A Novel Association between YKL-40, a Marker of Structural Lung Disease, and Short Telomere Length in 10-Year-Old Children with Bronchopulmonary Dysplasia

Abstract

Extremely preterm infants are born with immature lungs and are exposed to an inflammatory environment as a result of oxidative stress. This may lead to airway remodeling, cellular aging and the development of bronchopulmonary dysplasia (BPD). Reliable markers that predict the long-term consequences of BPD in infancy are still lacking. We analyzed two biomarkers of cellular aging and lung function, telomere length and YKL-40, respectively, at 10 years of age in children born preterm with a history of BPD (n = 29). For comparison, these markers were also evaluated in sex-and-age-matched children born at term with childhood asthma (n = 28). Relative telomere length (RTL) was measured in whole blood with qPCR and serum YKL-40 with ELISA, and both were studied in relation to gas exchange and the regional ventilation/perfusion ratio using three-dimensional V/Q-scintigraphy (single photon emission computer tomography, SPECT) in children with BPD. Higher levels of YKL-40 were associated with shorter leukocyte RTL (Pearson's correlation: -0.55, p = 0.002), but were not associated with a lower degree of matching between ventilation and perfusion within the lung. Serum YKL-40 levels were significantly higher in children with BPD compared to children with asthma (17.7 vs. 13.2 ng/mL, p < 0.01). High levels of YKL-40 and short RTLs were associated to the need for ventilatory support more than 1 month in the neonatal period (p < 0.01). The link between enhanced telomere shortening in childhood and structural remodeling of the lung, as observed in children with former BPD but not in children with asthma at the age of 10 years, suggests altered lung development related to prematurity and early life inflammatory exposure. In conclusion, relative telomere length and YKL-40 may serve as biomarkers of altered lung development as a result of early-life inflammation in children with a history of prematurity.

Keywords: SPECT; V/Q ratio; YKL-40; biomarker; bronchopulmonary dysplasia; inflammation-accelerated aging; lung function; oxidative stress; preterm; telomere length.

Figure 1

Flow chart of eligible patients from the original cohort of the PULMM study (PrematUre follow up with Lung function Mannitol and Methacholine). The final cohort included 29 children born preterm with bronchopulmonary dysplasia (BPD) at ten years of age. Lung function with spirometry, YKL-40 and relative telomere length (RTL) was analyzed in all children, and three-dimensional V/Q-scintigraphy (single photon emission computer tomography, SPECT) was analyzed in a subgroup of 25 children.

Figure 2

Correlation between relative telomere length (RTL) and YKL-40 at 10 years of age in 29 children born preterm with a history of BPD (p < 0.01). The darker circles represent good ventilation to perfusion ratios in more than 70% of the total lung volume (n = 15), and the brighter circles (n = 10) represent the group with more abnormalities (<70%).

Figure 3

Markers of structural lung damage and cellular aging at ten years of age in children born preterm with BPD in relation to the need for ventilatory support of more than one month in the neonatal period. The lines in the graph represent the median for RTL (1.58) and for YKL-40 (17.8 ng/mL).