Vitamin D Supplementation Reduces Induction of Epithelial-Mesenchymal Transition in Allergen Sensitized and Challenged Mice.

Asthma is a chronic disease of the lung associated with airway hyperresponsiveness (AHR), airway obstruction and airway remodeling. Airway remodeling involves differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal transition (EMT) to intensify the degree of subepithelial fibrosis. EMT involves loss in E-cadherin with an increase in mesenchymal markers, including vimentin and N-cadherin. There is growing evidence that vitamin D has immunomodulatory and anti-inflammatory properties. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we examined the contribution of vitamin D on the AHR, airway inflammation and expression of EMT markers in the airways of mice sensitized and challenged with a combination of clinically relevant allergens, house dust mite, ragweed, and Alternaria (HRA). Female Balb/c mice were fed with vitamin D-sufficient (2000 IU/kg) or vitamin D-supplemented (10,000 IU/kg) diet followed by sensitization with HRA. The density of inflammatory cells in the bronchoalveolar lavage fluid (BALF), lung histology, and expression of EMT markers by immunofluorescence were examined. Vitamin D-supplementation decreased AHR, airway inflammation in the BALF and the features of airway remodeling compared to vitamin D-sufficiency in HRA-sensitized and -challenged mice. This was accompanied with increased expression of E-cadherin and decreased vimentin and N-cadherin expression in the airways. These results indicate that vitamin D may be a beneficial adjunct in the treatment regime in allergic asthma.

The impact of vitamin D on asthmatic human airway smooth muscle.

Asthma is a chronic heterogeneous disorder, which involves airway inflammation, airway hyperresponsiveness (AHR) and airway remodeling. The airway smooth muscle (ASM) bundle regulates the broncho-motor tone and plays a critical role in AHR as well as orchestrating inflammation. Vitamin D deficiency has been linked to increased severity and exacerbations of symptoms in asthmatic patients. It has been shown to modulate both immune and structural cells, including ASM cells, in inflammatory diseases. Given that current asthma therapies have not been successful in reversing airway remodeling, vitamin D supplementation as a potential therapeutic option has gained a great deal of attention. Here, we highlight the potential immunomodulatory properties of vitamin D in regulating ASM function and airway inflammation in bronchial asthma.

Vitamin D regulating TGF-ß induced epithelial-mesenchymal transition.

BACKGROUND: Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma. A critical regulator of fibrosis, transforming growth factor ß (TGF-ß), can induce airway remodeling in epithelial cells through induction of epithelial-mesenchymal transition (EMT). Vitamin D has immunomodulatory functions, however, its effect on controlling subepithelial fibrosis is not known. METHODS: Human bronchial epithelial cells (BEAS-2B) were exposed to calcitriol followed by stimulation with TGF-ß1 or TGF-ß2. The protein expression and mRNA transcripts for E-cadherin, Snail, vimentin, and N-cadherin were analyzed by Western blot and qPCR. An invasion assay and scratch wound assay were performed to identify the migratory properties of the cells following treatments. RESULTS: TGF-ß1 decreased E-cadherin expression and increased protein expression and mRNA transcripts of Snail, vimentin, and N-cadherin together with increased cell invasion and migration. TGF-ß2 elicited migratory response similar to TGF-ß1 but induced the expression of EMT markers differently from that by TGF-ß1. Calcitriol attenuated TGF-ß1- and TGF-ß2-induced cell motility. Also, calcitriol inhibited the expression of EMT markers in TGF-ß1-treated epithelial cells with less effect on TGF-ß2. CONCLUSIONS: These data suggest that calcitriol inhibits both migration and invasion induced by TGF-ß1 and TGF-ß2 in human airway epithelial cells. However, the regulatory effect of vitamin D in epithelial-mesenchymal transition was more effective to TGF-ß1-induced changes. Thus, calcitriol could be a potential therapeutic agent in the prevention and management of subepithelial fibrosis and airway remodeling.

Hematopoietic stem and progenitor cells in inflammation and allergy.

Hematopoietic stem and progenitor cells contribute to allergic inflammation. Pro-inflammatory cytokines that are generated following allergen challenge can impact the differentiation of hematopoietic progenitor cells leading to increased production of effector cells such as eosinophils and basophils, which are key cells involved in the pathogenesis of allergic airway inflammation. Homing of stem cells to the lungs is associated with inflammatory and remodeling changes in asthmatics. Factors that modulate the differentiation and increased migration of stem cells to the site of inflammation in asthma remain to be defined. Stem cells can mature at the site of inflammation in response to inflammatory mediators and other components in the milieu. While the available data suggest that hematopoietic cells traffic to target tissues, the molecular factors underlying in situ differentiation have yet to be specified. Here, we critically evaluate the potential role of hematopoietic progenitors in contributing to the increased immune cell infiltrate in allergic asthma and the factors that drive their differentiation.