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.
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.