ALOX15对过敏性鼻炎患者鼻黏膜上皮紧密连接完整性的调控机制研究

Allergic rhinitis (AR) is a common nasal disease. The resent studies demonstrated that the disruption of nasal epithelial tight junction may play a key role in pathogenesis of AR. Arachidonate 15-lipoxygenase (ALOX15) is a kind of pivotal enzyme involved in the metabolism of arachidonate and it is highly associated with the Th2 airway disease. Our previous study found that: ALOX15 disrupted the nasal epithelial tight junction in the eosinophilic chronic rhinosinusitis (ECRS), whose pathogenesis was similar with AR. However, if ALOX15 disrupted the nasal epithelial tight junction of AR is unclear. Therefore, we hypothesized that ALOX15 disrupts the nasal epithelial tight junction of AR via Th2 cytokines. In this present study, we will construct Dermatophagoides pteronyssinus (Der p) induced AR nasal epithelial culture model. Epitheliums from AR mucosa were studied by technologies of cytology, immunology and molecular biology. The study will investigate ALOX15 function in AR pathogenesis and may find new target in the AR treatment.

过敏性鼻炎（AR）的发生发展与Th2炎症反应、鼻黏膜上皮紧密连接的破坏密切相关。花生四烯酸-15-脂加氧酶（ALOX15）是花生四烯酸的重要代谢酶，和Th2通路共同参与呼吸道黏膜炎性疾病的调控。申请人课题组已证实，ALOX15有破坏嗜酸性粒细胞鼻窦炎（ECRS）患者鼻黏膜上皮紧密连接的作用，但ALOX15是否影响AR鼻黏膜上皮紧密连接功能尚不明确。因此，本项目假设：ALOX15介导Th2通路，破坏AR患者鼻黏膜上皮紧密连接的完整性，从而促进AR的发病。本研究以AR患者鼻黏膜上皮细胞为切入点，构建屋尘螨刺激的鼻黏膜损伤模型，通过细胞学、免疫学、分子生物学等技术，明确ALOX15是否介导Th2细胞因子，对于AR患者鼻黏膜上皮紧密连接的完整性产生破坏作用，并探讨其分子机制。可能为AR提供新的治疗靶点。

过敏性鼻炎（Allergic rhinitis, AR）是一种常见的鼻黏膜慢性炎症性疾病，在全世界发病率非常高，会造成严重的社会负担和经济负担。鼻黏膜上皮屏障破坏是AR的重要特点。本项目探究ALOX15介导Th2炎症通路，对于紧密连接蛋白的调控机制，期望为AR提供新的治疗靶点。本研究采用细胞体外培养技术结合免疫和分子生物学技术，利用鼻黏膜上皮体外模型，从细胞、蛋白和基因水平，研究ALOX15对于AR鼻黏膜上皮紧密连接完整性的影响。我们的研究结果发现：1）ALOX15可介导Th2（IL-4,5,13）细胞因子，破坏AR患者鼻黏膜上皮紧密连接的完整性；2）ALOX15可通过紧密连接蛋白（Claudin-1,4,7, Occludin）的表达水平，调控AR鼻黏膜上皮紧密连接完整性；3）P物质、血管活性肠肽和降钙素基因相关肽等神经肽在过敏性鼻结膜炎（Allergic rhinoconjunctivitis, ARC）ARC发病机制中所发挥重要作用，且鼻部神经递质和神经肽可能比眼源性神经递质和神经肽具有更重要的作用；4）过敏性结膜炎（Allergic conjunctivitis, AC）泪液中的特异性IgE水平是否可以用于评判疾病的严重程度，并可预测AC的药物疗效；5）提出了慢性鼻炎鼻腔干燥的客观诊断标准。本项目明确了ALOX15介导Th2炎症通路，对于紧密连接蛋白的调控机制，从而为临床治疗AR提供新的治疗靶点。