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Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant
  1. Motaharehsadat Heydarian1,
  2. Prajakta Oak1,
  3. Xin Zhang1,
  4. Nona Kamgari1,
  5. Alida Kindt2,
  6. Markus Koschlig1,
  7. Tina Pritzke1,
  8. Erika Gonzalez-Rodriguez1,
  9. Kai Förster1,3,
  10. Rory E Morty4,
  11. Friederike Häfner1,
  12. Christoph Hübener5,
  13. Andreas W Flemmer3,
  14. Ali Oender Yildirim1,
  15. Deepti Sudheendra6,
  16. Xuefei Tian6,
  17. Agnese Petrera7,
  18. Holger Kirsten8,
  19. Peter Ahnert8,
  20. Nick Morrell9,
  21. Tushar J Desai6,
  22. Jennifer Sucre10,
  23. Edda Spiekerkoetter6,
  24. Anne Hilgendorff1,11
  1. 1Institute for Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany
  2. 2Division of Analytical Biosciences, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
  3. 3Department of Neonatology, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians University, LMU Hospital, Munich, Germany
  4. 4Department of Translational Pulmonology, University Hospital Heidelberg, Translational Lung Research Center campus of the German Center for Lung Research (DZL), Heidelberg, Germany
  5. 5Department of Obstetrics and Gynecology, Ludwig-Maximilians University, LMU Hospital, Munich, Germany
  6. 6Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, California, USA
  7. 7Research Unit Protein Science and Metabolomics and Proteomics Core, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
  8. 8Institute for Medical Informatics, Statistics, and Epidemiology (IMISE), associated partner of the German Center for Lung Research (DZL), University of Leipzig, Leipzig, Germany
  9. 9Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
  10. 10Mildred Stahlman Division of Neonatology, Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, USA
  11. 11Center for Comprehensive Developmental Care (CDeCLMU), Ludwig-Maximilians University, LMU Hospital, Munich, Germany
  1. Correspondence to Dr Anne Hilgendorff, Institute for Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Bayern, Germany; Anne.Hilgendorff{at}med.uni-muenchen.de

Abstract

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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Data availability statement

Data are available on reasonable request.

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Footnotes

  • Twitter @AlionderCPC

  • 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.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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