Sequential Exposure to Antenatal Microbial Triggers Attenuates Alveolar Growth and Pulmonary Vascular Development and Impacts Pulmonary Epithelial Stem/Progenitor Cells

Please always quote using this URN: urn:nbn:de:bvb:20-opus-229695
  • Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelialPerinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelial stem/progenitor cells and vascular maturation, which are crucial drivers of lung development. Therefore, a translational ovine model of antenatal infection/inflammation with consecutive exposures to chronic and acute stimuli was used. Ovine fetuses were exposed intra-amniotically to Ureaplasma parvum 42 days (chronic stimulus) and/or to lipopolysaccharide 2 or 7 days (acute stimulus) prior to preterm delivery at 125 days of gestation. Pulmonary inflammation, endogenous epithelial stem cell populations, vascular modulators and morphology were investigated in preterm lungs. Pre-exposure to UP attenuated neutrophil infiltration in 7d LPS-exposed lungs and prevented reduction of SOX-9 expression and increased SP-B expression, which could indicate protective responses induced by re-exposure. Sequential exposures did not markedly impact stem/progenitors of the proximal airways (P63+ basal cells) compared to single exposure to LPS. In contrast, the alveolar size was increased solely in the UP+7d LPS group. In line, the most pronounced reduction of AEC2 and proliferating cells (Ki67+) was detected in these sequentially UP + 7d LPS-exposed lambs. A similar sensitization effect of UP pre-exposure was reflected by the vessel density and expression of vascular markers VEGFR-2 and Ang-1 that were significantly reduced after UP exposure prior to 2d LPS, when compared to UP and LPS exposure alone. Strikingly, while morphological changes of alveoli and vessels were seen after sequential microbial exposure, improved lung function was observed in UP, 7d LPS, and UP+7d LPS-exposed lambs. In conclusion, although sequential exposures did not markedly further impact epithelial stem/progenitor cell populations, re-exposure to an inflammatory stimulus resulted in disturbed alveolarization and abnormal pulmonary vascular development. Whether these negative effects on lung development can be rescued by the potentially protective responses observed, should be examined at later time points.show moreshow less
Metadaten
Author: Helene Widowski, Niki L. Reynaert, Daan R. M. G. Ophelders, Matthias C. Hütten, Peter G. J. Nikkels, Carmen A. H. Severens-Rijvers, Jack P. M. Cleutjens, Matthew W. Kemp, John P. Newnham, Masatoshi Saito, Haruo Usuda, Matthew S. Payne, Alan H. Jobe, Boris W. Kramer, Tammo Delhaas, Tim G. A. M. Wolfs
URN:urn:nbn:de:bvb:20-opus-229695
Document Type:Journal article
Faculties:Medizinische Fakultät / Kinderklinik und Poliklinik
Language:English
Parent Title (English):Frontiers in Medicine
ISSN:2296-858X
Year of Completion:2021
Volume:8
Article Number:614239
Source:Frontiers in Medicine 2021, 8:614239. DOI: 10.3389/fmed.2021.614239
DOI:https://doi.org/10.3389/fmed.2021.614239
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:adverse pulmonary outcomes; antenatal inflammation; bronchopulmonary dysplasia; endogenous pulmonary stem cells; polymicrobial infection; preterm birth; vascular disturbances
Release Date:2022/02/02
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International