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.
- Paediatric Lung Disaese
Data availability statement
Data are available on reasonable request.
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MH, PO, XZ and NK contributed equally.
Contributors Conception and design of the manuscript was done by AH and ES. The data were acquired by PO, MH, NK, XZ, EG-R, JS, AP, MK, AWF, CH, DS, XT, AOY, TP. The data analysis and interpretation were done by AH, PO, MH, KF, JS, NM, AK, TP, PA, HK and REM. The manuscript was written by MH and AH. The manuscript was drafted for important intellectual content by AH, ES, JS, TJD. AH has full access to all the data in the study and takes the responsibility for the integrity of the data and the accuracy of the data analysis.
Funding The present study was supported by the Young Investigator Grant NWG VH-NG-829 by the Helmholtz Foundation and the Helmholtz Zentrum Muenchen, Germany, the International Research Group ‘Role of BMP signalling’ (01KI07110), Helmholtz Foundation (German Ministry of Education and Health (BMBF)) and the German Centre for Lung Research (DZL, German Ministry of Education and Health (BMBF)) as well as as well as the Research Training Group Targets in Toxicology (GRK2338) of the German Science and Research Organisation (DFG) and the Progress Study Group (BMBF Grant 01KI1010C, BMBF Grant 01KI1010I).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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