Premature infant lungs, due to immature lung development, are easily damaged when the infants move from a relatively hypoxic environment in utero (4%) to exposure to extrauterine hyperoxic respiratory support (≥21%) (Maltepe and Saugstad, 2009, Keszler and Sant'Anna, 2015). While oxygen therapy improves the treatment outcome of premature infants, the risk of bronchopulmonary dysplasia (BPD) also increases. BPD is a common chronic complication of the respiratory system of premature infants that is recognized as a disease caused by multiple factors, and its pathogenesis is very complex. An increasing number of studies have suggested that the lungs of premature infants lack antioxidant enzymes to resist oxidative stress (Berkelhamer SK and Farrow KN, 2014). When oxygen therapy is given to premature infants after birth, the lungs are continuously exposed to hyperoxia, which will produce excessive reactive oxygen species and increase the level of oxidative stress, thus leading to lung injury and lung epithelial cell apoptosis and resulting in the occurrence of bronchopulmonary dysplasia (Wang et al., 2022, Deng et al., 2022). BPD has high morbidity and fatality rates, which are inversely related to gestational age and body weight (Stoll BJ et al., 2010). Therefore, it is very important to identify effective prevention and treatment methods for BPD.

Clinical studies have found that breastfeeding reduces the incidence of BPD and improves the development of later respiratory disease in children with BPD, especially in very preterm or very low birth weight infants (Kim et al., 2019, Huang et al., 2019). Based on a better understanding of the composition of human milk, our previous research found that exosomes, as bilayer membrane vesicle structures with a diameter of 30-200 nm, are widely present in human milk. Furthermore, the exosomes can be absorbed by the intestine and reach the lungs through the blood circulation to inhibit the apoptosis of alveolar type II epithelial cells (AT II) to defend against BPD (Tkach M and Théry C, 2016; Zhou Y et al., 2022).

Human milk exosomes carry a variety of biomolecules, such as proteins, lipids, and RNA, and they can deliver carriers to receptors for information exchange (Admyre C et al., 2007). Circular RNAs (circRNAs) derived from human milk exosomes attracted our attention because of their stability. CircRNAs are a class of RNA molecules with a circular structure obtained by reverse splicing of pre-mRNA (Li Z et al., 2015). The circular structure makes circRNA less susceptible to digestion by digestive enzymes, more stable than other linear RNAs, and highly abundant and conserved in human and mammalian tissues (Rybak-Wolf A et al., 2015). A review of the literature shows that circRNAs can regulate various biological processes and affect the occurrence and progression of diseases. In addition, circRNAs in porcine milk were shown to regulate the intestinal barrier and intestinal immunity and participate in the occurrence of intestinal diseases, and circRNAs in bovine milk exosomes also play a role in regulating bacterial infection (Zeng et al., 2020, Ma et al., 2021). We speculate that circRNAs derived from human milk exosomes can affect BPD. Therefore, we screened circRNAs from preterm and term colostrum exosomes, of which 66 were upregulated and 42 were downregulated (|fold change>2|, p < 0.05) in preterm colostrum (Zhou Y et al., 2021). After bioinformatics analysis of the highly expressed circRNAs and a literature review, we found that one circRNA could promote cell proliferation and inhibit apoptosis (Jiang et al., 2022, Yang et al., 2021). Based on this and through preliminary experimental research, we found that this circRNA could play a role in BPD, so we named it circABPD1 (circRNA Anti-BPD1). However, the function and mechanism of circABPD1 derived from human milk exosomes in BPD are currently unknown.

In this article, we demonstrate that circABPD1 is derived from the antisense strand of the PTK2 gene, has circular RNA characteristics, improves alveolar simplification, promotes cell proliferation, and reduces oxidative stress levels and lung type II epithelial cell injury in in vitro and in vivo models of BPD. Notably, we found that circABPD1 affected cell proliferation and oxidative stress levels by sponging miR-330-3p, thereby increasing the expression of the target gene HIF1α in an in vitro model of BPD. Overall, our results suggest that circABPD1 inhibits the progression of BPD via the miR-330-3p/HIF1α axis and may serve as a novel approach for the treatment of BPD.