Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant

Abstract

IntroductionChronic 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.MethodsWe 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.ResultsWe 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.ConclusionWe 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.

Chronic neonatal lung disease: time to look beyond the alveolus

“…This paper by Heydarian et al 8 is encouraging for several reasons. First, it potentially identifies a subtype of pathology within nCLD.…”

“…In this edition of Thorax , Heydarian et al 8 establish that prenatal and postnatal lung injury impair endothelial BMP signalling and disrupt pulmonary vascular development driving the development of nCLD. This study takes a multilayered approach starting at the bedside of premature infants, confirming the findings in an animal model and finally examining molecular pathways, and targeted intervention at the cellular level.…”

Monocyte signature as a predictor of chronic lung disease in the preterm infant

“…One of the most prevalent morbidities bearing significant long-term consequences is the development of n e o n a t a l c h r o n i c l u n g d i s e a s e ( C L D ) , k n o w n a s bronchopulmonary dysplasia (BPD) with different severities ranging from mild to moderate and severe disease (2). BPD affects more than 30% of all very preterm infants (3,4) and determines the lung`s capacity to undergo structural and functional maturation as well as its potential to cope with second and third hit injury (5,6).…”

Pericytes: The lung-forgotten cell type

“…A number of genes found to predispose humans to the development of PH, i.e., BMPR2 , KCNK3 , and SMAD9 , as well as inflammatory genes associated with endothelial dysfunction (IL-6 and hypoxia-inducible factor) have been targeted to establish these models, with varying levels of success in inducing vascular inflammation, remodelling, and dysfunction (reviewed in detail by Dignam et al, (2022) ). However, as most of these models are induced in mice, a species that does not readily develop the full range of pathology observed in humans, a second stimulus (e.g., hypoxia ( Hilton et al, 2022 ) or cigarette smoke exposure ( Heydarian et al, 2022 )) is usually needed to establish a severe disease phenotype. Crucially, without a deeper understanding of the initiating factors driving PAH in humans, these mouse models will remain only an approximation of the clinical form of the disease; this may have important implications in the delineation of potential therapeutic targets.…”