Department of Pediatrics, School for Oncology and Developmental Biology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.
Am J Physiol Lung Cell Mol Physiol. 2013 Mar 15;304(6):L438-44. doi: 10.1152/ajplung.00251.2012. Epub 2013 Jan 18.
Inflammation and antenatal glucocorticoids, the latter given to mothers at risk for preterm birth, affect lung development and may contribute to the development of bronchopulmonary dysplasia (BPD). The effects of the combined exposures on inflammation and antenatal glucocorticoids on transforming growth factor (TGF)-β signaling are unknown. TGF-β and its downstream mediators are implicated in the etiology of BPD. Therefore, we asked whether glucocorticoids altered intra-amniotic lipopolysaccharide (LPS) effects on TGF-β expression, its signaling molecule phosphorylated sma and mothers against decapentaplegic homolog 2 (pSmad2), and the downstream mediators connective tissue growth factor (CTGF) and caveolin-1 (Cav-1). Ovine singleton fetuses were randomized to receive either an intra-amniotic injection of LPS and/or maternal betamethasone (BTM) intramuscularly 7 and/or 14 days before delivery at 120 days gestational age (GA; term = 150 days GA). Saline was used for controls. Protein levels of TGF-β1 and -β2 were measured by ELISA. Smad2 phosphorylation was assessed by immunohistochemistry and Western blot. CTGF and Cav-1 mRNA and protein levels were determined by RT-PCR and Western blot. Free TGF-β1 and -β2 and total TGF-β1 levels were unchanged after LPS and/or BTM exposure, although total TGF-β2 increased in animals exposed to BTM 7 days before LPS. pSmad2 immunostaining increased 7 days after LPS exposure although pSmad2 protein expression did not increase. Similarly, CTGF mRNA and protein levels increased 7 days after LPS exposure as Cav-1 mRNA and protein levels decreased. BTM exposure before LPS prevented CTGF induction and Cav-1 downregulation. This study demonstrated that the intrauterine inflammation-induced TGF-β signaling can be inhibited by antenatal glucocorticoids in fetal lungs.
炎症和产前糖皮质激素，后者用于有早产风险的母亲，影响肺发育，并可能导致支气管肺发育不良（BPD）的发展。联合暴露对炎症和产前糖皮质激素对转化生长因子（TGF）-β信号的影响尚不清楚。TGF-β及其下游介质与 BPD 的病因有关。因此，我们想知道糖皮质激素是否改变了羊水中脂多糖（LPS）对 TGF-β表达及其信号分子磷酸化 sma 和抗母育酚蛋白 2（pSmad2）的影响，以及下游介质结缔组织生长因子（CTGF）和小窝蛋白-1（Cav-1）。绵羊单胎胎儿随机接受宫内 LPS 注射和/或肌内倍他米松（BTM）注射，分别在 120 天妊娠龄（GA；足月= 150 天 GA）前 7 天和 14 天。生理盐水用于对照。通过 ELISA 测量 TGF-β1 和 -β2 的蛋白水平。通过免疫组织化学和 Western blot 评估 Smad2 磷酸化。通过 RT-PCR 和 Western blot 测定 CTGF 和 Cav-1 mRNA 和蛋白水平。尽管在 LPS 前 7 天暴露于 BTM 的动物中总 TGF-β2 增加，但 LPS 和/或 BTM 暴露后游离 TGF-β1 和 -β2 和总 TGF-β1 水平保持不变。尽管 pSmad2 蛋白表达没有增加，但 LPS 暴露 7 天后 pSmad2 免疫染色增加。同样，LPS 暴露 7 天后 CTGF mRNA 和蛋白水平增加，而 Cav-1 mRNA 和蛋白水平降低。LPS 前的 BTM 暴露可防止 CTGF 诱导和 Cav-1 下调。本研究表明，宫内炎症诱导的 TGF-β 信号可被胎儿肺部的产前糖皮质激素抑制。
