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

Autor:	Heydarian M; Institute 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., Oak P; Institute 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., Zhang X; Institute 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., Kamgari N; Institute 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., Kindt A; Division of Analytical Biosciences, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands., Koschlig M; Institute 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., Pritzke T; Institute 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., Gonzalez-Rodriguez E; Institute 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., Förster K; Institute 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.; Department of Neonatology, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians University, LMU Hospital, Munich, Germany., Morty RE; Department of Translational Pulmonology, University Hospital Heidelberg, Translational Lung Research Center campus of the German Center for Lung Research (DZL), Heidelberg, Germany., Häfner F; Institute 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., Hübener C; Department of Obstetrics and Gynecology, Ludwig-Maximilians University, LMU Hospital, Munich, Germany., Flemmer AW; Department of Neonatology, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians University, LMU Hospital, Munich, Germany., Yildirim AO; Institute 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., Sudheendra D; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, California, USA., Tian X; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, California, USA., Petrera A; Research Unit Protein Science and Metabolomics and Proteomics Core, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Kirsten H; Institute for Medical Informatics, Statistics, and Epidemiology (IMISE), associated partner of the German Center for Lung Research (DZL), University of Leipzig, Leipzig, Germany., Ahnert P; Institute for Medical Informatics, Statistics, and Epidemiology (IMISE), associated partner of the German Center for Lung Research (DZL), University of Leipzig, Leipzig, Germany., Morrell N; Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK., Desai TJ; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, California, USA., Sucre J; Mildred Stahlman Division of Neonatology, Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, USA., Spiekerkoetter E; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, California, USA., Hilgendorff A; Institute 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 Anne.Hilgendorff@med.uni-muenchen.de.; Center for Comprehensive Developmental Care (CDeCLMU), Ludwig-Maximilians University, LMU Hospital, Munich, Germany.
Jazyk:	angličtina
Zdroj:	Thorax [Thorax] 2022 Dec; Vol. 77 (12), pp. 1176-1186. Date of Electronic Publication: 2022 May 17.
DOI:	10.1136/thoraxjnl-2021-218083
Abstrakt:	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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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