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

Autor:	Widowski H; Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands.; Department of BioMedical Engineering, Maastricht University Medical Center, Maastricht, Netherlands.; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands., Reynaert NL; Department of Respiratory Medicine, Maastricht University, Maastricht, Netherlands.; NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands., Ophelders DRMG; Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands.; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands., Hütten MC; Neonatology, Pediatrics Department, Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Center, Maastricht, Netherlands.; University Children's Hospital Würzburg, University of Würzburg, Würzburg, Germany., Nikkels PGJ; Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands., Severens-Rijvers CAH; Department of Pathology, Maastricht University Medical Center, Maastricht, Netherlands., Cleutjens JPM; Department of Pathology, Maastricht University Medical Center, Maastricht, Netherlands.; CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, Netherlands., Kemp MW; Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, WA, Australia., Newnham JP; Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, WA, Australia., Saito M; Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, WA, Australia.; Tohoku University Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Usuda H; Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, WA, Australia.; Tohoku University Centre for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan., Payne MS; Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, WA, Australia., Jobe AH; Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, WA, Australia.; Perinatal Institute Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States., Kramer BW; Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands.; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands.; School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands., Delhaas T; Department of BioMedical Engineering, Maastricht University Medical Center, Maastricht, Netherlands.; CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, Netherlands., Wolfs TGAM; Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands.; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in medicine [Front Med (Lausanne)] 2021 Feb 22; Vol. 8, pp. 614239. Date of Electronic Publication: 2021 Feb 22 (Print Publication: 2021).
DOI:	10.3389/fmed.2021.614239
Abstrakt:	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 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Widowski, Reynaert, Ophelders, Hütten, Nikkels, Severens-Rijvers, Cleutjens, Kemp, Newnham, Saito, Usuda, Payne, Jobe, Kramer, Delhaas and Wolfs.)
Databáze:	MEDLINE
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