Airway diseases such as wheezing and asthma remain a significant clinical problem for infants and children, leading to emergency room visits and reduced quality of life. Asthma is characterized by chronic inflammation resulting in a thickened, hypercontractile airway. Although corticosteroids are effective in reducing inflammation, a substantial cohort of children develops corticosteroid insensitivity with poorly-controlled asthma. Recent studies in other diseases highlight a role for Vitamin D in alleviating inflammation, cell proliferation, and fibrosis. In adults, Vitamin D deficiency correlates to increased asthma, while Vitamin D supplementation can enhance effectiveness of corticosteroids. However, the mechanisms by which Vitamin D and corticosteroids interact to produce beneficial effects, or the role of Vitamin D in neonatal/pediatric asthma, are not known. Our goal is to determine the molecular mechanisms related to corticosteroid insensitivity and Vitamin D in the context of inflammation in the developing airway. Using an in vitro model of developing human airways, we will test the hypothesis that (1) inflammation contributes to corticosteroid insensitivity, and (2) Vitamin D potentiates corticosteroid blunting of inflammation These studies will lay the foundation for pre-clinical in vivo models and novel therapeutic strategies for vitamin supplementation in children with corticosteroid-resistant asthma.

Public Health Relevance

Asthma and wheezing in neonates and children, especially in children born prematurely, is a significant healthcare burden. This problem is exacerbated by the lack of responsiveness in some babies and children to standard therapies such as corticosteroids (steroid-resistant asthma). The intent of this proposal is to understand why developing airways show steroid resistance. Furthermore, the proposal will explore whether a simple and safe therapeutic strategy involving Vitamin D is beneficial. These studies to be conducted in cells from the developing human airway will the set the stage for larger studies in animal models and eventually in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL123075-01
Application #
8709047
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Colombini-Hatch, Sandra
Project Start
2014-05-07
Project End
2015-12-06
Budget Start
2014-05-07
Budget End
2015-05-06
Support Year
1
Fiscal Year
2014
Total Cost
$51,530
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Vogel, Elizabeth R; Britt Jr, Rodney D; Faksh, Arij et al. (2016) Moderate hyperoxia induces extracellular matrix remodeling by human fetal airway smooth muscle cells. Pediatr Res :
Faksh, Arij; Britt Jr, Rodney D; Vogel, Elizabeth R et al. (2016) Effects of antenatal lipopolysaccharide and postnatal hyperoxia on airway reactivity and remodeling in a neonatal mouse model. Pediatr Res 79:391-400
Britt Jr, Rodney D; Thompson, Michael A; Freeman, Michelle R et al. (2016) Vitamin D Reduces Inflammation-induced Contractility and Remodeling of Asthmatic Human Airway Smooth Muscle. Ann Am Thorac Soc 13 Suppl 1:S97-8
Faksh, Arij; Britt Jr, Rodney D; Vogel, Elizabeth R et al. (2016) TLR3 activation increases chemokine expression in human fetal airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 310:L202-11
Vogel, Elizabeth R; Britt Jr, Rodney D; Trinidad, Mari Charisse et al. (2015) Perinatal oxygen in the developing lung. Can J Physiol Pharmacol 93:119-27
Yarova, Polina L; Stewart, Alecia L; Sathish, Venkatachalem et al. (2015) Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med 7:284ra60
Britt Jr, Rodney D; Faksh, Arij; Vogel, Elizabeth R et al. (2015) Vitamin D attenuates cytokine-induced remodeling in human fetal airway smooth muscle cells. J Cell Physiol 230:1189-98
Britt Jr, Rodney D; Thompson, Michael A; Kuipers, Ine et al. (2015) Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 309:L537-42
Pearson, Helen; Britt Jr, Rodney D; Pabelick, Christine M et al. (2015) Fetal human airway smooth muscle cell production of leukocyte chemoattractants is differentially regulated by fluticasone. Pediatr Res 78:650-6
Thompson, Michael A; Britt Jr, Rodney D; Kuipers, Ine et al. (2015) cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle. Biochim Biophys Acta 1853:2506-14