Vitamin D Reduces Inflammation-induced Contractility and Remodeling of Asthmatic Human Airway Smooth Muscle

Abstract

BACKGROUND: Although multiple clinical studies have found an association between vitamin D (Vit D) deficiency and asthma, a recent clinical study suggested lack of therapeutic effect of Vit D supplementation. Nonetheless, the mechanisms by which Vit D influences airway structure and function in the context of inflammation and asthma remains undefined. In this regard, Vit D effects on airway smooth muscle (ASM) are important, given the role of this cell type in the hypercontractility and remodeling. We assessed the mechanisms by which Vit D modulates the enhancing effects of proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and IL-13 on intracellular Ca(2+) ([Ca(2+)]i) levels and remodeling in nonasthmatic versus asthmatic human ASM. METHODS: Human ASM was enzymatically isolated from surgical lung specimens of patients with clinically defined mild to moderate asthma versus no asthma. Cells were treated with 10 ng/ml TNF-alpha and 50 ng/ml IL-13 in the presence or absence of 100 nM calcitriol. MEASUREMENTS AND MAIN RESULTS: Interestingly, Vit D receptor (VDR) and retinoic X receptor-alpha levels were maintained, even increased, in subjects with asthma when treated with TNF-alpha and IL-13. Compared with untreated cells, calcitriol blunted the heightened effect of TNF-alpha on [Ca(2+)]i response to histamine in ASM. Calcitriol particularly blunted TNF-alpha and IL-13 effects on collagen and fibronectin deposition, especially in asthmatic ASM. Calcitriol stimulated VDR/retinoic X receptor dimerization and VDR activity even in subjects with asthma and with IL-13, highlighting retained functionality. Expression of Class I histone deacetylases 1-3 (HDAC) and overall HDAC activity were lower in IL-13-exposed ASM, but calcitriol enhanced HDAC expression/activity. CONCLUSIONS: In asthmatic ASM, Vit D functionality is maintained, allowing calcitriol to reduce the procontractile and proremodeling effects of inflammatory cytokines, particularly IL-13, which is relevant to asthma. These findings highlight a potential role for Vit D in asthma pathogenesis, particularly in the context of airway structure and functional changes early in disease.