MUC16 定义鼻息肉中一种伴糖皮质激素不敏感的纤维化内型

文献信息

中文摘要

背景： 慢性鼻窦炎伴鼻息肉（CRSwNP）是一种异质性炎症性疾病，其中持续的重塑和纤维化可能促成糖皮质激素难治。膜锚定黏蛋白，尤其是 MUC16，可能调控促纤维化和类固醇反应通路。
目的： 确定 MUC16 是否与 CRSwNP 中的纤维化和糖皮质激素不敏感相关，并明确其在成纤维细胞和上皮细胞中的功能效应。
方法： 采用组织学、免疫组化、羟脯氨酸定量和 RT-qPCR 分析来自 CRSwNP 亚组（包括口服糖皮质激素抵抗患者）的鼻息肉组织。原代鼻息肉成纤维细胞和上皮细胞，以及 MRC5、BEAS2B 和 HeLa 细胞，接受 TGF-β1 或 LPS 刺激并以地塞米松处理。使用 siRNA 沉默 MUC16，并评估促纤维化和糖皮质激素反应通路。
结果： 口服糖皮质激素抵抗的息肉表现出最高程度的纤维化（胶原、α-SMA 阳性成纤维细胞、TGF-β1、羟脯氨酸），尽管其并非嗜酸性粒细胞最多。MUC16 在这些息肉中升高，并与羟脯氨酸相关。其成纤维细胞过表达 MUC16，表现出地塞米松对 TGF-β1 诱导的 I 型胶原和增殖的抑制作用减弱。沉默 MUC16 可降低磷酸化 SMAD3 和 Smad 结合元件活性，恢复地塞米松敏感性，并减少增殖。在上皮中，沉默 MUC16 增强地塞米松对 LPS 诱导 IL-6 的抑制，降低 STAT3 磷酸化，并增加糖皮质激素反应元件活性、GR Ser211 磷酸化和 MKP1 诱导。
结论： 在人息肉组织中，MUC16 与纤维化、糖皮质激素不敏感的 CRSwNP 表型相关，而其与糖皮质激素信号受损的因果联系由体外功能缺失实验支持。MUC16 可能为难治性 CRSwNP 的候选生物标志物和潜在治疗靶点，但仍需前瞻性验证其作为内型定义性生物标志物的作用。

英文摘要

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease in which persistent remodeling and fibrosis may contribute to corticosteroid refractoriness. Membrane-tethered mucins, particularly MUC16, may regulate profibrotic and steroid-response pathways.
OBJECTIVES: To determine whether MUC16 is associated with fibrosis and corticosteroid insensitivity in CRSwNP and to define its functional effects in fibroblasts and epithelial cells.
METHODS: Nasal polyp tissue from CRSwNP subgroups, including oral corticosteroid-resistant patients, was analyzed by histology, immunohistochemistry, hydroxyproline quantification, and RT-qPCR. Primary nasal polyp fibroblasts and epithelial cells, and MRC5, BEAS2B, and HeLa cells, were stimulated with TGF-β1 or LPS and treated with dexamethasone. MUC16 was silenced with siRNA, and profibrotic and glucocorticoid-response pathways were evaluated.
RESULTS: Oral corticosteroid-resistant polyps showed the highest fibrosis (collagen, α-SMA-positive fibroblasts, TGF-β1, hydroxyproline), despite not being the most eosinophilic. MUC16 increased in these polyps and correlated with hydroxyproline. Their fibroblasts, overexpressing MUC16, showed reduced dexamethasone inhibition of TGF-β1-induced collagen I and proliferation. MUC16 silencing reduced phospho-SMAD3 and Smad-binding element activity, restored dexamethasone sensitivity, and reduced proliferation. In epithelium, MUC16 silencing enhanced dexamethasone suppression of LPS-induced IL-6, reduced STAT3 phosphorylation, and increased glucocorticoid response element activity, GR Ser211 phosphorylation, and MKP1 induction.
CONCLUSIONS: In human polyp tissue, MUC16 is associated with a fibrotic, corticosteroid-insensitive CRSwNP phenotype, whereas its causal link with impaired glucocorticoid signaling is supported by in vitro loss-of-function experiments. MUC16 may represent a candidate biomarker and potential therapeutic target in refractory CRSwNP, although prospective validation as an endotype-defining biomarker is still required.