Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus.

BackgroundCerebral palsy is a nonprogressive motor impairment syndrome that has no effective cure. The etiology of most cases of cerebral palsy remains unknown; however, recent epidemiologic data have demonstrated an association between fetal neurologic injury and infection/inflammation. Maternal infection/inflammation may be associated with the induction of placental cytokines that could result in increased fetal proinflammatory cytokine exposure, and development of neonatal neurologic injury. Therefore, we sought to explore the mechanism by which maternal infection may produce a placental inflammatory response. We specifically examined rat placental cytokine production and activation of the Toll-like receptor 4 (TLR4) pathway in response to lipopolysaccharide exposure at preterm and near-term gestational ages.MethodsPreterm (e16) or near-term (e20) placental explants from pregnant rats were treated with 0, 1, or 10 μg/mL lipopolysaccharide. Explant integrity was assessed by lactate dehydrogenase assay. Interleukin-6 and tumor necrosis alpha levels were determined using enzyme-linked immunosorbent assay kits. TLR4 and phosphorylated nuclear factor kappa light chain enhancer of activated B cells (NFκB) protein expression levels were determined by Western blot analysis.ResultsAt both e16 and e20, lactate dehydrogenase levels were unchanged by treatment with lipopolysaccharide. After exposure to lipopolysaccharide, the release of interleukin-6 and tumor necrosis alpha from e16 placental explants increased by 4-fold and 8-9-fold, respectively (P < 0.05 versus vehicle). Conversely, interleukin-6 release from e20 explants was not significantly different compared with vehicle, and tumor necrosis alpha release was only 2-fold higher (P < 0.05 versus vehicle) following exposure to lipopolysaccharide. Phosphorylated NFκB protein expression was significantly increased in the nuclear fraction from placental explants exposed to lipopolysaccharide at both e16 and e20, although TLR4 protein expression was unaffected.ConclusionLipopolysaccharide induces higher interleukin-6 and tumor necrosis alpha expression at e16 versus e20, suggesting that preterm placentas may have a greater placental cytokine response to lipopolysaccharide infection. Furthermore, increased phosphorylated NFκB indicates that placental cytokine induction may occur by activation of the TLR4 pathway

Case Study: Fetal Breathing Movements as a Proxy for Fetal Lung Maturity Estimation

Premature births can lead to complications, with fetal lung immaturity being a primary concern. Currently, fetal lung maturity (FLM) requires an invasive surfactant extraction procedure between the 32nd and 39th weeks of pregnancy. Unfortunately, there is no non-invasive method for FLM assessment. This work hypothesized that fetal breathing movement (FBM) and surfactant levels are inversely coupled and that FBM can serve as a proxy for FLM estimation. To investigate the correlation between FBM and FLM, antenatal corticosteroid (ACS) was administered to increase fetal pulmonary surfactant levels in a high-risk 35th-week pregnant woman showing intrauterine growth restriction. Synchronous sonographic and phonographic measurements were continuously recorded for 25 minutes before and after the ASC treatments. Before the ACS injection, 268 continuous movements FBM episodes were recorded. The number of continuous FBM episodes significantly decreased to 3, 43, and 79 within 24, 48, and 72 hours, respectively, of the first injection of ACS, suggesting an inversely coupled connection between FBM and surfactant level s. Therefore, FBM may serve as a proxy for FLM estimation. Quantitative confirmation of these findings would suggest that FBM measurements could be used as a non-invasive and widely accessible FLM-assessment tool for high-risk pregnancies and routine examinations.Comment: 4 pages, 3 figures, 50th Computing in Cardiology conference in Atlanta, Georgia, USA on 1st - 4th October 202

Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus.

BackgroundCerebral palsy is a nonprogressive motor impairment syndrome that has no effective cure. The etiology of most cases of cerebral palsy remains unknown; however, recent epidemiologic data have demonstrated an association between fetal neurologic injury and infection/inflammation. Maternal infection/inflammation may be associated with the induction of placental cytokines that could result in increased fetal proinflammatory cytokine exposure, and development of neonatal neurologic injury. Therefore, we sought to explore the mechanism by which maternal infection may produce a placental inflammatory response. We specifically examined rat placental cytokine production and activation of the Toll-like receptor 4 (TLR4) pathway in response to lipopolysaccharide exposure at preterm and near-term gestational ages.MethodsPreterm (e16) or near-term (e20) placental explants from pregnant rats were treated with 0, 1, or 10 μg/mL lipopolysaccharide. Explant integrity was assessed by lactate dehydrogenase assay. Interleukin-6 and tumor necrosis alpha levels were determined using enzyme-linked immunosorbent assay kits. TLR4 and phosphorylated nuclear factor kappa light chain enhancer of activated B cells (NFκB) protein expression levels were determined by Western blot analysis.ResultsAt both e16 and e20, lactate dehydrogenase levels were unchanged by treatment with lipopolysaccharide. After exposure to lipopolysaccharide, the release of interleukin-6 and tumor necrosis alpha from e16 placental explants increased by 4-fold and 8-9-fold, respectively (P < 0.05 versus vehicle). Conversely, interleukin-6 release from e20 explants was not significantly different compared with vehicle, and tumor necrosis alpha release was only 2-fold higher (P < 0.05 versus vehicle) following exposure to lipopolysaccharide. Phosphorylated NFκB protein expression was significantly increased in the nuclear fraction from placental explants exposed to lipopolysaccharide at both e16 and e20, although TLR4 protein expression was unaffected.ConclusionLipopolysaccharide induces higher interleukin-6 and tumor necrosis alpha expression at e16 versus e20, suggesting that preterm placentas may have a greater placental cytokine response to lipopolysaccharide infection. Furthermore, increased phosphorylated NFκB indicates that placental cytokine induction may occur by activation of the TLR4 pathway

Intestine and brain TLR-4 modulation following N-acetyl-cysteine treatment in NEC rodent model

Abstract Necrotizing enterocolitis (NEC) brain injury is mediated through Toll-like receptor 4 (TLR4) on the intestinal epithelium and brain microglia. Our aim was to determine whether postnatal and/or prenatal NAC can modify NEC associated intestinal and brain TLR4 expression and brain glutathione levels in a rat model of NEC. Newborn Sprague–Dawley rats were randomized into three groups: Control (n = 33); NEC (n = 32)—hypoxia and formula feeding; and NEC-NAC (n = 34)—received NAC (300 mg/kg IP) in addition to NEC conditions. Two additional groups included pups of dams treated once daily with NAC (300 mg/kg IV) for the last 3 days of pregnancy: NAC-NEC (n = 33) or NAC-NEC-NAC (n = 36) with additional postnatal NAC. Pups were sacrificed on the fifth day, and ileum and brains harvested for TLR-4 and glutathione protein levels. Brain and ileum TLR-4 protein levels were significantly increased in NEC offspring as compared to control (brain 2.5 ± 0.6 vs. 0.88 ± 0.12 U and ileum 0.24 ± 0.04 vs. 0.09 ± 0.01, p < 0.05). When NAC was administered only to dams (NAC-NEC) a significant decrease in TLR-4 levels was demonstrated in both offspring brain (1.53 ± 0.41 vs. 2.5 ± 0.6 U, p < 0.05) and ileum (0.12 ± 0.03 vs. 0.24 ± 0.04 U, p < 0.05) as compared to NEC. The same pattern was demonstrated when NAC was administered only or postnatally. The decrease in brain and ileum glutathione levels observed in NEC offspring was reversed with all NAC treatment groups. NAC reverses the increase in ileum and brain TLR-4 levels and the decrease in brain and ileum glutathione levels associated with NEC in a rat model, and thus may protect from NEC associated brain injury

Fetal Renal Duplicated Collecting System at 14–16 Weeks of Gestation

(1) Background: To examine the incidence of the prenatal diagnosis of the renal double-collecting system (rDCS) and describe its clinical outcome and associated genetic abnormalities. (2) Methods: This retrospective study included women who attended the obstetric clinic for early fetal anatomic sonography with findings of a renal DCS. Diagnosis was conducted by an expert sonographer using defined criteria. (3) Results: In total, 29,268 women underwent early ultrasound anatomical screening at 14–16 weeks, and 383 cases of rDCS were diagnosed (prevalence: 1:76). Associated abnormalities were diagnosed in eleven pregnancies; four had chromosomal aberrations. No chromosomal abnormalities were reported in isolated cases. Ectopic uretrocele and dysplastic kidney were diagnosed in 6 (1.5%) and 5 (1.3%) fetuses, respectively. One girl was diagnosed with vesicoureteral reflux and recurrent UTIs, and two boys were diagnosed with undescended testis. The recurrence rate of rDCS was 8% in subsequent pregnancies. (4) Conclusions: In light of its benign nature, we speculate that isolated rDCS may be considered a benign anatomic variant, but a repeat examination in the third trimester is recommended to assess hydronephrosis