The impact of hyperoxia and antibiotics on lung mesenchymal cells in experimental bronchopulmonary dysplasia.

IF 3.5 2区 医学 Q1 PHYSIOLOGY
Cathy van Horik, Joel Anne Meyboom, Anne Boerema-de Munck, Marjon J Buscop-van Kempen, Evelien Eenjes, Gabriëla G Edel, Demi Kortekaas, Rene Mh Wijnen, Wilfred F J van IJcken, Irwin K M Reiss, Robbert J Rottier, Jennifer J P Collins
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Abstract

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, Col13a1POS matrix fibroblasts and P2RY14POS 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.

高氧和抗生素对实验性支气管肺发育不良患者肺间充质细胞的影响。
支气管肺发育不良(BPD)是早产儿最常见的不良后果,也是早发性肺气肿和哮喘的高风险。由于多种致病因素,如高氧、炎症和生态失调,BPD以肺泡和微血管发育中断为特征。由此产生的临床表现具有挑战性,目前的治疗方案有限。为了改善治疗方案,必须了解潜在的原因。常驻肺间充质间质细胞(L-MSCs)对肺泡微血管形成、修复和再生至关重要。在这里,我们报告了高氧和抗生素诱导的细菌负荷降低对L-MSCs和肺泡发育的直接影响,使用高氧诱导的BPD小鼠模型。新生小鼠从出生后第4天(P4)至第14天暴露于高氧环境,从第14天至第21天恢复室内空气。从E15到P21,大坝接受了抗生素补充水(氨苄西林、庆大霉素和万古霉素)。高氧显著损害P14和P21之间肺泡发育,而高氧和抗生素暴露均损害肺微血管发育。此外,高氧降低了周细胞、增生性间充质祖细胞、Col13a1POS基质成纤维细胞和P2RY14POS肺泡肌成纤维细胞的数量。ly6a分选L-MSCs的RNA-Seq结果显示,高氧条件下103个基因的差异表达,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的分布,表明对肺部发育有额外的影响。在bpd小鼠模型中,高氧和抗生素暴露会影响重要L-MSC亚型的转录组景观和分布以及微血管发育。总之,我们发现高氧和抗生素诱导的细菌负荷减少会影响间充质细胞群,这可能有助于BPD的发展。
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来源期刊
CiteScore
9.20
自引率
4.10%
发文量
146
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.
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