Duan Su, Han Xinling, Jiao Jian, Wang Ming, Li Ying, Wang Yang, Zhang Luo
Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China.
Clin Exp Allergy. 2023 Apr;53(4):443-454. doi: 10.1111/cea.14258. Epub 2022 Dec 1.
Studies have independently indicated that eosinophils and histone deacetylases (HDACs) may compromise the integrity of the epithelial barrier in nasal polyps; however, the underlying mechanisms are not clear. In this study, we aimed to investigate the role of eosinophilia and HDACs in regulation of tight junctions (TJs) and nasal epithelial barrier integrity in chronic rhinosinusitis with nasal polyps (CRSwNP) patients.
Expression of mRNAs and proteins of TJs and HDACs of biopsy specimens and air-liquid interface (ALI) human nasal epithelial cell cultures (HNECs) from eosinophilic and noneosinophilic CRSwNP patients and healthy controls was assessed. The ALI HNECs were also assessed for changes in transepithelial electrical resistance (TER) and paracellular flux of fluorescein isothiocyanate (FITC)-labelled dextran. Meanwhile, the assessments for the effect of HDAC inhibitor in eosinophilic nasal polyps were also conducted.
Decreased TER and increased paracellular flux of FITC-labelled dextran in the ALI cultures were found in both eosinophilic and noneosinophilic CRSwNP, along with irregular, patchy and reduced expression of claudin-1, 4, 7, occludin, zonula occludens (ZO)-1 and ZO-2 and increased expression of HDAC1, 9 and SIRT7 for both ALI culture cells and biopsy specimens, especially for the eosinophilic CRSwNP group. Treatment of eosinophilic CRSwNP ALI-HNECs with an HDAC inhibitor improved the TJs expression and epithelial barrier integrity.
Our data suggest that eosinophilia and HDACs influence epithelial barrier function in CRSwNP patients by regulating TJ protein expression. Targeting HDACs with specific inhibitors may be a potential treatment option for patients with eosinophilic CRSwNP.
多项研究独立表明，嗜酸性粒细胞和组蛋白去乙酰化酶（HDACs）可能会破坏鼻息肉上皮屏障的完整性；然而，其潜在机制尚不清楚。在本研究中，我们旨在探讨嗜酸性粒细胞增多和HDACs在慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）患者紧密连接（TJs）调节及鼻上皮屏障完整性中的作用。
评估来自嗜酸性粒细胞性和非嗜酸性粒细胞性CRSwNP患者及健康对照的活检标本和气液界面（ALI）人鼻上皮细胞培养物（HNECs）中TJs和HDACs的mRNA和蛋白表达。还评估了ALI HNECs的跨上皮电阻（TER）变化以及异硫氰酸荧光素（FITC）标记的葡聚糖的细胞旁通量。同时，也进行了HDAC抑制剂对嗜酸性粒细胞性鼻息肉作用的评估。
在嗜酸性粒细胞性和非嗜酸性粒细胞性CRSwNP的ALI培养物中均发现TER降低以及FITC标记的葡聚糖的细胞旁通量增加，ALI培养细胞和活检标本中claudin-1、4、7、闭合蛋白、闭锁小带（ZO）-1和ZO-2的表达不规则、呈斑片状且减少，HDAC1、9和SIRT7的表达增加，尤其是嗜酸性粒细胞性CRSwNP组。用HDAC抑制剂处理嗜酸性粒细胞性CRSwNP的ALI-HNECs可改善TJs表达和上皮屏障完整性。
我们的数据表明，嗜酸性粒细胞增多和HDACs通过调节TJ蛋白表达影响CRSwNP患者的上皮屏障功能。用特异性抑制剂靶向HDACs可能是嗜酸性粒细胞性CRSwNP患者的一种潜在治疗选择。
