Britt Rodney D, Faksh Arij, Vogel Elizabeth R, Thompson Michael A, Chu Vivian, Pandya Hitesh C, Amrani Yassine, Martin Richard J, Pabelick Christina M, Prakash Y S
Departments of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
J Cell Physiol. 2015 Jun;230(6):1189-98. doi: 10.1002/jcp.24814.
Asthma in the pediatric population remains a significant contributor to morbidity and increasing healthcare costs. Vitamin D3 insufficiency and deficiency have been associated with development of asthma. Recent studies in models of adult airway diseases suggest that the bioactive Vitamin D3 metabolite, calcitriol (1,25-dihydroxyvitamin D3 ; 1,25(OH)2 D3 ), modulates responses to inflammation; however, this concept has not been explored in developing airways in the context of pediatric asthma. We used human fetal airway smooth muscle (ASM) cells as a model of the early postnatal airway to explore how calcitriol modulates remodeling induced by pro-inflammatory cytokines. Cells were pre-treated with calcitriol and then exposed to TNFα or TGFβ for up to 72 h. Matrix metalloproteinase (MMP) activity, production of extracellular matrix (ECM), and cell proliferation were assessed. Calcitriol attenuated TNFα enhancement of MMP-9 expression and activity. Additionally, calcitriol attenuated TNFα and TGFβ-induced collagen III expression and deposition, and separately, inhibited proliferation of fetal ASM cells induced by either inflammatory mediator. Analysis of signaling pathways suggested that calcitriol effects in fetal ASM involve ERK signaling, but not other major inflammatory pathways. Overall, our data demonstrate that calcitriol can blunt multiple effects of TNFα and TGFβ in developing airway, and point to a potentially novel approach to alleviating structural changes in inflammatory airway diseases of childhood.
儿童哮喘仍然是导致发病和医疗成本不断增加的一个重要因素。维生素D3不足和缺乏与哮喘的发生有关。最近在成人气道疾病模型中的研究表明，生物活性维生素D3代谢物骨化三醇（1,25 - 二羟基维生素D3；1,25(OH)2 D3）可调节对炎症的反应；然而，在儿童哮喘背景下的发育中的气道中，这一概念尚未得到探索。我们使用人胎儿气道平滑肌（ASM）细胞作为出生后早期气道的模型，以探讨骨化三醇如何调节促炎细胞因子诱导的重塑。细胞先用骨化三醇预处理，然后暴露于TNFα或TGFβ长达72小时。评估基质金属蛋白酶（MMP）活性、细胞外基质（ECM）的产生和细胞增殖。骨化三醇减弱了TNFα对MMP - 9表达和活性的增强作用。此外，骨化三醇减弱了TNFα和TGFβ诱导的胶原蛋白III表达和沉积，并且分别抑制了由任何一种炎症介质诱导的胎儿ASM细胞增殖。信号通路分析表明骨化三醇对胎儿ASM细胞的作用涉及ERK信号通路，但不涉及其他主要炎症通路。总体而言，我们的数据表明骨化三醇可以减弱TNFα和TGFβ在发育中的气道中的多种作用，并指出了一种缓解儿童炎症性气道疾病结构变化的潜在新方法。
