van Horik Cathy, Meyboom Joel Anne, Boerema-de Munck Anne, Buscop-van Kempen Marjon J, Eenjes Evelien, Edel Gabriëla G, Kortekaas Demi, Wijnen Rene Mh, van IJcken Wilfred F J, Reiss Irwin K M, Rottier Robbert J, Collins Jennifer J P
Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
Center for Biomics, Erasmus MC, Rotterdam, The Netherlands.
Am J Physiol Lung Cell Mol Physiol. 2025 Aug 18. doi: 10.1152/ajplung.00391.2024.
Bronchopulmonary dysplasia (BPD) is the most common adverse outcome in preterm neonates, and a high risk for early-onset emphysema and asthma. BPD is characterized by disrupted alveolar and microvascular development, due to a variety of pathogenic factors, such as hyperoxia, inflammation and dysbiosis. The resulting clinical manifestations are challenging and current treatment options are limited. To improve therapeutic options, it is imperative to understand underlying causes. Resident lung mesenchymal stromal cells (L-MSCs) are important for alveolar microvascularization, repair and regeneration. Here, we report the immediate effects of hyperoxia and antibiotics-induced reduced bacterial load on L-MSCs and alveolar development using the hyperoxia-induced BPD mouse model. Newborn mice were exposed to hyperoxia from postnatal day 4 (P4) to P14, with room air recovery from P14 to P21. Dams received antibiotics-supplemented water (ampicillin, gentamycin and vancomycin) from E15 to P21. Hyperoxia significantly impaired alveolar development between P14 and P21, whereas both hyperoxia and antibiotics exposure impaired lung microvascular development. Moreover, hyperoxia reduced the number of pericytes, proliferative mesenchymal progenitors, matrix fibroblasts and P2RY14 alveolar myofibroblasts. RNA-Seq of LY6A-sorted L-MSCs revealed differential expression of 103 genes in hyperoxia, 10 of which are related to mast cell biology. Antibiotics exposure also altered mesenchymal cell distribution, suggesting an additional impact on lung development. The transcriptomic landscape and distribution of important L-MSC subtypes, and microvascular development are affected by hyperoxia and antibiotics exposure in a BPD-mouse model. In conclusion, we show that hyperoxia and antibiotics-induced reduced bacterial loadaffect the mesenchymal cell population, which may contribute to the development of BPD.
支气管肺发育不良（BPD）是早产儿最常见的不良结局，也是早发性肺气肿和哮喘的高危因素。BPD的特征是肺泡和微血管发育受阻，这是由多种致病因素引起的，如高氧、炎症和微生物群失调。由此产生的临床表现具有挑战性，目前的治疗选择有限。为了改善治疗方案，必须了解其潜在原因。肺驻留间充质基质细胞（L-MSCs）对肺泡微血管化、修复和再生很重要。在这里，我们使用高氧诱导的BPD小鼠模型报告了高氧和抗生素诱导的细菌载量降低对L-MSCs和肺泡发育的即时影响。新生小鼠从出生后第4天（P4）至P14暴露于高氧环境，从P14至P21恢复至常氧环境。母鼠从胚胎第15天（E15）至P21饮用添加抗生素的水（氨苄青霉素、庆大霉素和万古霉素）。高氧显著损害了P14至P21期间的肺泡发育，而高氧和抗生素暴露均损害了肺微血管发育。此外，高氧减少了周细胞、增殖性间充质祖细胞、基质成纤维细胞和P2RY14肺泡肌成纤维细胞的数量。对LY6A分选的L-MSCs进行RNA测序显示，高氧环境下有103个基因表达差异，其中10个与肥大细胞生物学相关。抗生素暴露也改变了间充质细胞分布，表明对肺发育有额外影响。在BPD小鼠模型中，重要的L-MSC亚型的转录组图谱和分布以及微血管发育受到高氧和抗生素暴露的影响。总之，我们表明高氧和抗生素诱导的细菌载量降低会影响间充质细胞群体，这可能导致BPD的发生。
