Amitasrigowri Murthy

Polybrominated Diphenyl Ethers Enhance the Production of Proinflammatory Cytokines by the Placenta

Polybrominated diphenyl ether(s) (PBDE) are ubiquitous environmental contaminants that bind and cross the placenta but their effects on pregnancy outcome are unclear. It is possible that environmental contaminants increase the risk of inflammation-mediated pregnancy complications such as preterm birth by promoting a proinflammatory environment at the maternal-fetal interface. We hypothesized that PBDE would reduce IL-10 production and enhance the production of proinflammatory cytokines associated with preterm labor/birth by placental explants. Second-trimester placental explants were cultured in either vehicle (control) or 2 μM PBDE mixture of congers 47, 99 and 100 for 72 h. Cultures were then stimulated with 10(6) CFU/ml heat-killed Escherichia coli for a final 24 h incubation and conditioned medium was harvested for quantification of cytokines and PGE(2). COX-2 content and viability of the treated tissues were then quantified by tissue ELISA and MTT reduction activity, respectively. PBDE pre-treatment reduced E. coli-stimulated IL-10 production and significantly increased E. coli-stimulated IL-1β secretion. PBDE exposure also increased basal and bacteria-stimulated COX-2 expression. Basal, but not bacteria-stimulated PGE(2), was also enhanced by PBDE exposure. No effect of PBDE on viability of the explants cultures was detected. In summary, pre-exposure of placental explants to congers 47, 99, and 100 enhanced the placental proinflammatory response to infection. This may increase the risk of infection-mediated preterm birth by lowering the threshold for bacteria to stimulate a proinflammatory response(s).

Can oxygen tension contribute to an abnormal placental cytokine milieu

Citation Peltier MR, Gurzenda EM, Murthy A, Chawala K, Lerner V, Kharode I, Arita Y, Rhodes A, Maari N, Moawad A, Hanna N. Can oxygen tension contribute to an abnormal placental cytokine milieu? Am J Reprod Immunol 2011; 66: 279–285

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) enhances placental inflammation

Preterm birth is a leading cause of perinatal morbidity and mortality that is often associated with ascending infections from the lower genital tract. Recent studies with animal models have suggested that developmental exposure to the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can increase the risk of preterm birth in the offspring. How TCDD may modify placental immunity to ascending infections is unclear. Therefore, we studied the effects of TCDD treatment on basal and Escherichia coli-stimulated cytokine production by placental explants. Cultures of second-trimester placentas were treated with up to 40 nM TCDD for 72 h and then stimulated with 10(7)CFU/ml E. coli for an additional 24h. Concentrations of cytokines and PGE2 were measured in conditioned medium by immunoassay. TCDD exposure increased mRNA levels of IL-1β by unstimulated cultures, but no effects on protein levels of this cytokine were detected. TNF-α production was unaffected by TCDD for unstimulated cultures, but pre-treatment with 40 nM TCDD significantly increased E. coli-stimulated TNF-α production. Both basal and bacteria-stimulated PGE2 and COX-2 gene expression were enhanced by TCDD pretreatment. In contrast, production of the anti-inflammatory cytokine, IL-10, was reduced by TCDD pretreatment for both unstimulated and E. coli-stimulated cultures. No effect of TCDD on the viability of the cultures was detected. These results suggest that TCDD exposure may shift immunity to enhance a proinflammatory phenotype at the maternal-fetal interface that could increase the risk of infection-mediated preterm birth.

Effect of carbon monoxide on bacteria-stimulated cytokine production by placental explants.

Preterm birth is frequently caused by an inflammatory response to ascending infections of the reproductive tract. Carbon monoxide (CO) has potent anti‐inflammatory properties at subtoxic concentrations. Whether or not CO can modulate inflammatory responses by placental tissues is unclear.

Carbon monoxide attenuates bacteria-induced Endothelin-1 expression in second trimester placental explants

INTRODUCTION The pro-inflammatory mediator and potent vasoconstrictor Endothelin-1 (ET-1) is known to be expressed in the placenta. We have recently demonstrated that very low, non-toxic doses of carbon monoxide (CO), prevented infection-induced preterm birth in mice. However the effect(s) of CO on human gestational tissues is yet to be fully explored. We hypothesize that CO will have a protective role against inflammation-induced E. coli by down-regulating the ET axis in placental explants. METHODS Twenty placentas from elective termination of pregnancy in the second trimester were analyzed with or without exposure to heat killed E. coli over the course of 30 h. Placental ET-1, along with its biologically inactive precursor Big ET-1, and Endothelin Converting Enzyme-1 (ECE-1, responsible for the cleavage of Big ET-1 to ET-1), were analyzed by ELISA. Gene expression for ET-1 (EDN1), ECE-1 and the ETA receptor (EDNRA) were analyzed using qPCR. Localization of ET-1 expression was also demonstrated using immunohistochemistry. RESULTS E. coli significantly increased ET-1 transcription and secretion of BIG ET-1 and ET-1 in a time dependant manner which was ameliorated when exposed to CO at later time points. In the presence of CO, mRNA levels of ECE-1 were significantly reduced at 3 and 24 h, while EDNRA was significantly reduced at 6 and 18 h. CONCLUSIONS Up-regulation of ET-1 production in human placenta in the setting of infection can be attenuated by low doses of CO. Our results further explore the anti-inflammatory and regulatory mechanism(s) of CO on the ET axis components at the maternal fetal interface.

Evaluation of a novel program to encourage immediate postplacental insertion of intrauterine devices in an urban hospital

Objectives: To evaluate expulsion rates of patients who opt for immediate postplacental insertion of both the copper T 380 A and Levonorgestrel releasing system intrauterine devices (IUD). Materials: We conducted a retrospective chart review of electronic medical records (eg; delivery and postpartum notes, discharge summaries) of women who had IUD placement within 10 min of placental delivery between November 2010 and December 2011. Methods: This study is performed as a preliminary evaluation of a quality assurance program to provide immediate post placental insertion of IUDs to an urban population. We conducted a retrospective chart review of electronic medical records (eg; delivery and postpartum notes, discharge summaries) of women who had IUD placement within 10 min of placental delivery between November 2010 and December 2011. Results: During the period of interest, a total of 273 intrauterine devices were inserted in the immediate post partum period, but only 140 participants (50%) returned for follow-up. 164 (60%) were inserted after a vaginal delivery. 152 of the IUDs inserted were copper and of these, 84 (56.8%) were inserted after a vaginal delivery. 126 (45%) of the IUDs inserted were Mirena, and 63% of Mirenas were inserted after a vaginal delivery. There were 76 expulsions after vaginal delivery of which 5 were copper IUD and 13 were levonorgestrel releasing system. Of the IUDs inserted at cesarean delivery 0/25 copper IUDs expelled and 3/27 (11%) Mirena IUDs expelled. Of the IUDs inserted at vaginal delivery, 5/25 (20%) of Paraguard IUDs expelled, while 13/51 (25%) of Mirena IUDs expelled. The expulsion rate was significantly different by delivery mode (p =0.007) and approached but did not reach significance by type of IUD (p =0.09). Conclusions: Postplacental insertion of IUDs is safe and feasible. Expulsion rates are significantly higher after vaginal delivery, although the low rate of post partum follow up (50%) in this patient population may prove to be a significant justification for acceptance of this rate. Mirena IUD may have a slightly higher expulsion rate than Paraguard IUD, but our sample size was not large enough to detect a difference. Further research into postplacental IUD insertion is warranted, especially for populations with poor access to care.