Introduction

Bronchopulmonary Dysplasia (BPD) is a chronic respiratory disorder mainly seen in premature infants, marked by underdeveloped alveoli, impaired vascular growth in the lungs, and fibrotic changes in pulmonary tissue. This condition not only poses a threat to the short-term health of preterm infants but also exerts profound and lasting negative effects on their long-term quality of life and survival capabilities.1–4 Despite advancements in neonatal intensive care that have increased the survival rates of preterm infants in recent years, the incidence of BPD has not significantly declined and is even on the rise in some regions.5 Therefore, the identification of biomarkers for early prediction and intervention of BPD holds significant clinical importance.

Emerging evidence suggests that various cord blood biomarkers are linked to the pathogenesis and clinical course of bronchopulmonary dysplasia. Notably, studies indicate that decreased cord blood angiopoietin-1 concentrations may elevate susceptibility to BPD in preterm neonates. This suggests that angiopoietin-1 may serve as a potential biomarker for predicting BPD risk.6 A separate investigation employing high-performance liquid chromatography-mass spectrometry (HPLC-MS) compared cord blood samples from 205 extremely preterm infants (≤28 weeks gestation) and 51 term infants. The analysis detected 105 distinct adducts, with 51 known adducts—including small thiols, direct oxidation products, and reactive aldehydes—showing elevated levels in infants who developed BPD. This finding highlights the relationship between oxidative stress markers in cord blood and BPD.7 These discoveries provide important evidence for the early identification of BPD risk through cord blood biomarkers.

The primary pathogenesis of BPD involves inflammatory responses, oxidative stress, and abnormal lung development.8–10 C-X-C motif chemokine ligand 10 (CXCL10) is an important inflammation-related chemokine. In diseases such as Mycoplasma pneumoniae pneumonia, CXCL10 levels are positively correlated with the number of neutrophils and macrophages in bronchoalveolar lavage fluid and with clinical parameters, showing potential as a biomarker for inflammatory assessment.11 Matrix Metalloproteinase 8 (MMP8), a member of the zinc-dependent endopeptidase family, plays a crucial role in extracellular matrix (ECM) degradation and tissue remodeling processes. In pulmonary diseases, MMP8 degrades the alveolar basement membrane and collagen, leading to alveolar structural disruption and impaired lung function, and is an important pathological factor in pulmonary inflammation and injury.12 MMP8 can also cleave CXCL10, reducing its ability to recruit immune cells, enhancing fibrotic signaling pathways, and contributing to the occurrence and progression of BPD.13 Animal studies have shown that CXCL10 deficiency reduces macrophage infiltration and inflammatory responses in BPD models, protects lung matrix, and promotes lung growth, providing a new therapeutic target for BPD.14 However, there are currently limited studies on the levels of CXCL10 and MMP8 in cord blood of preterm infants with BPD and their clinical value.

This study aims to investigate the relationship between the levels of CXCL10 and MMP8 in cord blood of preterm infants and BPD, and to analyze their potential value as early predictive biomarkers. The findings may provide new evidence for the early diagnosis and intervention of BPD and could potentially offer new therapeutic targets for clinical treatment.

Materials and MethodsBioinformatics Analysis

The GSE220135 dataset (NCBI GEO) was analyzed to compare blood gene expression profiles between preterm neonates with and without BPD. Differential expression analysis (GEO2R; cutoff: |log2FC| >1, P <0.05) identified significant transcriptomic alterations in cord blood. The most significantly up-regulated targets were selected for subsequent analysis.

Study Population

Based on the reference,15 the incidence of BPD in preterm neonates <32 weeks’ gestation is 33.33%. Using PASS 15.0 (NCSS, LLC; Kaysville, UT, USA) with α=0.1 (two-sided) and 5% margin of error, we calculated a minimum required sample size of 259 subjects for adequate statistical power.

Preterm infants admitted to the Neonatal Intensive Care Unit (NICU) of Baoding Maternal and Child Health Hospital from January 2019 to December 2023 were included in this study. The inclusion criteria were: (1) gestational age <32 weeks or birth weight <1500 g; (2) diagnosis of BPD according to the criteria of the National Institute of Child Health and Human Development (NICHD),16 which is defined as a need for supplemental oxygen at a concentration greater than 21% for at least 28 days; (3) neonates requiring NICU admission for >5 days were included; (4) Infants receiving ≥80% human milk enteral intake during hospitalization; and (5) infants with complete clinical data and follow-up results. Exclusion criteria included: (1) infants with complex congenital heart disease; (2) infants with severe diseases of the heart, brain, lungs, kidneys, or other organs; (3) infants with a history of major surgery; (4) infants with non-planned discharge, transfer to another department, transfer to another hospital, or death; (5) infants with chromosomal disorders; (6) infants with immune system disorders; (7) infants with phenylketonuria or other genetic metabolic diseases; and (8) infants whose mothers had hereditary metabolic or endocrine diseases.

The study cohort comprised 272 preterm neonates, stratified into BPD (n=90) and non-BPD (n=182) groups according to disease status. The flowchart for participant enrollment is shown in Figure 1.

Figure 1 Flowchart of Participant Enrollment.

Clinical Data Collection

We retrospectively analyzed clinical data from 272 preterm infants, including neonatal characteristics (gestational age, birth weight, sex, delivery mode, plurality, and Apgar scores at 1/5 minutes), clinical complications and treatments (neonatal respiratory distress syndrome [NRDS], patent ductus arteriosus [PDA], neonatal sepsis [NS], pneumonia, mechanical ventilation duration, fraction of inspired oxygen [FiO2] stratified as <30% or ≥30%, caffeine therapy, and transfusion frequency), and maternal factors (age, smoking status, premature rupture of membranes [PROM], intrauterine infection, and pregnancy complications including hypertension and diabetes).

Cord Blood Sample Collection and Detection of CXCL10 and MMP8 Levels

Cord blood samples from all preterm infants were collected at birth from the umbilical cord stump17 and stored in our institution’s biobank. For this study, cord blood serum samples stored in our biobank were retrieved for analysis. Quantification of cord blood serum CXCL10 and MMP8 was performed using standardized enzyme-linked immunosorbent assays (ELISA) with quality controls (product numbers: SEKH-0070 and SEKH-0256, Solarbio, China). Prior to the experiment, the ELISA kits were equilibrated to room temperature (21–26°C). The serum samples were thawed slowly at 4°C. Before detection, both the ELISA kits and samples were brought to room temperature for 30 minutes. Based on preliminary trials, the dilution factors for CXCL10 (1:2 serial dilution) and MMP8 (1:4 diluent) ELISA kits were set to keep sample values within the standard curve’s linear range. ELISA kits were stored at 2–8°C, with reagents prepared immediately before use and unused portions stored at 4°C. Each sample was measured in duplicate, yielding intra- and inter-assay CVs <10%, indicating good precision and repeatability. Serum samples, stored at –20°C to –80°C, were thawed at 4°C and used immediately to prevent protein degradation from repeated freeze–thaw cycles. Each ELISA plate included positive (high-concentration CXCL10 and MMP8 serum) and negative (assay diluent without analyte) controls to ensure assay performance.

The ELISA procedure was performed as follows: samples and standards were added to antibody-precoated wells and incubated with agitation (120 min, 25±2°C). After four washes, biotinylated detection antibody was added (60 min incubation, 25±2°C). Following another four washes, enzyme conjugate was incubated (30 min, 25±2°C). After five final washes, TMB substrate was added for color development (15 min, dark). The reaction was stopped and absorbance was read at 450 nm using a microplate reader.

MMP8 concentrations were determined by adding standards and test samples to ELISA plates followed by static incubation (90 min, 37°C). The subsequent steps were the same as those for CXCL10. A standard curve was established for each detection, and sample concentrations were calculated based on the standard curve.

Statistical Analysis

Statistical analyses were performed using SPSS 26.0 (IBM Corp., Armonk, NY, USA). Data normality was assessed using Shapiro–Wilk tests. Normally distributed continuous variables were reported as mean ± standard deviation and compared using independent samples t-tests. Non-normally distributed data were expressed as median (interquartile range) and analyzed with Mann–Whitney U-tests. Categorical variables were presented as n (%) and evaluated by chi-square (χ2) tests. Spearman correlation examined relationships between CXCL10 and MMP8 levels. Binary logistic regression identified BPD risk factors, while receiver operating characteristic (ROC) curve analysis assessed diagnostic performance of biomarkers. Missing data (< 5% for any variable) were handled using multiple imputation by chained equations (m = 5); descriptive statistics before and after imputation were virtually identical. Statistical significance was set at P < 0.05 (two-tailed).

ResultsComparison of General Characteristics Between BPD and Non-BPD Groups

Preterm neonates with BPD demonstrated significantly lower birth weight (P<0.05), 1-minute Apgar scores (P<0.05), and 5-minute Apgar scores (P<0.05) compared to non-BPD controls. The BPD group showed higher prevalence of extreme prematurity (<28 weeks gestation; P<0.05), NRDS (P<0.05), prolonged mechanical ventilation (P<0.05), and requirement for higher oxygen concentrations (FiO2 ≥30%; P<0.05). Maternal factors including advanced age (P<0.05), antenatal smoking (P<0.05), and intrauterine infection (P<0.05) were more frequent in the BPD cohort. No other intergroup differences reached statistical significance (all P>0.05; see Table 1).

Table 1 Comparison of General Characteristics Between BPD and Non-BPD Groups

Comparison of CXCL10 and MMP8 Levels in Cord Blood Between BPD and Non-BPD Preterm Infants

Analysis of the GSE220135 microarray dataset (NCBI GEO accession: GSE220135) revealed significant upregulation of CXCL10 and MMP8 in cord blood from preterm infants with BPD compared to non-BPD controls (Figure 2). Validation in our institutional cohort demonstrated significantly elevated serum levels of both CXCL10 (P<0.001) and MMP8 (P<0.001) in BPD cases versus non-BPD controls (Figure 3).

Figure 2 Analysis Results of the GSE220135 Microarray.

Note: (A) Volcano plot of GSE220135 microarray data; (B and C) Expression levels of CXCL10 (B) and MMP8 (C) in BPD and non-BPD groups in the GSE220135 microarray.

Figure 3 Comparison of CXCL10 and MMP8 Levels in Cord Blood between BPD and Non-BPD Preterm Infants.

Note: (A) CXCL10 and (B) MMP8 concentrations in cord blood of BPD vs non-BPD preterm infants. *** indicates P < 0.001.

Correlation Analysis of CXCL10 and MMP8 in Cord Blood of Preterm Infants with BPD

A significant positive correlation was observed between CXCL10 and MMP8 levels in BPD-affected preterm neonates (Spearman’s r=0.332, P<0.001; Figure 4).

Figure 4 Correlation Analysis of CXCL10 and MMP8 Levels in Cord Blood of Preterm Infants with BPD.

Multivariate Logistic Regression (MLR) Analysis of Risk Factors for BPD in Preterm Infants

BPD occurrence was used as the dependent variable in the multiple logistic regression analyses (yes = 1, no = 0). The following independent variables were included: gestational age (<28 weeks=1, ≥28 weeks=0), birth weight (continuous variable), 1-minute Apgar score (0–3=1, 4–6=2, 7–10=3), 5-minute Apgar score (4–6=1, 7–10=0), presence of NRDS (yes=1, no=0), use of mechanical ventilation (yes=1, no=0), duration of mechanical ventilation (continuous variable), FiO2 (≥ 30%=1,<30%=0), maternal age (continuous variable), maternal smoking during pregnancy (yes=1, no=0), intrauterine infection (yes=1, no=0), and levels of CXCL10 and MMP8 in cord blood (continuous variables). The results indicated that birth weight, 1-minute Apgar score, and 5-minute Apgar score were protective factors against BPD. In contrast, the presence of NRDS, use of mechanical ventilation, prolonged duration of mechanical ventilation, maternal smoking during pregnancy, higher CXCL10 and MMP8 levels in umbilical cord blood were independently associated with BPD risk. Collinearity diagnostics showed all variance inflation factors (VIFs) < 3, suggesting no serious multicollinearity (Table 2 and Figure 5). The Hosmer–Lemeshow test yielded a χ2 = 8.21, P = 0.413, indicating no significant disagreement between predicted probabilities and observed event rates.

Table 2 Multivariate Logistic Regression Analysis of Risk Factors for BPD in Preterm Infants

Figure 5 Forest Plot of Multivariate Analysis for Risk Factors of BPD.

Assessment Value of CXCL10 and MMP8 in Cord Blood for BPD

The ROC curve analysis indicated that the AUC values for predicting BPD using cord blood CXCL10, MMP8 alone, and in combination were 0.814 (95% CI: 0.736–0.892), 0.854 (95% CI: 0.790–0.918), and 0.902 (95% CI: 0.866–0.938), respectively. The combined model of CXCL10 and MMP8 demonstrated a significantly higher discriminative power for BPD prediction compared to CXCL10 alone (P=0.045), but the difference was not statistically significant when compared with MMP8 alone (P=0.245) (Table 3 and Figure 6).

Table 3 Assessment Value of CXCL10 and MMP8 in Cord Blood for BPD

Figure 6 ROC Curves for Assessing BPD Using CXCL10 and MMP8 Levels in Cord Blood of Preterm Infants.

Discussion

BPD represents a multifactorial chronic pulmonary disorder predominantly observed in premature neonates, with etiological contributors including immature lung development, ventilator-induced injury, hyperoxia exposure, and infectious processes. These factors act in concert to impair the normal development of alveoli and pulmonary vasculature, resulting in injury to the immature lung.18 Infants with BPD often exhibit prolonged oxygen dependency after birth, along with symptoms such as respiratory distress and recurrent respiratory infections. In severe cases, complications like pulmonary hypertension and heart failure may occur, which can be life-threatening.19,20 Therefore, identifying biomarkers for the diagnosis of BPD is crucial for its prevention and treatment, and can improve the survival outcomes of preterm infants.

MLR analysis in this study indicated that levels of CXCL10 and MMP8 in cord blood of preterm infants are risk factors for the development of BPD, further supporting their potential as indicators for BPD risk assessment. Spearman correlation analysis demonstrated a positive association between CXCL10 and MMP8 concentrations in cord blood samples from preterm infants diagnosed with BPD, indicating that these two factors may interact cooperatively in the inflammatory processes underlying BPD. CXCL10, an important inflammation-related chemokine, attracts various immune cells and significantly increases in expression during inflammation, forming a positive feedback loop with cytokines such as IFN-γ to amplify the inflammatory response.21 MMP8, capable of degrading the extracellular matrix and secreted by neutrophils and macrophages, plays a role at sites of inflammation.22 The synergistic action of these two factors in the inflammatory response may exacerbate the pathological process of BPD.

Preterm infants developing BPD were more likely to be extremely premature (<28 weeks) and have maternal risk factors including smoking and intrauterine infection versus unaffected peers. This may be because the smaller the gestational age, the more immature the lung development, and the more severe the deficiency of pulmonary surfactant, which can lead to alveolar collapse and atelectasis, resulting in respiratory distress and hypoxemia. These infants require prolonged oxygen therapy and respiratory support, thereby increasing the risk of developing BPD.23,24 Additionally, the smaller the gestational age, the less developed the immune system, making these infants more susceptible to infections, which in turn can further exacerbate lung damage and create a vicious cycle that further increases the risk of BPD.25 Previous studies have shown that both maternal smoking during pregnancy and intrauterine infection increase the risk of BPD.26–28 In this study, maternal smoking during pregnancy was identified as a risk factor for BPD in preterm infants, further emphasizing the importance of prenatal health management, especially in preventing intrauterine infections and reducing smoking behaviors, which can effectively lower the risk of BPD.

MLR analysis also revealed that the presence of NRDS, use of mechanical ventilation, and prolonged duration of mechanical ventilation are risk factors for BPD in preterm infants. NRDS represents a prevalent pulmonary complication among premature infants, characterized by insufficient surfactant production resulting in alveolar instability, pulmonary collapse, and consequent respiratory failure with systemic hypoxia.29 To maintain adequate oxygenation and ventilation, affected infants often require mechanical ventilation. However, mechanical ventilation itself can cause injury to the immature lung tissue, resulting in alveolar hypoplasia and pulmonary fibrosis.30,31 Although mechanical ventilation can be life-saving in the short term for preterm infants, prolonged mechanical ventilation may lead to damage of alveolar epithelial cells and pulmonary vascular endothelial cells, triggering inflammatory responses that further promote the development of BPD. Current evidence supports ventilator duration reduction as a modifiable protective factor against BPD development in hemodynamically stable preterm neonates.

While elevated cord-blood CXCL10 and MMP8 are associated with BPD, the observational design precludes inference of causality. Mechanistic studies are warranted to clarify how these biomarkers contribute to BPD pathogenesis. Furthermore, prior work indicates that angiopoietin-1 also predicts BPD risk.6 Head-to-head comparison and combined modeling of these analytes may yield a more accurate and generalizable predictive algorithm. Preterm infants with greater birth weights and improved Apgar scores (1-min and 5-min) exhibit reduced susceptibility to BPD development. The reasons may be as follows: A higher birth weight indicates relatively better fetal development in utero, including more mature lung development, which allows for more efficient gas exchange. Consequently, these infants have a lower oxygen demand after birth and are less likely to develop prolonged oxygen dependency, thereby reducing the risk of BPD. Higher 1-minute and 5-minute Apgar scores suggest better physiological function states (eg, breathing, heart rate, muscle tone) at birth. These infants can adapt more quickly to the extrauterine environment, establish spontaneous breathing more effectively, and maintain stable circulation. This reduces the risk of lung damage caused by respiratory distress and hypoxia,32 thereby lowering the risk of BPD.

ROC curve analysis revealed that the combined evaluation of CXCL10 and MMP8 achieved an AUC of 0.902 for BPD prediction. This indicates that the combined detection of CXCL10 and MMP8 has high clinical value in the early assessment of BPD. The combined detection can more accurately identify preterm infants at risk of developing BPD, thereby aiding clinicians in early diagnosis and intervention of BPD. The prognosis of preterm infants may be improved and the occurrence of BPD - related complications may be reduced as a result. Furthermore, infants with CXCL10 levels exceeding 154.30 pg/mL and MMP8 levels above 2726.00 pg/mL are at an elevated risk for BPD. The incorporation of these biomarkers into clinical models can enhance the assessment of BPD risk. However, additional validation is required to confirm these cutoff values and to integrate them with other clinical factors. To facilitate better clinical application, we will conduct further studies to refine these values.

This study has certain limitations. This study has several limitations. The sample-size calculation used α = 0.10 to balance exploratory objectives with single-center feasibility, and larger cohorts with more stringent thresholds are required for validation. The absence of external multicenter data limits generalizability and necessitates collaboration across diverse populations and clinical settings. Excluding deaths and transfers may have omitted the most severely affected neonates and potentially underestimated both BPD incidence and baseline CXCL10/MMP8 concentrations. Long-term follow-up was not performed, so the association of these biomarkers with remote pulmonary outcomes remains to be defined. Future multicenter studies with extended follow-up, larger samples, and mechanistic investigations are warranted to validate their predictive value and explore therapeutic targeting of the CXCL10/MMP8 axis in BPD.

Conclusion

Elevated cord blood CXCL10 and MMP8 levels were independently associated with BPD in preterm infants; in our single-center retrospective cohort, their combined assessment demonstrated favorable early predictive performance, suggesting potential value as readily accessible biomarkers for early risk stratification. However, definitive cut-offs, cost-effectiveness, and generalizability remain to be established through prospective, multicenter, large-scale studies.

Data Sharing Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Ethical Statement

This study was conducted in accordance with the Declaration of Helsinki and received ethical approval from the Baoding Maternal and Child Health Care Hospital (Approval No. 2023-01-K006), The Ethics Committee independently reviewed the protocol with special attention to this vulnerable population. As the research utilized biobank samples and was retrospective in nature, the requirement for informed consent was waived by the Medical Ethics Committee of Baoding Maternal and Child Health Care Hospital. All data were anonymized via unique study codes accessible only to the research team and handled under strict confidentiality.

Funding

This study was supported by the S&T Program of Baoding (No. 2341ZF120).

Disclosure

The authors report no conflicts of interest in this work.

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