BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is an upper respiratory disease characterized by persistent inflammation of the nasal mucosa. However, the mechanism of abnormal Mucin5AC expression by CRSwNP epithelial cells is not fully understood.ObjectiveWe investigated the potential role of yes‐associated protein (YAP) underlying the mechanism of excessive epithelial Mucin5AC expression in CRSwNP in a hypoxic model.MethodsTissue biopsies of CRSwNP (n = 60), chronic rhinosinusitis without nasal polyps (CRSsNP) (n = 9) and healthy controls (n = 30) were investigated together with a well‐established hypoxic model of primary human nasal epithelial cells (hNECs). The expression levels of hypoxia inducible factor (HIF)‐1α and YAP, and the effect of the signaling axis on mucus secretion in hNECs were analyzed.ResultsWe observed a significant elevated expression levels of YAP in patients with CRSwNP and CRSsNP compared to controls. In addition, HIF‐1α expression of CRSwNP was higher than that of control group. Under hypoxic conditions, HIF‐1α was found to regulate the upregulation of YAP in hNECs. Further investigations revealed that HIF‐1α facilitated the activation and nuclear localization of active‐YAP by reducing the phosphorylation of YAP. This mechanism appeared to be linked to HIF‐1α‐mediated inhibition of LATS 1 phosphorylation and subsequent YAP degradation. HIF‐1α was shown to promote the expression of P63 and the levels of Mucin5AC in hNECs by enhancing YAP activation.ConclusionOur findings indicated that hypoxia enhances YAP activation by decreasing p‐LATS 1 and YAP phosphorylation. This has the potential to impact on the proliferation of basal cells and the differentiation of goblet cells in CRSwNP, ultimately leading to a pathological condition characterized by excessive Mucin5AC expression.

中文翻译：

---

缺氧减少的 YAP 磷酸化增强了慢性鼻-鼻窦炎伴鼻息肉鼻上皮细胞中 Mucin5AC 的表达


背景慢性鼻-鼻窦炎伴鼻息肉 （CRSwNP） 是一种上呼吸道疾病，其特征是鼻粘膜持续炎症。然而，CRSwNP 上皮细胞异常 Mucin5AC 表达的机制尚不完全清楚。目的在缺氧模型中，我们研究了 yes 相关蛋白 （YAP） 在 CRSwNP 中上皮 Mucin5AC 过度表达机制的潜在作用。方法研究了 CRSwNP （n = 60）、无鼻息肉的慢性鼻-鼻窦炎 （CRSsNP） （n = 9） 和健康对照 （n = 30） 的组织活检，以及原代人鼻上皮细胞 （hNEC） 的成熟缺氧模型。分析 hNECs 中缺氧诱导因子 （HIF）‐1α 和 YAP 的表达水平，以及信号轴对粘液分泌的影响。结果与对照组相比，我们观察到 CRSwNP 和 CRSsNP 患者 YAP 的表达水平显著升高。此外，CRSwNP 的 HIF-1α 表达高于对照组。在缺氧条件下，发现 HIF-1α 可调节 hNECs 中 YAP 的上调。进一步的研究表明，HIF-1α 通过减少 YAP 的磷酸化来促进活性 YAP 的激活和核定位。这种机制似乎与 HIF-1α 介导的 LATS 1 磷酸化抑制和随后的 YAP 降解有关。HIF-1α 通过增强 YAP 激活来促进 hNECs 中 P63 的表达和 Mucin5AC 的水平。结论我们的研究结果表明，缺氧通过降低 p-LATS 1 和 YAP 磷酸化来增强 YAP 激活。 这有可能影响 CRSwNP 中基底细胞的增殖和杯状细胞的分化，最终导致以 Mucin5AC 过度表达为特征的病理状况。