Vitamin D treatment improves survival and infant lung structure after intra-amniotic endotoxin exposure in rats: potential role for the prevention of bronchopulmonary dysplasia

Mandell, Erica W.; Seedorf, Gregory J.; Gien, Jason

doi:10.1152/ajplung.00344.2013

Cited by 64 publications

(62 citation statements)

References 46 publications

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“…These findings along with our previous findings in this model (23,37) demonstrate the important balance between proximal and distal artery development in infant pulmonary hemodynamics. Intra-amniotic ETX elevates pulmonary mean and systolic pressures, leading to increased proximal artery stiffness, total PVRI, and total PVSI.…”

Section: Discussionsupporting

confidence: 88%

“…We tested this hypothesis in our model of chorioamnionitis in infant lung development by measuring antenatal ETX effects on RV and PA dysfunction. Our results show that chorioamnionitis leads to pulmonary hypertension characterized by increased impedance due to increased proximal stiffening and increased PVR due to previously shown decreased distal vasculature (23,37) causing RV afterloads and workloads. Furthermore, we studied the effects of vit D therapy with ETX exposure.…”

Section: Discussionsupporting

confidence: 61%

“…The Institutional Animal Care and Use Committee at the University of Colorado Denver Anschutz Medical Campus approved all procedures and protocols. We utilized an animal model of chorioamnionitis as previously described (37) and vit D therapy as also previously described (23). In short, timed pregnant SpragueDawley rats were purchased from Charles River Laboratories (Wilmington, MA) and maintained in room air at Denver altitude (1,600 m; barometric pressure 630 mmHg; inspired oxygen tension 122 mmHg) for 1 wk prior to full term.…”

Section: Methodsmentioning

confidence: 99%

“…Using a rat model of chorioamnionitis caused by intrauterine amniotic exposure to endotoxin (ETX), we previously reported high mortality at birth, PH as assessed by right ventricular hypertrophy (RVH), and decreased distal alveolar and vascular growth (37). Vit D treatment reduces mortality, decreases RVH, and increases distal alveolar and vascular growth in this model (23). But whether antenatal [intra-amniotic (IA)] ETX impairs right ventricular performance, proximal PA stiffness, and ECM development in the lung and the impact of early vit D therapy remains unknown.…”

mentioning

confidence: 99%

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Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy

Mandell

Powers

Harral

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intraamniotic injections of ETX, ETXϩvit D, or saline at 20 days gestation (term ϭ 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased ␣-elastin, lysyl oxidase, collagen I, and collagen III proteins (P Ͻ 0.05) compared control and ETXϩvit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P Ͻ 0.05 vs. control and ETXϩvit D) and elastic potential energy (P Ͻ 0.05 vs. control and ETXϩvit D). Mechanical stiffness and ECM remodeling are increased in the PA (P Ͻ 0.05 vs. control and ETXϩvit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.chorioamnionitis; bronchopulmonary dysplasia; extracellular matrix; vascular remodeling; arterial stiffening CHANGES IN HEMODYNAMIC COMPONENTS, such as pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload, to the pathogenesis of pulmonary hypertension (PH) as bronchopulmonary dysplasia (BPD) in the neonate are not well defined and could offer insight into the mechanisms of the disease and treatment. PVR, a measure of heart workload, is a long established measure of pulmonary hypertension progression (1,2,15,16,31). PVR measures the resistance to flow and clinically describes the degree of vasoconstriction or angiogenic development of the distal vasculature. More recently, proximal PA stiffness has increasing interest as an important indicator of disease progression (20,32,35,36). Proximal PA stiffness through extracellular matrix (ECM) remodeling increases impedance that increase RV afterload (9,14). Both PVR and impedance components contribute to the pathogenesis and RV dysfunction in PH (35) but are poorly understood in the setting of BPD. Furthermore, neonatal complications of BPD have been clinically associated with global RV structural and functional differences in adult life (21), motivating the need to understand RV-PA function in the neonate.Chorioamnionitis, a disease characterized...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy

Mandell

Powers

Harral

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In a study from 2014, Mandell et al (59) examined the effects of vitamin D on neonatal rat pup survival after antenatal endotoxin injection and on isolated endothelial and ATII cells. Pregnant Sprague-Dawley rats received intra-amniotic injections at 20 days of gestation.…”

Section: Resultsmentioning

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

119

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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Research progress of microvascular development in bronchopulmonary dysplasia

Zhang,

Du,

Zhang

et al. 2024

Pediatric Investigation

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Bronchopulmonary dysplasia (BPD) is a chronic lung disease that arises during the neonatal period, and its underlying mechanisms are still not fully understood. The disorder of microvascular development plays a significant role in the development of BPD. This article presents a comprehensive review of the advancements made in understanding the mechanisms and treatment approaches related to microvascular development in the pathogenesis of BPD.

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Vitamin D treatment improves survival and infant lung structure after intra-amniotic endotoxin exposure in rats: potential role for the prevention of bronchopulmonary dysplasia

Cited by 64 publications

References 46 publications

Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy

Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy

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

Research progress of microvascular development in bronchopulmonary dysplasia

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