Department of Child Health, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK.
Proteomics Facility, Faculty of Life Sciences, University of Bristol, Bristol, UK.
Sci Rep. 2023 May 5;13(1):7330. doi: 10.1038/s41598-023-34233-5.
Despite evidence demonstrating persistent lung function deficits in preterm-born children, especially in those who had bronchopulmonary dysplasia (BPD) in infancy, the underlying biological mechanisms explaining these lung function deficits remain poorly understood. We characterised the exhaled breath condensate (EBC) proteome in preterm-born children, with and without BPD; and before and after inhaler treatment. EBC from children aged 7-12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) study, were analysed by Nano-LC Mass Spectrometry with Tandem Mass Tag labelling. Children with percent predicted forced expiratory volume in 1 second ≤ 85% were enrolled to a 12-week blinded randomised trial of inhaled corticosteroids alone (ICS) or with long-acting β-agonist (ICS/LABA) or placebo. EBC was analysed from 218 children at baseline, and 46 children received randomised inhaled therapy. 210 proteins were detected in total. For the 19 proteins present in every sample, the desmosome proteins: desmoglein-1, desmocollin-1 and plakoglobin were significantly decreased, and cytokeratin-6A was increased in preterm-born children with BPD when compared to preterm- and term-born controls. ICS/LABA treatment significantly increased abundance of desmoglein-1, desmocollin-1 and plakoglobin in the BPD group with low lung function, and significantly increased plakoglobin in those without BPD. No differences were noted after ICS treatment. Exploratory analyses of proteins not detected in all samples suggested decreased abundance of several antiproteases. This study provides proteomic evidence of ongoing pulmonary structural changes with decreased desmosomes in school-aged preterm-born children with BPD and low lung function, which was reversed with combined inhaled corticosteroids and long-acting β-agonists therapy.
尽管有证据表明早产儿，尤其是患有支气管肺发育不良（BPD）的早产儿存在持续性肺功能缺陷，但仍不清楚导致这些肺功能缺陷的潜在生物学机制。本研究旨在分析早产儿（伴有或不伴有 BPD）呼出气冷凝液（EBC）的蛋白质组学特征，以及在吸入治疗前后的变化。对来自新生儿呼吸健康结果研究（RHiNO）的年龄为 7-12 岁的儿童的 EBC 进行纳升液相色谱-串联质谱分析，并采用串联质量标签（Tandem Mass Tag）标记法。招募预计第一秒用力呼气量（FEV1）占预计值百分比＜85%的儿童，进行为期 12 周的吸入性皮质激素（ICS）单药、ICS 联合长效β激动剂（ICS/LABA）或安慰剂的双盲随机对照试验。在基线时对 218 名儿童进行 EBC 分析，46 名儿童接受随机吸入治疗。共检测到 210 种蛋白质。在所有样本中均存在的 19 种蛋白质中，桥粒蛋白：桥粒芯糖蛋白 1、桥粒胶蛋白 1 和斑联蛋白在伴有 BPD 的早产儿中明显减少，而细胞角蛋白-6A 增加。ICS/LABA 治疗可显著增加低肺功能的 BPD 患儿中桥粒芯糖蛋白 1、桥粒胶蛋白 1 和斑联蛋白的丰度，并显著增加无 BPD 患儿的斑联蛋白丰度。ICS 治疗后未观察到差异。对所有样本中未检测到的蛋白质进行的探索性分析表明，几种抗蛋白酶的丰度降低。本研究提供了蛋白质组学证据，表明患有 BPD 和低肺功能的学龄期早产儿存在持续性肺结构变化，桥粒减少，联合吸入皮质激素和长效β激动剂治疗可逆转这种变化。
