Role of Vitamin D Metabolism in CRS

慢性鼻窦炎（CRS）影响了16%的美国人口，几乎没有经过验证的治疗方法。 CRS伴鼻息肉（CRSwNP）是最难治疗的疾病形式，具有负面影响 对生活质量的影响超过其他慢性疾病，如心力衰竭和慢性阻塞性肺疾病 疾病CRSwNP的特征在于2型偏斜的炎性特征和增加的炎性细胞数目。 鼻窦成纤维细胞鉴于其抗炎特性，维生素D3（VD 3）可能是一种潜在的新药物。 治疗CRSwNP。我们已经证明CRSwNP患者的维生素D系统发生了改变， 这不仅仅是由饮食或生活方式引起的简单营养缺乏。CRSwNP患者减少 尽管VD 3的活性代谢物1，25（OH）2D 3有足够的循环形式， 前体或1，25（OH）2D 3本身。此外，人鼻窦上皮细胞（HSNEC）水平的降低 1α-羟化酶（负责最终羟基化生成1，25（OH）2D 3的酶）与 更严重的CRSwNP。这些研究的科学前提是确定增加当地的 1，25（OH）2D 3可以减轻鼻窦炎症，并作为CRSwNP的潜在治疗方法。在 初步研究，我们观察到1，25（OH）2D 3减少人鼻窦上皮细胞（HSNEC）， 鼻窦成纤维细胞（HSNF）产生2型介质。虽然HSNF可以响应1，25（OH）2D 3，但它们 不能自行代谢，只能依赖其他细胞类型，主要是HSNEC， 作为1，25（OH）2D 3的来源。 基于这些和其他数据，我们假设HSNECs 25（OH）D3代谢受损 导致1，25（OH）2D 3的局部缺乏，从而驱动2型炎症和成纤维细胞活化 与CRSwNP有关。我们将通过执行以下目标来检验这一假设。要求1 将检查25（OH）D3代谢对HSNEC衍生炎症的贡献，并确定25（OH）D3代谢对HSNEC衍生炎症的影响。 1，25（OH）2D 3调节内源性和外源性刺激炎症的能力， CRSwNP HSNEC。在目的2中，我们将确定人鼻窦上皮25（OH）D3代谢的作用， 和1，25（OH）2D 3在调节成纤维细胞衍生的炎症中的作用。在目标3中，我们将在体内测试， 利用小鼠模型研究鼻腔鼻窦维生素D代谢的改变对炎症和疾病严重程度的调节作用 特应性CRS模型。关于结果，这些研究将极大地扩展我们对如何 局部25（OH）D3代谢调节鼻窦炎症，并将测试可行性和潜在疗效 鼻窦递送1，25（OH）2D 3作为CRSwNP的治疗。除了直接适用于 这些发现对CRSwNP，我们的结果可能与其他呼吸系统疾病，特别是哮喘有关 过敏性鼻炎

Chronic rhinosinusitis (CRS) affects 16% of the United States' population with few proven treatments. CRS with nasal polyps (CRSwNP) is the most difficult form of the disease to treat and has a negative impact on quality of life that exceeds other chronic conditions, such as heart failure and chronic obstructive pulmonary disease. CRSwNP is characterized by a type 2 skewed inflammatory profile and increased numbers of sinonasal fibroblasts. Given its anti-inflammatory properties, vitamin D3 (VD3) may serve as a potential novel treatment for CRSwNP. We have shown that patients with CRSwNP have alterations to the vitamin D system that extends beyond a simple nutrient deficiency caused by diet or lifestyle. CRSwNP patients have reduced sinonasal levels of the active metabolite of VD3, 1,25(OH)2D3, despite adequate circulating forms of its precursors or 1,25(OH)2D3 itself. Furthermore, reductions in human sinonasal epithelial cell (HSNEC) levels of 1α-hydroxylase, the enzyme responsible for the final hydroxylation to make 1,25(OH)2D3, is associated with more severe CRSwNP. The scientific premise of these studies is to determine if increasing local levels of 1,25(OH)2D3 can reduce sinonasal inflammation and serve as a potential treatment for CRSwNP. In preliminary studies, we observed that 1,25(OH)2D3 reduced human sinonasal epithelial cell (HSNEC) and sinonasal fibroblast (HSNF) production of type 2 mediators. While HSNF can respond to 1,25(OH)2D3, they are not capable of metabolizing it themselves, leaving them dependent on other cell types, mainly HSNECs, as a source of 1,25(OH)2D3. Based on these and other data, we hypothesize that impaired 25(OH)D3 metabolism by HSNECs results in local deficiencies in 1,25(OH)2D3, thereby driving the type 2 inflammation and fibroblast activation associated with CRSwNP. We will test this hypothesis through the execution of the following aims. Aim 1 will examine the contribution of 25(OH)D3 metabolism to HSNEC-derived inflammation and determine the ability of 1,25(OH)2D3 to modulate endogenous and exogenously-stimulated inflammation by control and CRSwNP HSNECs. In Aim 2 we will determine the role of human sinonasal epithelial 25(OH)D3 metabolism and 1,25(OH)2D3 in the regulation of fibroblast-derived inflammation. In Aim 3 we will test, in vivo, how alterations in sinonasal vitamin D metabolism regulates inflammation and disease severity utilizing a murine model of atopic CRS. With respect to outcomes, these studies will greatly expand our understanding of how local 25(OH)D3 metabolism regulates sinonasal inflammation and will test the feasibility and potential efficacy of sinonasal delivery of 1,25(OH)2D3 as a treatment for CRSwNP. In addition to the direct applicability of these findings to CRSwNP, our results may be relevant to other respiratory diseases, most notably to asthma and allergic rhinitis.