University of Colorado School of Medicine, Aurora, Colorado.
Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
Am J Physiol Lung Cell Mol Physiol. 2022 Feb 1;322(2):L179-L190. doi: 10.1152/ajplung.00329.2021. Epub 2021 Dec 8.
Antenatal stressors such as chorioamnionitis (CA) increase the risk for bronchopulmonary dysplasia (BPD). Studies have shown that experimental BPD can be ameliorated by postnatal treatment with mesenchymal stromal cell-derived extracellular vesicles (MEx). However, the antenatal efficacy of MEx to prevent BPD is unknown. To determine whether antenatal MEx therapy attenuates intrauterine inflammation and preserves lung growth in a rat model of CA-induced BPD. At (), rat litters were treated with intra-amniotic injections of saline, endotoxin (ETX) to model chorioamnionitis, MEx, or ETX plus MEx followed by cesarean section delivery with placental harvest at . Placental and lung evaluations were conducted at and , respectively. To assess the effects of ETX and MEx on lung growth in vitro, lung explants were imaged for distal branching. Placental tissues from ETX-exposed pregnancies showed increased expression of inflammatory markers NLRP-3 and IL-1ß and altered spiral artery morphology. In addition, infant rats exposed to intrauterine ETX had reduced alveolarization and pulmonary vessel density (PVD), increased right ventricular hypertrophy (RVH), and decreased lung mechanics. Intrauterine MEx therapy of ETX-exposed pups reduced inflammatory cytokines, normalized spiral artery architecture, and preserved distal lung growth and mechanics. In vitro studies showed that MEx treatment enhanced distal lung branching and increased VEGF and SPC gene expression. Antenatal MEx treatment preserved distal lung growth and reduced intrauterine inflammation in a model of CA-induced BPD. We speculate that MEx may provide a novel therapeutic strategy to prevent BPD due to antenatal inflammation.
产前应激源，如绒毛膜羊膜炎（CA），增加了支气管肺发育不良（BPD）的风险。研究表明，实验性 BPD 可以通过间充质基质细胞衍生的细胞外囊泡（MEx）的产后治疗来改善。然而，MEx 预防 BPD 的产前疗效尚不清楚。为了确定产前 MEx 治疗是否可以减轻 CA 诱导的 BPD 大鼠模型中的宫内炎症并保留肺生长。在（），通过羊膜内注射生理盐水、内毒素（ETX）来模拟绒毛膜羊膜炎，或 MEx、ETX 加 MEx 来处理大鼠的胎鼠，并在（）进行剖宫产分娩以收获胎盘。分别在（）和（）进行胎盘和肺评估。为了评估 ETX 和 MEx 对体外肺生长的影响，对肺离体进行了远端分支成像。暴露于 ETX 的胎盘组织显示炎症标志物 NLRP-3 和 IL-1ß 的表达增加，并且螺旋动脉形态发生改变。此外，暴露于宫内 ETX 的婴儿大鼠肺泡化和肺血管密度（PVD）减少，右心室肥大（RVH）增加，肺力学降低。宫内 MEx 治疗 ETX 暴露的幼仔减少了炎症细胞因子，使螺旋动脉结构正常化，并保留了远端肺的生长和功能。体外研究表明，MEx 处理增强了远端肺分支，并增加了 VEGF 和 SPC 基因的表达。产前 MEx 治疗在 CA 诱导的 BPD 模型中保留了远端肺的生长并减轻了宫内炎症。我们推测，MEx 可能为预防因产前炎症引起的 BPD 提供一种新的治疗策略。
