Vitamin D Enhances Alveolar Development in Antenatal Lipopolysaccharide-Treated Rats through the Suppression of Interferon-γ Production

Abstract

Bronchopulmonary dysplasia (BPD) is characterized by the premature arrest of alveolar development. Antenatal exposure to inflammation inhibits lung morphogenesis, thereby increasing the risk for the development of BPD. Here, we investigated whether vitamin D (VitD) enhances alveolar development in antenatal lipopolysaccharide (LPS)-treated rats, which is a model for BPD. We used an established animal model of BPD, and random assignment to the control group, LPS group, or LPS with VitD group. Levels of interferon (IFN)-γ and interleukin-4 were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. IFN-γ producing CD8+ T cells were assessed by flow cytometry, and the methylation status of the VitD-response element (VDRE) was analyzed by bisulfite sequencing PCR. 25-hydroxyvitamin D levels were measured by liquid chromatography tandem mass spectrometry in maternal serum samples collected from 86 pregnant women in a prospective birth cohort enrolled from 2012 to 2013. Our results showed that VitD effectively alleviated the simplification of the lung alveolar structure in BPD rats and suppressed LPS-induced IFN-γ expression in the lung and spleen tissues. Further investigation revealed that VitD suppressed IFN-γ production in CD8+ T cells. Specifically, VitD increased the methylation percentage of the VDRE in the IFN-γ-promoter region and suppressed LPS-induced expression of IFN-γ. Additionally, we observed an association between maternal VitD exposure during pregnancy and neonatal IFN-γ levels in a prospective birth cohort, with a trend similar to that observed in the animal model. Our data suggested that supplementation of VitD could suppress IFN-γ production, resulting in improved alveolar development in an LPS-induced BPD rat model.

Lung development and emerging roles for type 2 immunity

“…Similar effects on murine lung development were observed following lipopolysaccharide (LPS) administration . Early postnatal exposure impaired alveolarisation and angiogenesis , which could be alleviated by administration of vitamin D through reducing interferon (IFN)‐γ . Inhibiting NF‐κB signalling worsened the LPS‐induced phenotype, suggesting an anti‐inflammatory function in the developing lung .…”

<p>Reduced Vitamin D Levels are Associated with Stroke-Associated Pneumonia in Patients with Acute Ischemic Stroke</p>

“…46,47 Vitamin D supplementation ameliorated pulmonary morphological alternations in LPS-induced bronchopulmonary dysplasia, inhibited IFN-γ overproduction and, thereby, suppressed inflammation. 48 Vitamin D was also confirmed to enhance the ability of neutrophils to kill Streptococcus pneumoniae and inhibit excessive inflammation and apoptosis. 49 Similar beneficial effects of vitamin D were observed in paraquat-induced lung fibrosis; vitamin D exhibited its anti-inflammatory effects by decreasing the secretion of pro-inflammatory cytokines.…”

Low-Dose Vitamin D Protects Hyperoxia-Induced Bronchopulmonary Dysplasia by Inhibiting Neutrophil Extracellular Traps

“…Kose et al (14) demonstrated that treatment with VD protected against hyperoxia-induced lung injury by decreasing MLI and apoptosis and increasing the proliferating cell nuclear antigen (PCNA) index. Liu et al (19) suggested that supplementation with VD could enhance alveolar development in an LPS-induced BPD rat model through the suppression of IFN-γ production. However, whether other regulatory mechanisms are involved in VD as a treatment in hyperoxia-induced lung injury remains unknown.…”