Ellen M. Gurzenda

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).

Actin is oxidized during myocardial ischemia.

Exposure of isolated rat hearts to 30 min global ischemia followed by 60 min reperfusion resulted in a significant 80% increase (p <.05) in actin content of carbonyl groups, which was associated with significant depression (p <.05) of postischemic contractile function. This result supports the hypothesis that one mechanism of postischemic contractile dysfunction may be oxidation of contractile proteins.

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

IL-10 modulates placental responses to TLR ligands.

Problem  Intra‐uterine infections increase production of pro‐inflammatory cytokines. It is unclear whether different infectious agents determine the relative expression of pro‐and anti‐inflammatory cytokines.

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.

ORIGINAL ARTICLE: IL-10 Modulates Placental Responses to TLR Ligands

Problem  Intra‐uterine infections increase production of pro‐inflammatory cytokines. It is unclear whether different infectious agents determine the relative expression of pro‐and anti‐inflammatory cytokines.

Promotion of copper excretion from the isolated rat heart attenuates postischemic cardiac oxidative injury

This study examined the role of Cu as a mediator of cardiac postischemic oxidative injury. Isolated rat hearts were subjected to 20 min of normothermic global ischemia, followed by 30 min of reperfusion; after 20 min of preischemic loading with Krebs-Henseleit buffer ± 20 or 30 μM zinc-bis-histidinate (Zn-His2), 0.5 mM deferoxamine (DEF) or 42 μM neocuproine (NEO). Postischemic developed systolic pressure and rate-pressure product were highest and postischemic end-diastolic pressure was lowest in hearts treated with 20 or 30 μM Zn-His2 and 0.5 mM DEF. Cu efflux was significantly increased by 225 and 290% (end of preischemic loading), and 325 and 375% (immediate postischemic period) of control basal rates in hearts treated with 30 μM Zn-His2 and 0.5 mM DEF, respectively. NEO did not effect any of these parameters. By the end of ischemia, protein carbonyls were lowest in Zn-His2-treated hearts and highest in DEF-treated hearts when compared with control hearts. The results of this study suggest that removal of redox-active Cu before ischemia has beneficial effects, indicating a mediatory role in postischemic cardiac oxidative injury.

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.

Can carbon monoxide prevent infection-mediated preterm birth in a mouse model?

Preterm birth is frequently caused by intrauterine infection and inflammation. Recent studies have demonstrated that carbon monoxide (CO), which is produced endogenously, has potent anti‐inflammatory properties. Whether or not CO can prevent infection‐mediated preterm birth is unknown.

ORIGINAL ARTICLE: IL-10 Modulates Placental Responses to TLR Ligands: PLACENTAL RESPONSES TO TLR LIGANDS

Problem  Intra‐uterine infections increase production of pro‐inflammatory cytokines. It is unclear whether different infectious agents determine the relative expression of pro‐and anti‐inflammatory cytokines.