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

Abstract

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.

Maternal and neonatal 25‐hydroxyvitamin D concentrations and school‐age lung function, asthma and allergy. The Generation R Study

“…Genomic studies showed that 1,25‐dihydroxyvitamin D, the biologically active form, already in these stages of lung development influences the expression of genes, which have previously been associated with lung development and asthma pathogenesis . Furthermore, in vivo mice studies reported that in utero 25‐hydroxyvitamin D deficiency can result in a reduced lung volume, a diminished tracheal diameter and alveolar simplification, as well an altered lung function with increased airway resistance and decreased pulmonary compliance . Our observations that higher 25‐hydroxyvitamin D concentrations are associated with a higher FVC are in line with these studies.…”

Prenatal vitamin D status and respiratory and allergic outcomes in childhood: A meta‐analysis of observational studies

“…Experimental and human studies have revealed vitamin D to play a key role in lung maturation by modulating type II alveolar cell differentiation and by stimulating surfactant synthesis and release . Antenatal vitamin D deficiency impairs airway and alveolar development and limits lung function in mice . Moreover, vitamin D deficiency may provoke proliferation and hypertrophy of smooth muscle, contributing to airway remodeling and increased airway smooth muscle mass …”

“…[62][63][64][65] Antenatal vitamin D deficiency impairs airway and alveolar development and limits lung function in mice. 9 Moreover, vitamin D deficiency may provoke proliferation and hypertrophy of smooth muscle, contributing to airway remodeling and increased airway smooth muscle mass. 66 Thus, an adequate prenatal vitamin D status could turn into beneficial effects on lung function and reduction in lung reactivity to diverse environmental triggers.…”

Maternal and Foetal Health Implications of Vitamin D Status during Pregnancy

“…First, VDRs are present in immune cells and the airways [86]. Second, vitamin D plays multiple effects on foetal maturation and the developing immune system [87,88]. Third, polymorphisms in VDR and metabolism genes are associated with childhood asthma susceptibility [89,90].…”