Early Angiogenic Proteins Associated with High Risk for Bronchopulmonary Dysplasia and Pulmonary Hypertension in Preterm Infants.

INTRODUCTION Early pulmonary vascular disease in preterm infants is associated with the subsequent development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH), however, mechanisms that contribute to or identify infants with increased susceptibility for BPD and/or PH are incompletely understood. Therefore, we tested if changes in circulating angiogenic peptides during the first week of life are associated with the later development of BPD and/or PH. We further sought to determine alternate peptides and related signalling pathways with the risk for BPD or PH. METHODS We prospectively enrolled infants with gestational age <34 weeks gestation and collected blood samples during their first week of life. BPD and PH were assessed at 36 weeks postmenstrual age. Samples were assayed for each of the 1121 peptides included in the SOMAscanTM technology, with subsequent pathway analysis. RESULTS Of 102 study infants, 82 had BPD and 13 had PH. Multiple angiogenic proteins (PF-4, VEGF121, ANG-1, BMP10, HGF, ANG2) were associated with the subsequent diagnosis of BPD, and FGF-19, PF-4, CTAP-III and PDGF-AA levels were associated with BPD severity. Early increases in BMP10 was strongly associated with the late risk for BPD and PH. CONCLUSION We found that early alterations of circulating angiogenic peptides and others were associated with the subsequent development of BPD. We further identified peptides that were associated with BPD severity and BPD-associated PH, including BMP10. We speculate that proteomic biomarkers during the first week of life may identify infants at risk for BPD and/or PH to enhance care and research.

[1]  Liqun He,et al.  Lung developmental arrest caused by PDGF-A deletion: consequences for the adult mouse lung. , 2020, American journal of physiology. Lung cellular and molecular physiology.

[2]  B. Poindexter,et al.  Early Pulmonary Vascular Disease in Preterm Infants Is Associated with Late Respiratory Outcomes in Childhood , 2019, American journal of respiratory and critical care medicine.

[3]  R. Keller,et al.  Recent advances in antenatal factors predisposing to bronchopulmonary dysplasia. , 2018, Seminars in perinatology.

[4]  A. Bos,et al.  Identification of gaps in the current knowledge on pulmonary hypertension in extremely preterm infants: A systematic review and meta‐analysis , 2018, Paediatric and perinatal epidemiology.

[5]  Fabian J Theis,et al.  Early Identification of Bronchopulmonary Dysplasia Using Novel Biomarkers by Proteomic Screening , 2017, American journal of respiratory and critical care medicine.

[6]  Charlie M. Carpenter,et al.  Proteomic Profiles Associated with Early Echocardiogram Evidence of Pulmonary Vascular Disease in Preterm Infants , 2017, American journal of respiratory and critical care medicine.

[7]  P. Shaw,et al.  Bronchopulmonary Dysplasia and Perinatal Characteristics Predict 1-Year Respiratory Outcomes in Newborns Born at Extremely Low Gestational Age: A Prospective Cohort Study. , 2017, The Journal of pediatrics.

[8]  B. Poindexter,et al.  Antenatal Determinants of Bronchopulmonary Dysplasia and Late Respiratory Disease in Preterm Infants , 2017, American journal of respiratory and critical care medicine.

[9]  N. Gotteiner,et al.  Cord Blood Biomarkers of Placental Maternal Vascular Underperfusion Predict Bronchopulmonary Dysplasia‐Associated Pulmonary Hypertension , 2017, The Journal of pediatrics.

[10]  S. Abman,et al.  Fetal Vascular Origins of Bronchopulmonary Dysplasia. , 2017, The Journal of pediatrics.

[11]  R. A. Sinkin,et al.  Evidence of Early Pulmonary Hypertension Is Associated with Increased Mortality in Very Low Birth Weight Infants , 2017, American Journal of Perinatology.

[12]  M. Nold,et al.  Biomarkers in Lung Diseases : from Pathogenesis to Prediction to New Therapies BNP , troponin I , and YKL-40 as screening markers in extremely preterm infants at risk for pulmonary hypertension associated with bronchopulmonary dysplasia , 2016 .

[13]  H. Ohta,et al.  Roles of FGF Signals in Heart Development, Health, and Disease , 2016, Front. Cell Dev. Biol..

[14]  N. Ambalavanan,et al.  Searching for better animal models of BPD: a perspective. , 2016, American journal of physiology. Lung cellular and molecular physiology.

[15]  David L. Gibbs,et al.  Combining Dependent P-values with an Empirical Adaptation of Brown’s Method , 2015, bioRxiv.

[16]  Wei Li,et al.  Regulation of the ALK1 ligands, BMP9 and BMP10. , 2016, Biochemical Society transactions.

[17]  Xu Shi,et al.  Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease , 2016, Circulation.

[18]  Mark R Segal,et al.  Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients With Stable Coronary Heart Disease. , 2016, JAMA.

[19]  Thiennu H. Vu,et al.  Hepatocyte growth factor as a downstream mediator of vascular endothelial growth factor-dependent preservation of growth in the developing lung. , 2016, American journal of physiology. Lung cellular and molecular physiology.

[20]  R. Gibbs,et al.  The relationship of circulating proteins in early pregnancy with preterm birth. , 2016, American journal of obstetrics and gynecology.

[21]  T. Vu,et al.  VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development. , 2016, American journal of physiology. Lung cellular and molecular physiology.

[22]  R. Ehrenkranz,et al.  Biochemical Screening for Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia , 2016, Neonatology.

[23]  Henning Hermjakob,et al.  The Reactome pathway Knowledgebase , 2015, Nucleic acids research.

[24]  N. Ambalavanan,et al.  Biomarkers, Early Diagnosis, and Clinical Predictors of Bronchopulmonary Dysplasia. , 2015, Clinics in perinatology.

[25]  B. Poindexter,et al.  Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. , 2015, American journal of respiratory and critical care medicine.

[26]  J. Padbury,et al.  Pulmonary hypertension in preterm infants: prevalence and association with bronchopulmonary dysplasia. , 2014, The Journal of pediatrics.

[27]  Larry Gold,et al.  Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents , 2014, Molecular therapy. Nucleic acids.

[28]  B. Schmidt,et al.  Bronchopulmonary dysplasia: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. , 2014, Annals of the American Thoracic Society.

[29]  O. Eickelberg,et al.  Chronic lung disease in the preterm infant. Lessons learned from animal models. , 2013, American journal of respiratory cell and molecular biology.

[30]  Jos Boekhorst,et al.  Data mining in the Life Sciences with Random Forest: a walk in the park or lost in the jungle? , 2012, Briefings Bioinform..

[31]  L. Stein,et al.  Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome , 2012, Cancers.

[32]  W. Carlo,et al.  Prospective Analysis of Pulmonary Hypertension in Extremely Low Birth Weight Infants , 2012, Pediatrics.

[33]  Atul J. Butte,et al.  Ten Years of Pathway Analysis: Current Approaches and Outstanding Challenges , 2012, PLoS Comput. Biol..

[34]  B. Poindexter,et al.  Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network , 2010, Pediatrics.

[35]  Q. Mao,et al.  Angiogenesis-related gene expression profiling in ventilated preterm human lungs , 2010, Experimental lung research.

[36]  G. Kim,et al.  Review article DOI: 10.3345/kjp.2010.53.6.688 , 2010 .

[37]  A. de Silvestri,et al.  Circulating endothelial progenitor cells in preterm infants with bronchopulmonary dysplasia. , 2009, American journal of respiratory and critical care medicine.

[38]  P. Harris,et al.  Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support , 2009, J. Biomed. Informatics.

[39]  D. McElhinney,et al.  Pulmonary Artery Hypertension in Formerly Premature Infants With Bronchopulmonary Dysplasia: Clinical Features and Outcomes in the Surfactant Era , 2007, Pediatrics.

[40]  E. Baraldi,et al.  Chronic lung disease after premature birth. , 2007, The New England journal of medicine.

[41]  B. Thébaud,et al.  Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. , 2007, American journal of respiratory and critical care medicine.

[42]  K. Stenmark,et al.  Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. , 2005, Annual review of physiology.

[43]  G. Escobar,et al.  Rehospitalization in the first year of life among infants with bronchopulmonary dysplasia. , 2004, The Journal of pediatrics.

[44]  M. Walsh,et al.  Safety, Reliability, and Validity of a Physiologic Definition of Bronchopulmonary Dysplasia , 2003, Journal of Perinatology.

[45]  R. Watkins,et al.  Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. , 2001, American journal of respiratory and critical care medicine.

[46]  P. Heikkilä,et al.  Pulmonary vascular endothelial growth factor and Flt-1 in fetuses, in acute and chronic lung disease, and in persistent pulmonary hypertension of the newborn. , 2001, American journal of respiratory and critical care medicine.

[47]  S. Abman Bronchopulmonary dysplasia: "a vascular hypothesis". , 2001, American journal of respiratory and critical care medicine.

[48]  N. Voelkel,et al.  Inhibition of angiogenesis decreases alveolarization in the developing rat lung. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[49]  E. Bancalari,et al.  Bronchopulmonary dysplasia. , 2001, American journal of respiratory and critical care medicine.

[50]  David A. Freedman,et al.  A Nonstochastic Interpretation of Reported Significance Levels , 1983 .

[51]  W. Northway,et al.  Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. , 1967, The New England journal of medicine.