hormonal mechanisms involved in normal and abnormal labor have led to clinical research into the roles of hormones and cytokines in preterm labor. This article reviews the current status of assays for estriol, activin, corticotropin-releasing hormone, interleukin-6, and relaxin as predictors of preterm labor and delivery.

Activins↗
PubMed1997

Action of immunoregulatory agents on 5-HETE production by cultured human amnion cells.

Labor in women is associated with increased amniotic fluid prostaglandin (PG) concentrations. AF of women with term and preterm labor also contains elevated concentrations of arachidonic acid metabolites from the lipoxygenase pathway including 5-hydroxyeicosatetraenoic acid (5-HETE). We and others have shown that 5-HETE production within the uterus is increased by inflammatory cytokines. The purpose of this study was to determine whether 5-HETE production is regulated by immunotherapeutic agents that inhibit prostaglandin E2 (PGE2) production, such as interleukin-10 (IL-10) and cyclosporin A (CsA). Cultured confluent amnion cells were incubated for 16 hr with IL-10 (1 100 ng/ml), CsA (1 1000 ng/ml), or controls. Additional incubation of IL-10 and CsA (both at 10 and 100 ng/ml) were conducted on amnion cells in the presence and absence of interleukin-1 beta at 1 ng/ml. 5-HETE was measured by radioimmunoassay and cellular protein determined. IL-1 beta stimulated amnion cell 5-HETE production as expected. However, 5-HETE production by amnion cells was significantly inhibited by incubation with IL-10 and CsA, and both significantly attenuated 5-HETE production in response to IL-1 beta. We speculate that the inhibitory effect of IL-10 and CsA on amnion cell 5-HETE production is at the level of substrate release or inhibition of 5-lipoxygenase and that the use of these agents during pregnancy may not adversely affect pregnancy outcomes.

Amnion↗
PubMed1997

Pre-term labor: an intra-uterine inflammatory response syndrome?

Emerging concepts of sepsis suggest that the host response to an infectious stimulus results in some cases of uncontrolled release of inflammatory cytokines leading to signs of sepsis. Systemic inflammatory response syndrome (SIRS) has been suggested as a diagnosis when no etiologic organism can be found. Infection may account for up to 30% of cases of pre-term labor, and may either be clinically-evident or sub-clinical. Inflammatory cytokines can be detected in elevated concentrations in the amniotic fluid and plasma of women with pre-term labor, and human gestational tissues are potentially rich sources of inflammatory cytokines, as found in in vivo and in vitro studies. Also, maternal decidua and fetal membranes produce mRNA for inflammatory cytokines in the setting of infection-associated pre-term labor and normal term labor. Notably, anti-inflammatory cytokines, such as interleukin-10 (IL-10) do not appear to be present in substantial quantities in these pathophysiologic and physiologic conditions. Animal models indicate that pre-term labor can be stimulated by bacteria, bacterial cell wall products, and inflammatory cytokines such as IL-1 and tumor necrosis factor. These findings suggest that: (1) infectious stimuli may result in the liberation of inflammatory cytokines from gestational tissues leading inevitably to pre-term labor and delivery; (2) inhibition of this process may either be overcome or abrogated, and (3) the mechanisms regulating cytokine production in maternal and fetal tissues are disturbed. Thus, pre-term labor associated with sub-clinical infection may result in a dysregulated local inflammatory response, in which the maternal host response causes an 'intra-uterine inflammatory response syndrome' leading to pre-term labor and delivery.

Amniotic Fluid↗
PubMed1997

Regulation of decidual cell chemokine production by group B streptococci and purified bacterial cell wall components.

OBJECTIVE: Our purpose was to determine whether cultured human decidual cells produce chemokines in response to different strains of group B streptococci and purified bacterial cell wall components. STUDY DESIGN: Human decidual cells were cultured from term placentas by standard techniques. Different strains of group B streptococci were isolated from neonates with early-onset group B streptococci sepsis. Confluent cell monolayers were incubated with these different strains of group B streptococci and various concentrations of purified bacterial cell wall components (including lipoteichoic acid, sialic acid, lipopolysaccharide, and lipid A) for 16 hours at 37 degrees C. Culture supernatants were collected and assayed for macrophage inflammatory protein-1 alpha and interleukin-8. Statistical analysis was by analysis of variance. RESULTS: We found that cultured human decidual cells produced significant amounts of the two chemokines macrophage inflammatory protein-1 alpha and interleukin-8 in a strain-specific fashion to the various different strains of group B streptococci tested, from 215% to 421% over baseline production (p < 0.05 by analysis of variance). Also, we found that incubation of decidual cells with various concentrations of lipoteichoic acid, sialic acid, lipopolysaccharide, and lipid A resulted in significant concentration-dependent increases in decidual cell macrophage inflammatory protein-1 alpha and interleukin-8 production (p < 0.05.) CONCLUSIONS: Decidual cells produced significant amounts of the chemokines macrophage inflammatory protein-1 alpha and interleukin-8 in response to intact group B streptococci in a strain-specific fashion and in response to various concentrations of different bacterial cell wall components. Because chemokines are important mediators signaling migration of different immune effector cells into areas of inflammation, we suggest that decidual cell chemokine production in response to bacteria and bacterial cell wall components may be a key early event in the pathogenesis of infection-associated preterm labor.

Analysis of Variance↗
PubMed1997

Bacterial lipopolysaccharide-mediated murine fetal death: the role of interleukin-1.

OBJECTIVE: Our purpose was to determine whether interleukin-1 is an important mediator of lipopolysaccharide-induced fetal death and, if so, whether interleukin-1 causes fetal death by inducing prostanoid formation in gestational tissues. STUDY DESIGN: Pregnant C3H/HeN mice were administered lipopolysaccharide, interleukin-1alpha, interleukin-beta, or vehicle on days 11 to 13 of pregnancy. Mice were killed 72 hours later and the fetal status was determined. Some mice were pretreated with anti-interleukin-1-receptor antibodies or indomethacin. Decidual explants were established from treated mice, and supernatants were assayed for interleukin-1beta and prostaglandin E2. RESULTS: Decidua taken from lipopolysaccharide-treated mice produced significantly increased amounts of interleukin-1beta, and pretreatment with anti-interleukin-1-receptor antibodies reduced the proportion of fetal deaths after lipopolysaccharide administration from 100% to 33%. The administration of interleukin-1alpha caused fetal death in a dose-dependent fashion, and decidua taken from interleukin-1-treated mice produced significantly increased amounts of prostaglandin E2. However, pretreatment with doses of indomethacin that abrogated decidual prostaglandin E2 production did not reduce the proportion of fetal death after interleukin-1alpha administration. CONCLUSIONS: Interleukin-1 is an important mediator of lipopolysaccharide-induced fetal death and causes fetal death by prostaglandin-independent effects.

Animals↗
PubMed1997

Optimism for perilous times: a survey of American Association of Obstetricians and Gynecologists Foundation and Reproductive Scientist Development Program postdoctoral research fellows.

OBJECTIVE: Our purpose was to survey fellows of the American Association of Obstetricians and Gynecologists Foundation and Reproductive Scientist Development Program regarding their successes and problems and to solicit suggestions for improvement. STUDY DESIGN: A survey was mailed to each past and current fellow participating in the research fellowships sponsored by the two organizations. The survey requested from each respondent information regarding current research, funding, and academic status and problems they have encountered. Additionally, each respondent was encouraged to make specific suggestions on how to improve these programs. RESULTS: Of the 54 surveys sent, all were returned (100%). Of these respondents, 30 had American Association of Obstetricians and Gynecologists Foundation fellowships and 24 were in the Reproductive Scientist Development Program, representing 29 different academic programs. Forty-nine (91 %) had academic appointments and 6 were either division directors or departmental chairs. Of 39 graduates, 23 (59%) received funding from the National Institutes of Health. Thirty-one past fellows continued basic research and 23 (73%) work in their own or departmental laboratories. Of all respondents, 78% felt that they had good to excellent chances of obtaining funding, and 94% felt that participating in the research training fellowships was critically important for their academic careers. CONCLUSIONS: Research training fellowships sponsored by the American Association of Obstetricians and Gynecologists Foundation and the Reproductive Scientist Development Program have been extremely successful at keeping talented young obstetricians and gynecologists in academic medicine. Most fellows continue basic science research and have obtained extramural funding. In spite of the current stresses in academic medicine regarding financial restructuring and research funding, these fellowships continue to provide outstanding opportunities for motivated young obstetricians and gynecologists to achieve academic success.

Data Collection↗
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

Regulation of decidual cell and chorion cell production of interleukin-10 by purified bacterial products.

PROBLEM: To determine whether cultured human decidual cells and chorion cells produce interleukin-10 (IL-10) after incubation with purified bacterial products. METHOD OF STUDY: Decidual cell cultures and chorion cell cultures were established by standard techniques. With confluence, monolayers of each culture were incubated with purified bacterial products, including various concentrations of lipopolysaccharide (LPS), lipid A, and lipoteichoic acid (LTA) for 16 hr in quadruplicate. Culture supernatants were collected and assayed for immunodetectable IL-10 by enzyme-linked immunoadsorbent assay (ELISA). RESULTS: Both decidual cell cultures and chorion cell cultures produced significant quantities of IL-10 after stimulation with LPS, lipid A, and LTA. Cultures of decidual cells produced more IL-10 than did chorion cell cultures. CONCLUSIONS: Our data indicate that both maternal decidual cells and fetally derived chorion cells can produce IL-10 after incubation with bacterial virulence factors. This finding contrasts with our previous findings in which chorion cells did not produce IL-10 after stimulation with IL-1 beta, suggesting that chorion cell production after incubation with bacterial products is independent of IL-1 beta. We speculate that the contribution of anti-inflammatory IL-10 production by human gestational tissues to the inflammatory process in these tissues may be overcome or abrogated by the pro-inflammatory process.

Bacterial Infections↗
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

A population-based study of congenital diaphragmatic hernia in Utah: 1988-1994.

OBJECTIVE: To define the natural history of congenital diaphragmatic hernia and to determine the potential impact of fetal therapy. METHODS: This retrospective case series consisted of all fetuses and neonates with congenital diaphragmatic hernia born between 1988 and 1994 in the state of Utah that could be identified through genetic counseling referrals, delivery logs, and neonatal intensive care unit discharge diagnosis records. Maternal and neonatal hospital records were reviewed for antepartum, intrapartum, and postpartum variables. Based on existing recommendations, fetuses who might have benefited from fetal therapy were identified. RESULTS: Ninety-six cases were identified, for a frequency of one case in 2710 live births per year. Five pregnancies were terminated before 21 weeks' gestation. The overall survival rate excluding these five cases was 58.2%. Among the remaining 91 cases, survival was significantly better for infants diagnosed in the neonatal period than for those diagnosed prenatally (78% versus 35%; P < .001). The frequency of associated anomalies was similar for antepartum and postpartum cases. Sixty-two percent of nonsurvivors had some type of other anomaly, but no pattern was apparent. There were no accurate prenatal predictors for lethal pulmonary hypoplasia, but preterm birth and the presence of severe cardiac anomalies were predictors of neonatal death. Only two of 96 fetuses would have potentially benefited from fetal therapy. CONCLUSION: The outcome of infants with congenital diaphragmatic hernia is worse with preterm birth and if diagnosed prenatally. The survival rate we found was better than that reported in earlier studies, suggesting improved perinatal and neonatal management. Fetal therapy based on current eligibility criteria would have a minimal impact on survival of fetuses with congenital diaphragmatic hernia.

Congenital Abnormalities↗
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

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

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↗