Biomarkers of angiogenesis as a component of a prognostic model for the formation of bronchopulmonary dysplasia in premature infants

Introduction. Angiogenesis of pulmonary vessels is an integral part of the development of lung tissue capable of effective gas exchange. Exposure to high concentrations of oxygen, to which premature infants are exposed, disrupts the physiological process of alveolar development and suppresses angiogenesis, leading to abnormal vascular growth and the development of interstitial fibrosis, underlying bronchopulmonary dysplasia. To prevent the development of this disabling pathology, prevention should be started at the earliest possible time. To achieve this aim, it is necessary to identify new available predictors of the development of bronchopulmonary dysplasia during the neonatal period.
Objective. To search for new biomarkers as predictors of the formation of bronchopulmonary dysplasia in premature newborns in the structure of creating a prognostic model.
Materials and methods. Two hundred four premature infants were included in the study. All premature infants were analyzed for clinical, anamnestic parameters, and duration of various respiratory therapy methods. Serum concentrations of 13 biomarkers of angiogenesis were identified by enzyme immunoassay in all patients.
Results. The significant role of anamnestic risk factors for the formation of bronchopulmonary dysplasia in premature infants and the duration of respiratory therapy has been confirmed. There have been identified 6 prognostically significant biomarkers of angiogenesis (angiopoietin-1, angiopoietin-2, platelet growth factor BB, platelet/endothelial cell adhesion molecule 1 (PECAM-1), vascular endothelial growth factors A and D), changes in the concentration of which can also be considered as predictors of the development of bronchopulmonary dysplasia in premature infants.

premature infants, angiogenesis, bronchopulmonary dysplasia, cytokines

1. Cui X., Fu J. Early prediction of bronchopulmonary dysplasia: can noninvasive monitoring methods be essential? ERJ Open Res. 2023; 9(2): 00621–2022. https://doi.org/10.1183/23120541.00621-2022

2. Селиверстова А.А., Давыдова И.В., Басаргина М.А., Фисенко А.П., Семикина Е.Л. Механизмы развития легочной гипертензии у детей с бронхолёгочной дисплазией. Доктор.Pу. 2022; 21(7): 35–40. https://doi.org/10.31550/1727-2378-2022-21-7-6-11 https://elibrary.ru/lllqsc

3. Galambos C., deMello D.E. Molecular mechanisms of pulmonary vascular development. Pediatr. Dev. Pathol. 2007; 10(1): 1–17. https://doi.org/10.2350/06-06-0122.1

4. Schittny J.C. Development of the lung. Cell Tissue Res. 2017; 367(3): 427–44. https://doi.org/10.1007/s00441-016-2545-0

5. Stevens R.P., Lee J.Y., Bauer N., Stevens T. Got oxygen? Studies on mesenchymal cell hypoxia inducible factor-1α in lung development. Am. J. Respir. Cell Mol. Biol. 2023; 69(4): 380–2. https://doi.org/10.1165/rcmb.2023-0247ED

6. Kindt A.S.D., Förster K.M., Cochius-den Otter S.C.M., Flemmer A.W., Hauck S.M., Flatley A., et al. Validation of disease-specific biomarkers for the early detection of bronchopulmonary dysplasia. Pediatr. Res. 2023; 93(3): 625–32. https://doi.org/10.1038/s41390-022-02093-w

7. Thomas W., Seidenspinner S., Kramer B.W., Kawczyńska-Leda N., Chmielnicka-Kopaczyk M., Marx A., et al. Airway concentrations of angiopoietin-1 and endostatin in ventilated extremely premature infants are decreased after funisitis and unbalanced with bronchopulmonary dysplasia/death. Pediatr. Res. 2009; 65(4): 468–73. https://doi.org/10.1203/PDR.0b013e3181991f35

8. Kim D.H., Kim H.S. Serial changes of serum endostatin and angiopoietin-1 levels in preterm infants with severe bronchopulmonary dysplasia and subsequent pulmonary artery hypertension. Neonatology. 2014; 106(1): 55–61. https://doi.org/10.1159/000358374

9. Sehgal A., Gwini S.M., Menahem S., Allison B.J., Miller S.L., Polglase G.R. Preterm growth restriction and bronchopulmonary dysplasia: the vascular hypothesis and related physiology. J. Physiol. 2019; 597(4): 1209–20. https://doi.org/10.1113/JP276040

10. Villar J., Zhang H., Slutsky A.S. Lung repair and regeneration in ARDS: Role of PECAM1 and Wnt signaling. Chest. 2019; 155(3): 587–94. https://doi.org/10.1016/j.chest.2018.10.022

11. Hoffman J.I.E. Interaction between pulmonary vasculature and the patent ductus arteriosus in very premature infants. J. Neonatal. Perinatal. Med. 2021; 14(2): 159–61. https://doi.org/10.3233/NPM-190278

12. Oak P., Pritzke T., Thiel I., Koschlig M., Mous D.S., Windhorst A., et al. Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease. EMBO Mol. Med. 2017; 9(11): 1504–20. https://doi.org/10.15252/emmm.201607308

13. Lassus P., Ristimäki A., Ylikorkala O., Viinikka L., Andersson S. Vascular endothelial growth factor in human preterm lung. Am. J. Respir. Crit. Care Med. 1999; 159(5 Pt. 1): 1429–33. https://doi.org/10.1164/ajrccm.159.5.9806073

14. Melincovici C.S., Boşca A.B., Şuşman S., Mărginean M., Mihu C., Istrate M., et al. Vascular endothelial growth factor (VEGF) – key factor in normal and pathological angiogenesis. Rom. J. Morphol. Embryol. 2018; 59(2): 455–67.

15. Dakshinamurti S. Thrombospondin in the puzzle of bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 2022; 205(6): 610–2. https://doi.org/10.1164/rccm.202201-0101ED

16. Calthorpe R.J., Poulter C., Smyth A.R., Sharkey D., Bhatt J., Jenkins G., et al. Complex roles of TGF-β signaling pathways in lung development and bronchopulmonary dysplasia. Am. J. Physiol. Lung. Cell Mol. Physiol. 2023; 324(3): L285–96. https://doi.org/10.1152/ajplung.00106.2021

17. Pease J.E., Sabroe I. The role of interleukin-8 and its receptors in inflammatory lung disease: implications for therapy. Am. J. Respir. Med. 2002; 1(1): 19–25. https://doi.org/10.1007/BF03257159

18. Тополянская С.В. Фактор роста соединительной ткани в норме и патологии. Архивъ внутренней медицины. 2020; 10(4): 254–61. https://doi.org/10.20514/2226-6704-2020-10-4-254-261 https://elibrary.ru/zosnpr

19. Benjamin J.T., Smith R.J., Halloran B.A., Day T.J., Kelly D.R., Prince L.S. FGF-10 is decreased in bronchopulmonary dysplasia and suppressed by Toll-like receptor activation. Am. J. Physiol. Lung. Cell Mol. Physiol. 2007; 292(2): L550–8. https://doi.org/10.1152/ajplung.00329.2006

20. Mohamed W.A., Aseeri M.A. Cord blood fibroblast growth factor-10 as a possible predictor of bronchopulmonary dysplasia in preterm infants. J. Neonatal. Perinatal. Med. 2014; 7(2): 101–5. https://doi.org/10.3233/NPM-1476613

21. Селиверстова А.А., Давыдова И.В., Фисенко А.П., Басаргина М.А., Сновская М.А., Жужула А.А. Биомаркеры нарушения ангиогенеза при формировании бронхолегочной дисплазии у недоношенных детей. Кремлевская медицина. Клинический вестник. 2023; (3): 56–9. https://doi.org/10.48612/cgma/4vn9-u38n-p76a https://elibrary.ru/jfcibb

22. Xie Y., Wang Y., Liu K., Li X. Correlation analysis between mechanical power, transforming growth factor-β1, and connective tissue growth factor levels in acute respiratory distress syndrome patients and their clinical significance in pulmonary structural remodeling. Medicine (Baltimore). 2019; 98(29): e16531. https://doi.org/10.1097/MD.0000000000016531