Role of Vitamin D Metabolism in CRS

维生素 D 代谢在 CRS 中的作用

• 批准号: 10158396
• 负责人: Jennifer Konopa Mulligan
• 金额: $ 47.97万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158396
• 关键词: Affect; Allergic rhinitis; Anti-Inflammatory Agents; Antigens; Aspergillus fumigatus; Asthma; Automobile Driving; CYP27B1 gene; Cell physiology; Cell secretion; Cholecalciferol; Chronic; Chronic Obstructive Airway Disease; Chronic Sinusitis; Data; Diet; Disease; Enzymes; Epithelial; Epithelial Cells; FGF2 gene; Fibroblasts; Heart failure; Human; Hydroxylation; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Investigation; Life Style; Lung diseases; Mediator of activation protein; Metabolism; Mixed Function Oxygenases; Mus; Nasal Polyps; Nutrient; Outcome Study; Patients; Permeability; Phenotype; Population; Production; Property; Quality of life; Regulation; Respiratory physiology; Role; Severity of illness; Source; Steroids; Symptoms; System; Testing; United States; Vitamin D; airway epithelium; airway inflammation; base; cell type; chemokine; chronic rhinosinusitis; cytokine; efficacy testing; feasibility testing; improved; in vivo; insight; mouse model; novel; prevent; vitamin metabolism

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.

慢性鼻窦炎 (CRS) 影响着 16% 的美国人口，且几乎没有经过验证的治疗方法。 伴有鼻息肉的慢性鼻窦炎 (CRSwNP) 是最难治疗的疾病，并且会产生负面影响 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 CRSwNP 的特点是 2 型炎症特征和数量增加。 鉴于其抗炎特性，维生素 D3 (VD3) 可能成为一种潜在的新型药物。 CRSwNP 的治疗 我们已经证明，CRSwNP 患者的维生素 D 系统发生了改变。 不仅仅是由饮食或生活方式引起的简单营养缺乏，CRSwNP 患者的患病率也有所降低。 VD3 活性代谢物 1,25(OH)2D3 的鼻腔水平，尽管其有足够的循环形式 前体或 1,25(OH)2D3 本身此外，人鼻腔上皮细胞 (HSNEC) 水平降低。 1α-羟化酶（负责最终羟基化以生成 1,25(OH)2D3 的酶）与 这些研究的科学前提是确定是否会增加当地的 CRSwNP 水平。 1,25(OH)2D3 可以减轻鼻窦炎症，并可作为 CRSwNP 的潜在治疗方法。 初步研究，我们观察到 1,25(OH)2D3 减少了人鼻腔上皮细胞 (HSNEC) 和 鼻腔成纤维细胞 (HSNF) 产生 2 型介质 虽然 HSNF 可以响应 1,25(OH)2D3，但它们 自身无法代谢它，使它们依赖于其他细胞类型，主要是 HSNEC， 作为 1,25(OH)2D3 的来源。 基于这些和其他数据，我们勇敢地承认 HSNEC 的 25(OH)D3 代谢受损 导致 1,25(OH)2D3 局部缺乏，从而驱动 2 型炎症和成纤维细胞活化 我们将通过执行以下目标 1 来检验这一假设。 将检查 25(OH)D3 代谢对 HSNEC 衍生炎症的贡献，并确定 1,25(OH)2D3 通过控制和调节内源性和外源性刺激炎症的能力 CRSwNP HSNEC 在目标 2 中，我们将确定人鼻腔上皮 25(OH)D3 代谢的作用。 和 1,25(OH)2D3 在调节成纤维细胞衍生的炎症中的作用 在目标 3 中，我们将在体内测试如何调节。 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 就结果而言，这些研究将极大地扩展我们对特应性 CRS 模型的理解。 局部25(OH)D3代谢调节鼻腔炎症，将测试可行性和潜在功效 除了直接应用 1,25(OH)2D3 作为 CRSwNP 的治疗方法之外。 这些针对 CRSwNP 的发现，我们的结果可能与其他呼吸系统疾病相关，尤其是哮喘 和过敏性鼻炎。