Activation of the NF-kappa B pathway alters the phenotype of MSCs in the tracheal aspirates of preterm infants with severe BPD

Reicherzer, Tobias; Haeffner, Susanne; Shahzad, Tayyab; Gronbach, Judith; Mysliwietz, Josef; Hubener, Christoph; Hasbargen, Uwe; Gertheiss, Jan; Schulze, Andreas; Bellusci, Saverio; Morty, Rory E.; Hilgendorff, Anne und Ehrhardt, Harald (2018): Activation of the NF-kappa B pathway alters the phenotype of MSCs in the tracheal aspirates of preterm infants with severe BPD. In: American Journal of Physiology-Lung Cellular and Molecular Physiology, Bd. 315, Nr. 1: L87-L101

Abstract

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 NF kappa Bp65 and was accompanied by reduced expression of cytosolic alpha-smooth muscle actin (alpha-SMA). The central role of NF-kappa B signaling was confirmed by inhibition of I kappa B alpha phosphorylation. The combined score of proliferative capacity, accumulation of NF kappa Bp65, and expression of alpha-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-1 beta and TNF-alpha. 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 NF kappa Bp65 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. NF kappa Bp65 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1040-0605
• Sprache: Englisch