Role of Vitamin D Metabolism in CRS

慢性鼻-鼻窦炎(CRS)影响着美国16%的人口，几乎没有得到证实的治疗方法。 CRS合并鼻息肉(CRSwNP)是最难治疗的疾病，具有负面影响 生活质量超过其他慢性疾病，如心力衰竭和慢性阻塞性肺疾病 疾病。CRSwNP的特征是2型偏斜的炎症特征和数量增加的 鼻窦成纤维细胞。鉴于其抗炎特性，维生素D3(VD3)可能是一种潜在的新药 CRSwNP的治疗。我们已经证明CRSwNP患者的维生素D系统发生了变化 这不仅仅是饮食或生活方式造成的简单营养缺乏。CRSwNP患者减少了 VD3活性代谢物1，25(OH)2D3的鼻腔水平，尽管其循环形式充足 前体或1，25(OH)2D3本身。此外，人鼻窦上皮细胞(HSNEC)水平的降低 在1α-羟基酶中，负责最终羟化生成1，25(OH)2D3的酶与 更严重的CRSwNP。这些研究的科学前提是确定是否增加地方的 1，25(OH)2D3可减轻鼻腔炎症，可作为CRSwNP的一种潜在治疗方法。在……里面 初步研究发现，1，25(OH)2D3对人鼻窦上皮细胞(HSNEC)有明显的抑制作用。 鼻窦成纤维细胞(HSNF)产生2型介质。虽然HSNF对1，25(OH)2D3有反应，但它们 不能自己代谢，使它们依赖于其他类型的细胞，主要是HSNEC， 作为1，25(OH)2D3的来源。 基于这些和其他数据，我们假设HSNECs的25(OH)D3代谢受损 导致局部1，25(OH)2D3的缺乏，从而推动2型炎症和成纤维细胞的激活 与CRSwNP相关。我们将通过执行以下目标来检验这一假设。目标1 将研究25(OH)D3代谢在HSNEC衍生炎症中的作用，并确定 1，25(OH)2D3调节内源性和外源性刺激炎症的能力 CRSWNP HSNECs。在目标2中，我们将确定人鼻腔上皮细胞25(OH)D3代谢的作用 和1，25(OH)2D3在调节成纤维细胞源性炎症中的作用。在目标3中，我们将在体内测试如何 利用小鼠鼻腔维生素D代谢的改变调节炎症和疾病严重程度 特应性CRS模型。关于结果，这些研究将极大地扩大我们对 局部25(OH)D3代谢调节鼻腔炎症，并将测试其可行性和潜在疗效 鼻腔给药1，25(OH)2D3作为CRSwNP的治疗。除了直接适用于 这些发现对CRSwNP来说，我们的结果可能与其他呼吸系统疾病相关，最明显的是哮喘 和过敏性鼻炎。

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.