Division of Neonatology, University Children's Hospital, Perinatal Center, Ludwig-Maximilians-University, Campus Grosshadern, Munich , Germany.
Comprehensive Pneumology Center, Ludwig-Maximilians-University, Asklepios Hospital, and Helmholtz Center Munich , Munich , Germany.
Am J Physiol Lung Cell Mol Physiol. 2018 Jul 1;315(1):L87-L101. doi: 10.1152/ajplung.00505.2017. Epub 2018 Apr 12.
Mesenchymal stromal cells (MSCs) are released into the airways of preterm infants following lung injury. These cells display a proinflammatory phenotype and are associated with development of severe bronchopulmonary dysplasia (BPD). We aimed to characterize the functional properties of MSCs obtained from tracheal aspirates of 50 preterm infants who required invasive ventilation. Samples were separated by disease severity. The increased proliferative capacity of MSCs was associated with longer duration of mechanical ventilation and higher severity of BPD. Augmented growth depended on nuclear accumulation of NFκBp65 and was accompanied by reduced expression of cytosolic α-smooth muscle actin (α-SMA). The central role of NF-κB signaling was confirmed by inhibition of IκBα phosphorylation. The combined score of proliferative capacity, accumulation of NFκBp65, and expression of α-SMA was used to predict the development of severe BPD with an area under the curve (AUC) of 0.847. We mimicked the clinical situation in vitro, and stimulated MSCs with IL-1β and TNF-α. Both cytokines induced similar and persistent changes as was observed in MSCs obtained from preterm infants with severe BPD. RNA interference was employed to investigate the mechanistic link between NFκBp65 accumulation and alterations in phenotype. Our data indicate that determining the phenotype of resident pulmonary MSCs represents a promising biomarker-based approach. The persistent alterations in phenotype, observed in MSCs from preterm infants with severe BPD, were induced by the pulmonary inflammatory response. NFκBp65 accumulation was identified as a central regulatory mechanism. Future preclinical and clinical studies, aimed to prevent BPD, should focus on phenotype changes in pulmonary MSCs.
间质基质细胞（MSCs）在早产儿肺损伤后会释放到气道中。这些细胞表现出促炎表型，与严重支气管肺发育不良（BPD）的发展有关。我们旨在描述从 50 名需要有创通气的早产儿气管吸出物中获得的 MSCs 的功能特性。根据疾病严重程度对样本进行了分离。MSCs 增殖能力的增强与机械通气时间延长和 BPD 严重程度增加有关。生长增强依赖于 NFκBp65 的核积累，并伴随着胞质 α-平滑肌肌动蛋白（α-SMA）表达减少。通过抑制 IκBα 磷酸化证实了 NF-κB 信号的核心作用。增殖能力、NFκBp65 积累和 α-SMA 表达的综合评分用于预测严重 BPD 的发展，曲线下面积（AUC）为 0.847。我们在体外模拟了临床情况，并使用 IL-1β 和 TNF-α 刺激 MSCs。两种细胞因子都诱导了类似于从严重 BPD 早产儿中获得的 MSCs 中观察到的相似且持续的变化。RNA 干扰用于研究 NFκBp65 积累与表型改变之间的机制联系。我们的数据表明，确定驻留肺 MSC 的表型代表了一种有前途的基于生物标志物的方法。在严重 BPD 早产儿的 MSCs 中观察到的表型持续改变是由肺部炎症反应引起的。NFκBp65 积累被确定为中央调节机制。未来旨在预防 BPD 的临床前和临床研究应集中于肺 MSC 的表型变化。
