Bronchopulmonary dysplasia (BPD) is the most common and serious respiratory complication in preterm infants. Advances in perinatal medical therapy, including the prenatal use of glucocorticoids, and the postnatal use of lung surfactants and non-invasive assisted ventilation, have gradually improved the survival rate of preterm infants, particularly very low and ultra-low birth weight infants. However, the incidence of BPD has not decreased significantly (Bancalari and Jain, 2019). The National Institute of Child Health and Human Development (NICHD) reported that up to 40% of very preterm infants develop BPD (Stoll et al., 2010). In 2019, the Chinese Neonatal Collaborative Network reported that among 57 preterm infants born before 32 weeks of gestational age in China, the incidence of BPD was 29.2%. (Cao et al., 2021), which was six times higher than the incidence in retrospective surveys in China from 2006 to 2008 (4.2%) (Collaborative Study Group for Bronchopulmonary Dysplasia of Prematurity in China, 2011). Premature infants with severe BPD often die of respiratory failure (Nakashima et al., 2021), and those who survive are not only prone to recurrent respiratory infections and reduced lung function during childhood, but also are at increased risk of developing chronic obstructive pulmonary disease in adulthood (Sillers et al., 2020). Children with BPD not only place a heavy burden on their families, but also have a major impact on the quality of our birth population. Therefore, there is an urgent need to seek preventive and therapeutic measures for BPD and to explore its mechanisms of action in depth.
Fetal lung maturation occurs during the alveolar phase of lung development, during which type II pneumocytes are responsible for the production of pulmonary surfactant (PS), which is distributed on the surface of the molecular layer of alveolar fluid and has the effect of reducing the surface tension of the alveoli, maintaining the relative stability of large and small alveolar volumes, and preventing the infiltration of fluid from alveolar capillaries into the alveoli. The main components of PS include phospholipids and surface-active substance binding proteins. Among them, phosphatidylcholine (PC), also known as lecithin, is a phospholipid present in mature PS, which is secreted and stored by the laminae, and a ratio of lecithin to sphingomyelin of ≥ 2:1 is characteristic of the mature fetal lung (Bernhard, 2016). It has been suggested that synthetic immaturity of PS is an important cause of BPD, and that lipid metabolism might influence the development of BPD by altering the lipid composition of PS (Yue et al., 2021). In recent years, the relationship between BPD and lipid metabolism has received increased attention. Studying the role of lipids in BPD pathology can help to reveal the pathogenesis of BPD and provide new avenues for its treatment.
Mass spectrometry analysis of bronchoalveolar lavage fluid and lung tissue from rats and human children with BPD showed that PC levels changed significantly during alveolar development, with PC (16:0/14:0) concentrations increasing during alveolarization and decreasing in chronic lung diseases, such as BPD and emphysema (Ridsdale et al., 2005; Bernhard et al., 2011, Bernhard et al., 2011). PC deficiency plays an important role in the development of BPD; however, no studies have assessed the role of PC (16:0/14:0) in BPD, and the mechanism of the protective effect of PC (16:0/14:0) in BPD is unclear.
The present study aimed to investigate the role and mechanism of PC (16:0/14:0) in BPD. Our study showed that PC (16:0/14:0) ameliorated alveolar injury and the expression of AT II cell surfactant protein C (SPC) and surfactant protein D (SPD) in an animal model of BPD. Our hypothesis was that PC (16:0/14:0) ameliorates alveolar type II (AT II) cell injury induced by hyperoxia exposure. Therefore, the effect of PC (16:0/14:0) on hyperoxia-induced AT II cell injury was assessed in a hyperoxia-induced A549 cell line. The results indicated that PC (16:0/14:0) has a protective effect on AT II cells. To explore the mechanism of action of PC (16:0/14:0), we performed RNA sequencing (RNA-Seq) on lung tissues from the BPD and PC (16:0.14:0) rat intervention groups to identify differential expressed genes between the two groups. The results revealed that the expression of Cldn1 (encoding claudin 1) differed distinctly between the two groups. Furthermore, we used small interfering RNA (siRNA) to knock down the expression of CLDN1 in the BPD model based on A549 cells, and found that the protective effect of PC (16:0/14:0) on BPD was lost. The above experiments demonstrated that PC (16:0.14:0) could prevent and treat BPD by repairing the intercellular barrier function via upregulating the expression of CLDN1. Therefore, this study might provide a new approach and ideas for the prevention and treatment of BPD.