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.
Highlights
Bronchopulmonary dysplasia (BPD) has a complex pathogenesis involving multiple insults to the immature lungs that result in varying degrees of alveolar simplification and structural and functional modifications of the arterioles and bronchioles [1, 2].The cellular and molecular mechanisms leading to abnormal lung development in BPD are poorly understood
We examined the effect of vitamin D (VitD) treatment on LPS-induced alveolar simplification (Figure 1A)
In terms of the secondary septa, the difference between P1 and P7 was not significant in the LPS groups with or without VitD (Figure 1B). These results suggested that VitD effectively alleviated lung alveolar structure simplification induced by LPS
Summary
Bronchopulmonary dysplasia (BPD) has a complex pathogenesis involving multiple insults to the immature lungs that result in varying degrees of alveolar simplification and structural and functional modifications of the arterioles and bronchioles [1, 2].The cellular and molecular mechanisms leading to abnormal lung development in BPD are poorly understood. Several animal models of neonatal lung injury or BPD with an emphasis on postnatal inflammation have been reported [5]. Antenatal endotoxins can induce lung inflammation, leading to high neonatal mortality and subsequent arrests in alveolarization in the lungs of infant rats, which is one of the classic animal models of BPD [6]. Lung inflammation is recognized as an important risk factor for predisposing the infant to BPD before birth, and cytokines, including interleukin (IL)-1β and interferon (IFN)-γ, play an important roles in this process [4, 7]. IFN-γ is a proinflammatory cytokine detected in lungs exposed to inflammation and an inducer of effector mechanisms, thereby qualifying it as an early mediator of BPD development [6, 8]. Higher serum concentrations of IL-1β and IFN-γ and lower concentrations of other cytokines (IL-17) are associated with the development of BPD in preterm babies [10]
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