Vitamin D related genes in lung development and asthma pathogenesis

Kho, Alvin T.; Sharma, Sunita; Qiu, Weiliang; Gaedigk, Roger; Klanderman, Barbara J.; Niu, Simin; Anderson, Chris; Leeder, J. Steven; Weiss, Scott T.; Tantisira, Kelan G.

doi:10.1186/1755-8794-6-47

Cited by 63 publications

(65 citation statements)

References 52 publications

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“…These findings support previously published epidemiologic data that have linked vitamin D-responsive genes to early lung development and asthma phenotypes (35,36). Vitamin D3 at the cellular level functions as a growth factor for alveolar type II cells, which are important in promoting alveolarization during lung growth and development (37).…”

Section: Discussionsupporting

confidence: 80%

Effect of Prenatal versus Postnatal Vitamin D Deficiency on Pulmonary Structure and Function in Mice

Saadoon¹,

Ambalavanan²,

Zinn

et al. 2017

Am J Respir Cell Mol Biol

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Epidemiologic studies have linked gestational vitamin D deficiency to respiratory diseases, although mechanisms have not been defined. We hypothesized that antenatal vitamin D deficiency would impair airway development and alveolarization in a mouse model. We studied the effect of antenatal vitamin D deficiency by inducing it in pregnant mice and then compared lung development and function in their offspring to littermate controls. Postnatal vitamin D deficiency and sufficiency models from each group were also studied. We developed a novel tracheal ultrasound imaging technique to measure tracheal diameter in vivo. Histological analysis estimated tracheal cartilage total area and thickness. We found that vitamin D-deficient pups had reduced tracheal diameter with decreased tracheal cartilage minimal width. Vitamin D deficiency increased airway resistance and reduced lung compliance, and led to alveolar simplification. Postnatal vitamin D supplementation improved lung function and radial alveolar count, a parameter of alveolar development, but did not correct tracheal narrowing. We conclude that antenatal vitamin D deficiency impairs airway and alveolar development and limits lung function. Reduced tracheal diameter, cartilage irregularity, and alveolar simplification in vitamin D-deficient mice may contribute to increased airways resistance and diminished lung compliance. Vitamin D supplementation after birth improved lung function and, potentially, alveolar simplification, but did not improve defective tracheal structure. This mouse model offers insight into the mechanisms of vitamin D deficiency-associated lung disease and provides an in vivo model for investigating preclinical preventive and therapeutic strategies. Clinical RelevanceThis murine investigation details structural and physiologic aberrances resulting from prenatal and postnatal vitamin D deficiency. In addition to modeling consequences on lung development, our findings emphasize differential benefit of prenatal versus postnatal vitamin D supplementation. These data provide mechanistic insight into clinical consequences of vitamin D deficiency-induced lung disease and the utility of a mouse model to test preventive and therapeutic interventions.

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Section: Discussionsupporting

confidence: 80%

Effect of Prenatal versus Postnatal Vitamin D Deficiency on Pulmonary Structure and Function in Mice

Saadoon¹,

Ambalavanan²,

Zinn

et al. 2017

Am J Respir Cell Mol Biol

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“…Evidence suggests that vitamin D may stimulate regulatory T cell development and T cell function to suppress inappropriate Th1 and Th2 responses to environmental exposure (i.e., allergens, infection load), leading to a more balanced immune response inhibiting autoimmune diseases (with Th1 dominance) and allergic diseases (Th2 dominance) (55). Vitamin D could therefore be involved in lung diseases of early childhood through immunomodulatory effects.Although controversial, several epidemiological studies have described an association between maternal vitamin D deficiency and the development of early childhood respiratory infections, wheezing, and asthma later in life (15,16,47,91).Human lung development begins in the fifth fetal week and continues throughout the first few years of life. It includes five phases: the embryonic, pseudoglandular, canalicular, saccular, and alveolar phase ( Fig.…”

mentioning

confidence: 99%

“…Although controversial, several epidemiological studies have described an association between maternal vitamin D deficiency and the development of early childhood respiratory infections, wheezing, and asthma later in life (15,16,47,91).…”

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confidence: 99%

The impact of vitamin D on fetal and neonatal lung maturation. A systematic review

Lykkedegn

Sørensen

Beck-Nielsen

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

122

104

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-Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) are major complications to preterm birth. Hypovitaminosis D is prevalent in pregnancy. We systematically reviewed the evidence of the impact of vitamin D on lung development, surfactant synthesis, RDS, and BPD searching PubMed, Embase, and Cochrane databases with the terms vitamin D AND (surfactant OR lung maturation OR lung development OR respiratory distress syndrome OR fetal lung OR prematurity OR bronchopulmonary dysplasia). Three human studies, ten animal studies, two laboratory studies, and one combined animal and laboratory study were included. Human evidence was sparse, allowing no conclusions. BPD was not associated with vitamin D receptor polymorphism in a fully adjusted analysis. Animal and laboratory studies showed substantial positive effects of vitamin D on the alveolar type II cell, fibroblast proliferation, surfactant synthesis, and alveolarization. These data support the hypothesis of hypovitaminosis D as a frequent, modifiable risk factor of RDS and BPD, which should be tested in randomized controlled trials on pregnant women, those with threatening preterm delivery, or in the preterm neonates. Future experimental and human studies should aim to identify optimal time windows, vitamin D doses, and cut-off levels for 25-hydroxyvitamin D in interventions against RDS, BPD, and later adverse respiratory outcomes. vitamin D; fetus; lung; surfactant; preterm; neonate THE IMPORTANCE OF VITAMIN D in nonskeletal fetal and childhood health has become increasingly recognized in the last decades (19,65). The impact of vitamin D on early lung development and maturation and lung diseases of early life is an emerging field of research. Hypovitaminosis D during pregnancy is associated with reduced placental development and weight, leading to a presumed risk of preterm birth (24,25), which per se may lead to respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). Moreover, vitamin D is suggested to play a role in the embryogenesis and in cellular growth and differentiation, including lung development and regulation of lung maturation in the fetus (23,29,38,70,71,108), whereby hypovitaminosis D could be hypothesized to aggravate premature neonatal lung diseases.Vitamin D is involved in the development of the innate and adaptive immune system, and, because of its unique capacity to bind to the vitamin D receptor (VDR) and thereby to serve as a transcriptional factor, vitamin D can regulate gene expression and exert widespread immunomodulatory effects including proliferation, differentiation, and complex regulation (19, 56, 58 -61, 64, 65, 68, 69, 105). Evidence suggests that vitamin D may stimulate regulatory T cell development and T cell function to suppress inappropriate Th1 and Th2 responses to environmental exposure (i.e., allergens, infection load), leading to a more balanced immune response inhibiting autoimmune diseases (with Th1 dominance) and allergic diseases (Th2 dominance) (55). Vitamin D could therefore be inv...

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“…First, vitamin D deficiency is recognized worldwide, and there are data indicating that levels have decreased over time, coincident with the rise in autoimmunity and asthma (11). Next, vitamin D has effects on the developing lung (12), and we have shown that vitamin D-related developmental genes are up-regulated in early lung development and that these same genes are linked to asthma (13). Third, vitamin D has effects on a variety of immune processes and cells that are critical to normal immune functioning (14).…”

mentioning

confidence: 87%

Vitamin D, the Gut Microbiome, and the Hygiene Hypothesis. How Does Asthma Begin?

Weiss

Litonjua²

2015

Am J Respir Crit Care Med

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Vitamin D related genes in lung development and asthma pathogenesis

Cited by 63 publications

References 52 publications

Effect of Prenatal versus Postnatal Vitamin D Deficiency on Pulmonary Structure and Function in Mice

Effect of Prenatal versus Postnatal Vitamin D Deficiency on Pulmonary Structure and Function in Mice

The impact of vitamin D on fetal and neonatal lung maturation. A systematic review

Vitamin D, the Gut Microbiome, and the Hygiene Hypothesis. How Does Asthma Begin?

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