Vitamin D Shows Therapeutic Potential for Preterm Infant Lung Development

Research study background

Bronchopulmonary dysplasia (BPD) is a complex chronic lung disease predominantly affecting preterm infants born before 28 weeks of gestation. It disrupts normal lung development, leading to impaired formation of alveoli (tiny air sacs needed for gas exchange) and abnormal vascular growth. Infants with BPD face increased risk for long-term respiratory issues, including pulmonary hypertension (PH), a serious complication of elevated blood pressure in the lungs and vascular system. Maternal preeclampsia, a disorder characterized by vascular dysfunction and elevated circulating antiangiogenic factors (inhibitors of new blood vessel growth) like soluble VEGF receptor-1 (sFlt-1), is increasingly recognized as a key prenatal risk factor for developing BPD.

Vitamin D, traditionally known for its role in calcium and bone metabolism, also regulates lung development through its receptor, which is expressed in many lung cell types, including epithelial and endothelial cells. Importantly, pulmonary endothelial cells (PEC) play a key role in coordinating lung vascular growth and alveolar formation.

In previous research, investigators at Children’s Hospital Colorado demonstrated the therapeutic benefits of the biologically active form of vitamin D in a rat model of chorioamnionitis, an inflammatory disorder impacting the fetus. They found intraamniotic (IA) treatment with 1,25 dihydroxyvitamin D (1,25(OH)₂D) improved placental angiogenesis, enhanced alveolarization (formation of alveoli in the lungs) and prevented right ventricular hypertrophy (RVH), an early indicator of PH.

In this study, the team examined whether IA treatment with 1,25(OH)₂D could preserve lung growth, angiogenesis and pulmonary function in a near-term newborn rat model of BPD exposed to sFlt-1. Researchers compared four groups injected at day 20 of gestation: control (saline), sFlt-1 alone, 1,25(OH)₂D alone, or a combination of sFlt-1 and 1,25(OH)₂D. The rat models were analyzed upon delivery (day 22 of gestation) and again at 14 days of life to assess for alveolar and vascular growth. They also conducted in vitro experiments to measure PEC function.

Exposure to sFlt-1 alone reduced alveolarization by 44% and vessel density by 43%. It also reduced PEC growth and tube formation in vitro and increased both respiratory resistance and RVH, as seen in BPD. However, simultaneous IA treatment with sFlt-1 and 1,25(OH)₂D preserved near-normal lung alveolar and vascular structure. It also improved PEC growth and tube formation in vitro and significantly reduced the PH marker RVH, indicating protection against sFlt-1–induced lung injury. Neither 1,25(OH)₂D alone nor the control harmed healthy lungs.

Clinical implications

This study is the first to demonstrate that IA treatment with biologically active vitamin D reduces lung injury caused by sFlt-1-induced vascular dysfunction and supports PEC-driven angiogenesis in a preeclampsia-related model of BPD. Although IA treatment is not currently clinically practical in humans, the findings highlight vitamin D’s role in early lung vascular development and its potential to prevent BPD-associated PH. These insights lay the groundwork for future translational research exploring vitamin D-based therapies and interventions for this vulnerable population.