Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.
PLoS One. 2012;7(5):e38257. doi: 10.1371/journal.pone.0038257. Epub 2012 May 31.
Chorioamnionitis is associated with preterm delivery and involution of the fetal thymus. Women at risk of preterm delivery receive antenatal corticosteroids which accelerate fetal lung maturation and improve neonatal outcome. However, the effects of antenatal corticosteroids on the fetal thymus in the settings of chorioamnionitis are largely unknown. We hypothesized that intra-amniotic exposure to lipopolysaccharide (LPS) causes involution of the fetal thymus resulting in persistent effects on thymic structure and cell populations. We also hypothesized that antenatal corticosteroids may modulate the effects of LPS on thymic development.
Time-mated ewes with singleton fetuses received an intra-amniotic injection of LPS 7 or 14 days before preterm delivery at 120 days gestational age (term = 150 days). LPS and corticosteroid treatment groups received intra-amniotic LPS either preceding or following maternal intra-muscular betamethasone. Gestation matched controls received intra-amniotic and maternal intra-muscular saline. The fetal intra-thoracic thymus was evaluated.
Intra-amniotic LPS decreased the cortico-medullary (C/M) ratio of the thymus and increased Toll-like receptor (TLR) 4 mRNA and CD3 expression indicating involution and activation of the fetal thymus. Increased TLR4 and CD3 expression persisted for 14 days but Foxp3 expression decreased suggesting a change in regulatory T-cells. Sonic hedgehog and bone morphogenetic protein 4 mRNA, which are negative regulators of T-cell development, decreased in response to intra-amniotic LPS. Betamethasone treatment before LPS exposure attenuated some of the LPS-induced thymic responses but increased cleaved caspase-3 expression and decreased the C/M ratio. Betamethasone treatment after LPS exposure did not prevent the LPS-induced thymic changes.
Intra-amniotic exposure to LPS activated the fetal thymus which was accompanied by structural changes. Treatment with antenatal corticosteroids before LPS partially attenuated the LPS-induced effects but increased apoptosis in the fetal thymus. Corticosteroid administration after the inflammatory stimulus did not inhibit the LPS effects on the fetal thymus.
绒毛膜羊膜炎与早产和胎儿胸腺退化有关。有早产风险的孕妇接受产前皮质类固醇治疗，这可以加速胎儿肺成熟并改善新生儿结局。然而，在绒毛膜羊膜炎的情况下，产前皮质类固醇对胎儿胸腺的影响在很大程度上尚不清楚。我们假设羊水中内毒素（LPS）的暴露会导致胎儿胸腺退化，从而对胸腺结构和细胞群产生持续影响。我们还假设产前皮质类固醇可能会调节 LPS 对胸腺发育的影响。
时间匹配的怀有单胎胎儿的母羊在妊娠 120 天（足月= 150 天）前早产时接受羊膜内 LPS 注射。LPS 和皮质类固醇治疗组在接受母羊肌肉内倍他米松之前或之后接受羊膜内 LPS 治疗。胎龄匹配的对照组接受羊膜内和母羊肌肉内生理盐水注射。评估胎儿胸腔内的胸腺。
羊膜内 LPS 降低了胸腺的皮质-髓质（C/M）比值，并增加了 Toll 样受体（TLR）4 mRNA 和 CD3 的表达，表明胎儿胸腺的退化和激活。增加的 TLR4 和 CD3 表达持续 14 天，但 Foxp3 表达减少，表明调节性 T 细胞发生变化。对 T 细胞发育起负调节作用的 Sonic hedgehog 和骨形态发生蛋白 4 mRNA 对羊膜内 LPS 的反应减少。LPS 暴露前的倍他米松治疗减轻了 LPS 引起的一些胸腺反应，但增加了裂解的 caspase-3 表达并降低了 C/M 比值。LPS 暴露后的倍他米松治疗并不能防止 LPS 引起的胸腺变化。
羊膜内 LPS 的暴露激活了胎儿胸腺，同时伴有结构变化。LPS 前皮质类固醇治疗部分减轻了 LPS 引起的作用，但增加了胎儿胸腺的细胞凋亡。炎症刺激后的皮质类固醇给药并不能抑制 LPS 对胎儿胸腺的影响。
