The impact of vitamin D on asthmatic human airway smooth muscle

Abstract

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.

Keywords: Asthma airway hyperresponsiveness airway smooth muscle cells; immunomodulation remodeling vitamin D.

Figure 1. Airway smooth muscle cells in the pathogenesis of asthma

Injury to the airway epithelium, by allergens or environmental factors, lead to the release of mediators that contribute to smooth muscle cell proliferation. Activation of ASM cells by TSLP promotes increased smooth muscle contraction as well as the release of CCL11, IL-6 and IL-8 which recruit inflammatory cells. ASM cells also secrete TSLP which is believed to cat in a paracrine manner. ASM cell also express cell adhesion molecules such as ICAM-1 and VCAM-1 as well as SCF which enables adhesion of mast cells and T-cells to ASM bundle. Mast cells, under the influence of ASM chemokines, undergo degranulation releasing leukotrienes and prostaglandins. These mediators contribute to ASM contraction and ECM deposition which can in turn contribute to airway hyperresponsiveness and airway remodeling in asthma. DC, dendritic cell; Th, T helper; MC, mast cell; TSLP, thymic stromal lymphopoietin; MCP, monocyte chemotactic protein; CCL, chemokine ligand; CXC, C-X-chemokine; ECM, extra cellular matrix; SCF, stem cell factor; CADM, cell adhesion molecule; ICAM, intracellular adhesion molecule; VCAM, vascular cell adhesion molecule; LFA, lymphocyte function-associated antigen; VLA, very late antigen

Figure 2. Immunomodulatory effects of vitamin D on airway smooth muscle cell

Vitamin D from the sunlight or the diet is converted to 25(OH)D₃, the main circulating form, by CYP27A1. It is further hydrolyzed to its active form, 1,25(OH)₂D₃ by CYP27B1which enables binding of the active form to the vitamin D receptor in the cytoplasm. The VDR associates with RXR and is translocated to the nucleus where it can regulate gene expression. In ASM cells, vitamin D has been shown inhibit the progression of the cell cycle thus decreasing ASM proliferation; decrease the production of potent inflammatory mediators such as TNF-α, IL-8 and RANTES which result in reduced chemotaxis of inflammatory cells to the airways. Vitamin D has also been shown to modulate the expression of mediators involved in collagen deposition and airway remodeling. The overall effect of this modulation is decreased inflammation, airway hyperresponsiveness and airway remodeling associated with asthma. VDR, vitamin D receptor; RXR, retinoid X receptor; VDRE, vitamin D response element; ASM, airway smooth muscle; MMP, matrix metalloproteinase; ADAM, a disintegrin metalloprotease; TNF, tumor necrosis factor; TGF, transforming growth factor; RANTES, regulated upon activation, normal T-cell expressed and secreted.