Human milk-derived peptide MDABP ameliorates hyperoxia lung damage via inhibiting the ferroptosis signaling pathway

Abstract

Human breast milk, the best source of nutrition for newborns, can reduce the incidence of bronchopulmonary dysplasia (BPD). Bioactive peptides are important components of human breast milk. However, their function in BPD are unclear. We screened a novel peptide (named MDABP) in the breast milk of mothers of premature infants, which has beneficial effects in experimental BPD. This study aimed to investigate the role and mechanism of MDABP in vivo and vitro. Newborn Sprague-Dawley (SD) rats were exposed to normoxia (21 % O2) or hyperoxia (85 % O2) and injected with MDABP or PBS from postnatal days 1 to 7 (PN1-PN7). On PN7, the lungs were harvested for histological and biochemical analysis. The results revealed that MDABP improved alveolar simplification and pulmonary vascular retardation, promoted alveolar epithelial cell (AEC) proliferation and inhibited cell apoptosis. In vitro, MDABP, but not scrambled MDABP, promoted cell proliferation and reduced cell injury without obvious toxicities. RNA-sequencing in A549 cells showed a total of 214 genes were significantly differentially expressed between the MDABP + hyperoxia and hyperoxia groups, including 80 upregulated and 134 downregulated genes. KEGG pathway analysis showed that significant differentially expressed genes were related to the ferroptosis signaling pathway. Rescue experiments showed that MDABP reduced the hyperoxia- and ferroptosis-induced damage to AEC by decreasing the levels of Fe2+ and ROS and increasing the levels of GSH and GPX4. The p-value of the above experiment was less than 0.05, which was considered statistically significant. This study provides a new basis for developing treatments for BPD.

Keywords

• Bronchopulmonary dysplasia
• MDABP
• Hyperoxia
• Ferroptosis