Differences in autophagy marker levels at birth in preterm vs. term infants

Abstract

Background: Preterm infants are susceptible to oxidative stress and prone to respiratory diseases. Autophagy is an important defense mechanism against oxidative-stress-induced cell damage and involved in lung development and respiratory morbidity. We hypothesized that autophagy marker levels differ between preterm and term infants.

Methods: In the prospective Basel-Bern Infant Lung Development (BILD) birth cohort we compared cord blood levels of macroautophagy (Beclin-1, LC3B), selective autophagy (p62) and regulation of autophagy (SIRT1) in 64 preterm and 453 term infants.

Results: Beclin-1 and LC3B did not differ between preterm and term infants. However, p62 was higher (0.37, 95% confidence interval (CI) 0.05;0.69 in log2-transformed level, p = 0.025, p_adj = 0.050) and SIRT1 lower in preterm infants (-0.55, 95% CI -0.78;-0.31 in log2-transformed level, p_adj < 0.001). Furthermore, p62 decreased (p_adj-value for smoothing function was 0.018) and SIRT1 increased (0.10, 95% CI 0.07;0.13 in log2-transformed level, p_adj < 0.001) with increasing gestational age.

Conclusion: Our findings suggest differential levels of key autophagy markers between preterm and term infants. This adds to the knowledge of the sparsely studied field of autophagy mechanisms in preterm infants and might be linked to impaired oxidative stress response, preterm birth, impaired lung development and higher susceptibility to respiratory morbidity in preterm infants.

Impact: To the best of our knowledge, this is the first study to investigate autophagy marker levels between human preterm and term infants in a large population-based sample in cord blood plasma This study demonstrates differential levels of key autophagy markers in preterm compared to term infants and an association with gestational age This may be linked to impaired oxidative stress response or developmental aspects and provide bases for future studies investigating the association with respiratory morbidity.

Fig. 1. Autophagy marker levels at different gestational ages.

a Beclin-1, b LC3B, c p62 and d SIRT1 marker levels are presented in log2-transformed level. Data are presented as median, lower and upper quartile, minimum and maximum data value and outliers.

Fig. 2. Association between gestational age and p62 level estimated using generalized additive Tobit model adjusted for small for gestational age (SGA), mode of delivery, sex, birth order, maternal smoking during pregnancy, time until processing, temporary fridge storage and center.

p62 levels are presented in log2-transformed level. P_adj-value for the smoothing function was 0.018. The gray area represents the 95% confidence interval. Adjusted p-values were calculated using the Benjamini–Hochberg method.

Fig. 3. Comparison of associations between autophagy markers in preterm and term infants.

Marker levels are presented in log2-transformed level, legend shows Spearman’s correlation coefficient (rho) with adjusted p-values using the Benjamini–Hochberg method. Association between (a) Beclin-1 and LC3B and between (b) p62 and LC3B are shown.