Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Dynamic association between plasma interleukin-1 family concentrations and bronchopulmonary dysplasia in extremely premature infants

Journal of Perinatology (2025)Cite this article

Subjects

Abstract

Objective

To evaluate the longitudinal changes of IL-1α, IL-1β, and IL-1Ra in extremely preterm infants and investigate the dynamic association with bronchopulmonary dysplasia (BPD).

Methods

Plasma samples were collected from extremely preterm infants at postnatal day (PD) 7,28 and PMA 36 weeks. IL-1 cytokines concentrations were measured by Bio-Plex Pro (human cytokine panel). Univariate and multivariate logistic regression analysis were conducted to explore the association between the cytokines and BPD.

Results

BPD infants exhibited significantly higher concentrations of IL-1α (10.75 vs. 8.18 pg/ml, p = 0.026), IL-1β (2.00 vs. 1.50 pg/ml, p = 0.046), and IL-1Ra (878.50 vs. 262.40 pg/ml, p = 0.011) compared to non-BPD infants at PD 28. Higher IL-1α concentration (≥8.09 pg/ml) at PD 28 was independently associated with BPD development (OR: 8.272, 95% CI: 1.127–60.705, p = 0.038).

Conclusions

Increased IL-1α concentrations at PD 28 were independently associated with an increased risk of BPD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Flowchart of case selection.
Fig. 2: Box plots of plasma IL-1 family in BPD and non-BPD groups at different time points.
Fig. 3: The forest plot of the multivariate logistic regression analysis.

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Gilfillan M, Bhandari A, Bhandari V. Diagnosis and management of bronchopulmonary dysplasia. BMJ. 2021;375:n1974.

    Article  PubMed  Google Scholar 

  2. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126:443–56.

    Article  PubMed  Google Scholar 

  3. Bell EF, Hintz SR, Hansen NI, Bann CM, Wyckoff MH, De Mauro SB, et al. Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013–2018. JAMA. 2022;327:248–63.

    Article  PubMed  Google Scholar 

  4. Savani RC. Modulators of inflammation in bronchopulmonary dysplasia. Semin Perinatol. 2018;42:459–70.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Álvarez-Fuente M, Moreno L, Mitchell JA, Reiss IK, Lopez P, Elorza D, et al. Preventing bronchopulmonary dysplasia: new tools for an old challenge. Pediatr Res. 2019;85:432–41.

    Article  PubMed  Google Scholar 

  6. Rudloff I, Cho SX, Bui CB, McLean C, Veldman A, Berger PJ, et al. Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia. J Cell Mol Med. 2017;21:1128–38.

    Article  CAS  PubMed  Google Scholar 

  7. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018;281:8–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013;39:1003–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sims JE, March CJ, Cosman D, Widmer MB, MacDonald HR, McMahan CJ, et al. cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science. 1988;241:585–9.

    Article  CAS  PubMed  Google Scholar 

  10. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol. 2010;10:89–102.

    Article  CAS  PubMed  Google Scholar 

  11. Fritzsching B, Zhou-Suckow Z, Trojanek JB, Schubert SC, Schatterny J, Hirtz S, et al. Hypoxic epithelial necrosis triggers neutrophilic inflammation via IL-1 receptor signaling in cystic fibrosis lung disease. Am J Respir Crit Care Med. 2015;191:902–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Borthwick LA. The IL-1 cytokine family and its role in inflammation and fibrosis in the lung. Semin Immunopathol. 2016;38:517–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Omer M, Melo AM, Kelly L, Mac Dermott EJ, Leahy TR, Killeen O, et al. Emerging role of the NLRP3 inflammasome and interleukin-1β in Neonates. Neonatology. 2020;117:545–54.

    Article  CAS  PubMed  Google Scholar 

  14. Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F, et al. Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol. 1997;177:825–30.

    Article  CAS  PubMed  Google Scholar 

  15. Kazzi SN, Romero R, McLaughlin K, Ager J, Janisse J. Serial changes in levels of IL-6 and IL-1beta in premature infants at risk for bronchopulmonary dysplasia. Pediatr Pulmonol. 2001;31:220–6.

    Article  CAS  PubMed  Google Scholar 

  16. Ambalavanan N, Carlo WA, D’Angio CT, McDonald SA, Das A, Schendel D, et al. Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics. 2009;123:1132–41.

    Article  PubMed  Google Scholar 

  17. Mao X, Qiu J, Zhao L, Xu J, Yin J, Yang Y, et al. Vitamin D and IL-10 deficiency in preterm neonates with bronchopulmonary dysplasia. Front Pediatr. 2018;6:246.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang Z, Wu W, Hou L, Jiang J, Wan W, Li Z. Cytokines and exhaled nitric oxide are risk factors in preterm infants for bronchopulmonary dysplasia. Biomed Res Int. 2021;2021:6648208.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Butler B, De Dios R, Nguyen L, McKenna S, Ghosh S, Wright CJ. Developmentally regulated innate immune NFκB signaling mediates IL-1α expression in the perinatal murine lung. Front Immunol. 2019;10:1555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eldredge LC, Creasy RS, Presnell S, Debley JS, Juul SE, Mayock DE, et al. Infants with evolving bronchopulmonary dysplasia demonstrate monocyte-specific expression of IL-1 in tracheal aspirates. Am J Physiol Lung Cell Mol Physiol. 2019;317:L49–l56.

    Article  CAS  PubMed  Google Scholar 

  21. Nold MF, Mangan NE, Rudloff I, Cho SX, Shariatian N, Samarasinghe TD, et al. Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. Proc Natl Acad Sci USA. 2013;110:14384–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gupta GK, Cole CH, Abbasi S, Demissie S, Njinimbam C, Nielsen HC, et al. Effects of early inhaled beclomethasone therapy on tracheal aspirate inflammatory mediators IL-8 and IL-1ra in ventilated preterm infants at risk for bronchopulmonary dysplasia. Pediatr Pulmonol. 2000;30:275–81.

    Article  CAS  PubMed  Google Scholar 

  23. Kakkera DK, Siddiq MM, Parton LA. Interleukin-1 balance in the lungs of preterm infants who develop bronchopulmonary dysplasia. Biol Neonate. 2005;87:82–90.

    Article  CAS  PubMed  Google Scholar 

  24. Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. an evidence-based approach. Am J Respir Crit Care Med. 2019;200:751–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Davis P, Turner-Gomes S, Cunningham K, Way C, Roberts R, Schmidt B. Precision and accuracy of clinical and radiological signs in premature infants at risk of patent ductus arteriosus. Arch Pediatr Adolesc Med. 1995;149:1136–41.

    Article  CAS  PubMed  Google Scholar 

  26. Dani C, Bertini G, Reali MF, Murru P, Fabris C, Vangi V, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatr. 2000;89:1369–74.

    Article  CAS  PubMed  Google Scholar 

  27. Subspecialty Group of Neonatology, the Society of Pediatric, Chinese Medical Association; Professional Committee of Infectious Diseases, Neonatology Society, Chinese Medical Doctor Association. Expert consensus on the diagnosis and management of neonatal sepsis (version 2019). Zhonghua Er Ke Za Zhi. 2019;57:252–7.

  28. Willet KE, Kramer BW, Kallapur SG, Ikegami M, Newnham JP, Moss TJ, et al. Intra-amniotic injection of IL-1 induces inflammation and maturation in fetal sheep lung. Am J Physiol Lung Cell Mol Physiol. 2002;282:L411–420.

    Article  CAS  PubMed  Google Scholar 

  29. Sosenko IR, Kallapur SG, Nitsos I, Moss TJ, Newnham JP, Ikegami M, et al. IL-1 alpha causes lung inflammation and maturation by direct effects on preterm fetal lamb lungs. Pediatr Res. 2006;60:294–8.

    Article  CAS  PubMed  Google Scholar 

  30. Rider P, Carmi Y, Voronov E, Apte RN. Interleukin-1α. Semin Immunol. 2013;25:430–8.

    Article  CAS  PubMed  Google Scholar 

  31. Osei ET, Noordhoek JA, Hackett TL, Spanjer AI, Postma DS, Timens W, et al. Interleukin-1α drives the dysfunctional cross-talk of the airway epithelium and lung fibroblasts in COPD. Eur Respir J. 2016;48:359–69.

    Article  CAS  PubMed  Google Scholar 

  32. Aden N, Nuttall A, Shiwen X, de Winter P, Leask A, Black CM, et al. Epithelial cells promote fibroblast activation via IL-1alpha in systemic sclerosis. J Invest Dermatol. 2010;130:2191–2200.

    Article  CAS  PubMed  Google Scholar 

  33. Piper SC, Ferguson J, Kay L, Parker LC, Sabroe I, Sleeman MA, et al. The role of interleukin-1 and interleukin-18 in pro-inflammatory and anti-viral responses to rhinovirus in primary bronchial epithelial cells. PLoS One. 2013;8:e63365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Montgomery ST, Dittrich AS, Garratt LW, Turkovic L, Frey DL, Stick SM, et al. Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis. J Cyst Fibros. 2018;17:715–22.

    Article  CAS  PubMed  Google Scholar 

  35. Liao J, Kapadia VS, Brown LS, Cheong N, Longoria C, Mija D, et al. The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia. Nat Commun. 2015;6:8977.

    Article  CAS  PubMed  Google Scholar 

  36. Green EA, Metz D, Galinsky R, Atkinson R, Skuza EM, Clark M, et al. Anakinra Pilot - a clinical trial to demonstrate safety, feasibility and pharmacokinetics of interleukin 1 receptor antagonist in preterm infants. Front Immunol. 2022;13:1022104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Solomonidi N, Vlachoyiannopoulos PG, Pappa M, Liantinioti G, Ktena S, Theotikos E, et al. A randomized clinical trial of bermekimab treatment for clinical improvement of systemic sclerosis. iScience. 2023;26:107670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Markota Čagalj A, Marinović B, Bukvić Mokos Z. New and emerging targeted therapies for hidradenitis suppurativa. Int J Mol Sci. 2022;23:3753.

  39. Tao X, Mo L, Zeng L. Hyperoxia induced bronchopulmonary dysplasia-like inflammation via miR34a-TNIP2-IL-1β pathway. Front Pediatr. 2022;10:805860.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Köksal N, Kayik B, Çetinkaya M, Özkan H, Budak F, Kiliç Ş, et al. Value of serum and bronchoalveolar fluid lavage pro- and anti-inflammatory cytokine levels for predicting bronchopulmonary dysplasia in premature infants. Eur Cytokine Netw. 2012;23:29–35.

    Article  PubMed  Google Scholar 

  41. Rocha G, Proença E, Guedes A, Carvalho C, Areias A, Ramos JP, et al. Cord blood levels of IL-6, IL-8 and IL-10 may be early predictors of bronchopulmonary dysplasia in preterm newborns small for gestational age. Dis Markers. 2012;33:51–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Doyle LW. Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Neonatology. 2021;118:244–51.

    Article  CAS  PubMed  Google Scholar 

  43. Rindfleisch MS, Hasday JD, Taciak V, Broderick K, Viscardi RM. Potential role of interleukin-1 in the development of bronchopulmonary dysplasia. J Interferon Cytokine Res. 1996;16:365–73.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge Zilu Huang and Yijun Liu for their assistance in acquiring the blood samples.

Funding

This study is supported by National Natural Science Foundation of China (82101803 & 82371707 & 32100082), Sanming Project of Medicine in Shenzhen (SZSM202211001), and Shenzhen Key Laboratory of Maternal and Child Health and Diseases (ZDSYS20230626091559006).

Author information

Authors and Affiliations

  1. Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, the First School of Clinical Medicine, Southern Medical University, Shenzhen, China

    Qingling Li, Cuihui Li, Yunbei Rao, Dongshan Han, Xuan Wang, Lingling Yang, Chuanzhong Yang & Xueyu Chen

  2. Guangzhou Center for Disease Control and Prevention, Guangzhou, China

    Yiran Chen

  3. Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, China

    Chuanzhong Yang & Xueyu Chen

Authors
  1. Qingling Li
    View author publications

    Search author on:PubMed Google Scholar

  2. Cuihui Li
    View author publications

    Search author on:PubMed Google Scholar

  3. Yunbei Rao
    View author publications

    Search author on:PubMed Google Scholar

  4. Dongshan Han
    View author publications

    Search author on:PubMed Google Scholar

  5. Xuan Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Lingling Yang
    View author publications

    Search author on:PubMed Google Scholar

  7. Yiran Chen
    View author publications

    Search author on:PubMed Google Scholar

  8. Chuanzhong Yang
    View author publications

    Search author on:PubMed Google Scholar

  9. Xueyu Chen
    View author publications

    Search author on:PubMed Google Scholar

Contributions

XYC, CZY, and QLL conceived the study and designed the experiments. QLL, XYC, CHL, and YBR carried out the clinical data collection. DSH, XW, and LLY collected the clinical samples. QLL, XYC, and YRC performed data analysis. QLL and XYC wrote the manuscript. XYC and CZY reviewed and revised the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Chuanzhong Yang or Xueyu Chen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

The study was approved by the Shenzhen Maternity & Child Healthcare Hospital Institutional Ethical Committee [SFYLS (2021) 019].

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Q., Li, C., Rao, Y. et al. Dynamic association between plasma interleukin-1 family concentrations and bronchopulmonary dysplasia in extremely premature infants. J Perinatol (2025). https://doi.org/10.1038/s41372-025-02275-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41372-025-02275-4

Search

Advanced search

Quick links