Meng Lingzhao, Qu Xiaopeng, Tao Pengyu, Dong Jiajia, Guo Rui
Department of Otolaryngology Head and Neck Surgery, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.
Mol Biotechnol. 2024 Sep 6. doi: 10.1007/s12033-024-01269-5.
Chronic rhinosinusitis (CRS) is a common chronic inflammatory upper respiratory tract, has a major subtype of CRS without nasal polyps (CRSsNP), constituting a great global health problem. Quercetin exerts the important roles in several inflammatory diseases. However, its function in CRSsNP remains unclear. In this study, quercetin dose-dependently alleviated allergic nasal symptoms of increased frequencies of sneezing and nasal scratching in Staphylococcus aureus-constructed CRSsNP mice. Importantly, quercetin attenuated the histopathological changes of nasal mucosa tissue in model mice, including mucosal thickening, glandular hyperplasia, noticeable mast cells, and inflammatory cell infiltration. Concomitantly, quercetin alleviated the increased mucosal inflammation in CRSsNP mice by suppressing the transcripts and releases of pro-inflammatory IL-1β, IL-6, and IL-4. Notably, quercetin restrained X-box binding protein 1 (XBP1)-mediated activation of the HIF-1α/wnt-β-catenin axis in nasal mucosal tissues in CRSsNP model. Intriguingly, intranasal instillation of Lv-XBP1 offset the protective efficacy of quercetin against the progression of CRSsNP by suppressing the production of inflammatory cytokine IL-1β, IL-6, and IL-4, frequency of sneezing and nasal scratching, and histopathological changes of nasal mucosa tissues. In vitro, higher expression of XBP1 was observed in human nasal epithelial cells (HNECs) of CRSsNP relative to the normal HNECs. Moreover, elevation of XBP1 by Lv-XBP1 treatment suppressed cell proliferation and increased apoptosis of CRSsNP HNECs. Mechanistically, XBP1 overexpression increased the expression of HIF-1α and β-catenin, indicating the activation of the HIF-1α/wnt-β-catenin axis. Nevertheless, treatment with quercetin inhibited XBP1-induced cell apoptosis and reversed XBP1-mediated inhibition in cell proliferation in HNECs, as well as the activation of the HIF-1α/wnt-β-catenin axis. Thus, these findings reveal that quercetin may attenuate the progression of CRSsNP by inhibiting nasal mucosal inflammation and epithelial barrier dysfunction via blocking the XBP1/HIF-1α/wnt-β-catenin pathway, supporting a promising agent against CRSsNP.
慢性鼻窦炎（CRS）是一种常见的慢性炎症性上呼吸道疾病，其主要亚型为无鼻息肉的慢性鼻窦炎（CRSsNP），这是一个全球性的重大健康问题。槲皮素在多种炎症性疾病中发挥重要作用。然而，其在CRSsNP中的功能仍不清楚。在本研究中，槲皮素剂量依赖性地减轻了金黄色葡萄球菌构建的CRSsNP小鼠中打喷嚏频率增加和鼻搔抓等变应性鼻症状。重要的是，槲皮素减轻了模型小鼠鼻黏膜组织的组织病理学变化，包括黏膜增厚、腺体增生、明显的肥大细胞和炎症细胞浸润。同时，槲皮素通过抑制促炎细胞因子IL-1β、IL-6和IL-4的转录和释放，减轻了CRSsNP小鼠黏膜炎症的增加。值得注意的是，槲皮素抑制了CRSsNP模型鼻黏膜组织中X盒结合蛋白1（XBP1）介导的HIF-1α/wnt-β-连环蛋白轴的激活。有趣的是，鼻内滴注Lv-XBP1通过抑制炎症细胞因子IL-1β、IL-6和IL-4的产生、打喷嚏和鼻搔抓频率以及鼻黏膜组织的组织病理学变化，抵消了槲皮素对CRSsNP进展的保护作用。在体外，相对于正常人类鼻上皮细胞（HNECs），CRSsNP患者的HNECs中观察到XBP1的表达更高。此外，通过Lv-XBP1处理提高XBP1水平可抑制CRSsNP患者HNECs的细胞增殖并增加其凋亡。机制上，XBP1过表达增加了HIF-1α和β-连环蛋白的表达，表明HIF-1α/wnt-β-连环蛋白轴被激活。然而，槲皮素处理可抑制XBP1诱导的细胞凋亡，并逆转XBP1介导的HNECs细胞增殖抑制以及HIF-1α/wnt-β-连环蛋白轴的激活。因此，这些发现表明，槲皮素素可能通过阻断XBP1/HIF-1α/wnt-β-连环蛋白途径抑制鼻黏膜炎症和上皮屏障功能障碍，从而减轻CRSsNP的进展，这支持了槲皮素是一种有前景的抗CRSsNP药物。
