ALOX15在慢性鼻窦炎伴鼻息肉黏膜组织重塑中的功能与机制研究

Sustained mucosal remodeling in injury-repair cycle of nasal epithelial cells refers to continuous epithelial-to-mesenchymal transition(EMT), which leads to poor resting barrier function and is one of the most crucial pathogenesis for chronic rhinosinusitis with nasal polyps(CRSwNP). Eosinophils infiltration plays an important role in the procedure, however, the molecules involved are not fully understood. Our previous research found that: 1. Compared with noneosinophilic CRSwNP (nonECRSwNP) and healthy control(HC), EMT was enhanced in eosinophilic CRSwNP(ECRSwNP); 2. Th2 cytokines could regulate mucosal remodeling gene expression; 3. The protein and mRNA level of Arachidonate 15-lipoxygenase(ALOX15) was significantly increased in ECRSwNP compared to both nonECRSwNP and HC; 4. Th2 cytokines could induce ALOX15 expression; 5. ALOX15 inhibitor could suppress EMT. The data indicate that ALOX15 may play functions in Th2-induced mucosal remodeling. In this study, we will construct adenovirus mediated overexpression or knock-down of ALOX15 to study the function on mucosal remodeling. Epitheliums from polyps or mucosa were studied by technologies of immunology and molecular biology. The study will investigate ALOX15 function in mucosal remodeling, explore the mechanism of different subtype of CRSwNP.

鼻黏膜上皮修复障碍是慢性鼻窦炎伴鼻息肉（CRSwNP）的重要发病机制，表现为持续性黏膜重塑，即上皮细胞不断向间质细胞转化（EMT），无法形成紧密连接发挥屏障功能。目前认为嗜酸性粒细胞在其中发挥作用，但机理不明确。本团队前期研究表明1.嗜酸性粒细胞型CRSwNP（ECRSwNP）EMT增强；2.Th2因子调节重塑；3.ALOX15在ECRSwNP中表达显著增高，且与重塑相关分子表达相关；4.Th2因子促进ALOX15表达；5.ALOX15抑制剂能抑制EMT。据此提示ALOX15在Th2介导的鼻黏膜重塑中发挥作用。本课题以鼻息肉及正常黏膜上皮为研究对象，构建ALOX15过表达及敲减（knock-down）腺病毒，应用免疫学及分子生物学手段，探索ALOX15在鼻黏膜修复中的功能与机制。本研究对全面理解ALOX15对鼻黏膜组织重塑的作用，深入挖掘不同亚型CRSwNP的发病机制有重要意义。

慢性鼻窦炎伴鼻息肉（Chronic rhinosinusitis with nasal polyps, CRSwNP）是鼻科常见慢性炎性疾病，世界范围内患病率约为4.3%，以鼻黏膜2型炎症及组织重塑为显著病理特征。花生四烯酸15-脂氧合酶（arachidonate 15-lipoxygenase, ALOX15）是近年新发现的2型炎症标志物，团队前期研究表明ALOX15能促进鼻黏膜重塑，机制尚不清楚，且不同慢性鼻窦炎亚型中其代谢产物谱差异及与临床特征的相关性也不明确。采用靶向代谢方式检测不同类型CRSwNP的代谢差异，在嗜酸性粒细胞增多的CRSwNP中ALOX15代谢通路被异常活化，其代谢产物15S-HETE显著增高。进一步通过含有15S-HETE的培养基对鼻息肉来源的原代上皮细胞培养，观察15S-HETE对上皮的作用，发现其对上皮重塑的作用，TGF-beta在其中发挥调控作用。嗜酸性粒细胞增多的CRSwNP是最易复发的类型，通过病例对照研究探索ALOX15在ECRSwNP、nonECRSwNP及健康对照组中表达及对ECRSwNP的预测意义，发现ALOX15能预测ECRSwNP并具有高度的精确性，而ALOX15与血嗜酸细胞联合可提高预测ECRSwNP的精确性。上述研究结果表明，ALOX15mRNA水平或与血嗜酸性粒细胞联合可能是预测ECRSwNP诊断的可靠生物学标记物。