Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant.
Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant.
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慢性肺部疾病，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导致气体交换区形成错误而发展起来的。随后的血管疾病及其进展为肺动脉高压对BPD婴儿的长期预后至关重要，但缺乏早期疾病定义变化的识别。我们将骨形态发生蛋白（BMP）信号受损与人类早产儿肺部血管病理的最早发病联系起来，并在使用野生型和转基因新生小鼠的多层动物模型中，模拟临床相关条件，描述了最常见的产前和产后临床危险因素对肺损伤的具体影响。我们证明(1)在早产儿肺部血管病变开始时BMP受体2 （BMPR2）表达显著降低，随后在BPD患儿血浆BMP蛋白水平降低中反映出来；(2)BMPR2信号在出生后暴露于高氧和机械通气时迅速受损（和持续改变）。在临床前小鼠模型中，产前吸烟加剧了这一问题；(3)血小板衍生生长因子受体α缺乏与肺泡分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用FK506进行bmpr2靶向治疗，部分逆转了血管病理。我们发现受损的BMP信号是受伤新生儿肺部早期血管疾病的标志，同时概述了其作为未来生物标志物或治疗靶点的潜力，这是一个不断增长的高风险患者群体。
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. 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. 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. 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.
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BMPR2在氧化过程中保留线粒体功能和DNA，以促进内皮细胞的存活和反向肺动脉高压。
影响因子：
29
作者：
Diebold I;Hennigs JK;Miyagawa K;Li CG;Nickel NP;Kaschwich M;Cao A;Wang L;Reddy S;Chen PI;Nakahira K;Alcazar MA;Hopper RK;Ji L;Feldman BJ;Rabinovitch M
通讯作者：
Rabinovitch M
DOI：
10.1152/ajplung.00050.2006
发表时间：
2007-02-01
影响因子：
4.9
作者：
Alejandre-Alcazar, Miguel A.;Kwapiszewska, Grazyna;Morty, Rory E.
通讯作者：
Morty, Rory E.
影响因子：
10
作者：
Gilliland, FD;Berhane, K;Peters, JM
通讯作者：
Peters, JM
影响因子：
3.7
作者：
Li A;Xia X;Yeh J;Kua H;Liu H;Mishina Y;Hao A;Li B
通讯作者：
Li B
影响因子：
82.9
作者：
Compernolle, V;Brusselmans, K;Carmeliet, P
通讯作者：
Carmeliet, P