Introduction Chronic lung disease, that is, bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and develops as a consequence of the misguided formation of the gas-exchange area undergoing prenatal and postnatal injury. Subsequent vascular disease and its progression into pulmonary arterial hypertension critically determines long-term outcome in the BPD infant but lacks identification of early, disease-defining changes. Methods We link impaired bone morphogenetic protein (BMP) signalling to the earliest onset of vascular pathology in the human preterm lung and delineate the specific effects of the most prevalent prenatal and postnatal clinical risk factors for lung injury mimicking clinically relevant conditions in a multilayered animal model using wild-type and transgenic neonatal mice. Results We demonstrate (1) the significant reduction in BMP receptor 2 (BMPR2) expression at the onset of vascular pathology in the lung of preterm infants, later mirrored by reduced plasma BMP protein levels in infants with developing BPD, (2) the rapid impairment (and persistent change) of BMPR2 signalling on postnatal exposure to hyperoxia and mechanical ventilation, aggravated by prenatal cigarette smoke in a preclinical mouse model and (3) a link to defective alveolar septation and matrix remodelling through platelet derived growth factor-receptor alpha deficiency. In a treatment approach, we partially reversed vascular pathology by BMPR2-targeted treatment with FK506 in vitro and in vivo. Conclusion We identified impaired BMP signalling as a hallmark of early vascular disease in the injured neonatal lung while outlining its promising potential as a future biomarker or therapeutic target in this growing, high-risk patient population. Data are available on reasonable request.

中文翻译：

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BMP信号受损与早产儿早期血管损伤临床危险因素的关系


简介 慢性肺病，即支气管肺发育不良 (BPD) 是早产儿最常见的并发症，是由于产前和产后损伤时气体交换区域形成错误造成的。随后的血管疾病及其进展为肺动脉高压对 BPD 婴儿的长期结局至关重要，但缺乏对早期疾病定义变化的识别。方法 我们将受损的骨形态发生蛋白 (BMP) 信号传导与人类早产肺血管病理的最早发作联系起来，并在多层动物模型中模拟临床相关条件，描述最常见的产前和产后肺损伤临床危险因素的具体影响使用野生型和转基因新生小鼠。结果 我们证明 (1) 早产儿肺部血管病变发生时 BMP 受体 2 (BMPR2) 表达显着降低，随后患有 BPD 的婴儿血浆 BMP 蛋白水平降低，(2) 快速损伤BMPR2 信号传导在出生后暴露于高氧和机械通气时的（和持续变化），在临床前小鼠模型中因产前吸烟而加剧；（3）通过血小板衍生生长因子受体 α 缺乏与肺泡间隔缺陷和基质重塑有关。在治疗方法中，我们通过体外和体内 FK506 的 BMPR2 靶向治疗部分逆转了血管病理。结论 我们确定 BMP 信号传导受损是新生儿肺损伤早期血管疾病的一个标志，同时概述了其作为这一不断增长的高危患者群体的未来生物标志物或治疗靶点的潜力。 可根据合理要求提供数据。