Liu Peiqiang, Fan Wenjun, Xu Yu
Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, Wuhan, China.
Int Arch Allergy Immunol. 2025;186(8):747-757. doi: 10.1159/000543408. Epub 2025 Jan 3.
Osthole, a naturally occurring coumarin derivative, has been isolated from the traditional Chinese medicinal herb Cnidium monnieri. This compound exhibits a range of pharmacological properties, including anticancer, antioxidant, anti-inflammatory, and immunomodulatory effects. The objective of this study was to investigate the role of osthole in tissue remodeling in chronic rhinosinusitis with nasal polyp (CRSwNP).
The effects of osthole on nasal polyp (NP) formation were examined within a mouse model of NPs induced by cigarette smoke (CS). The detection of polypoid changes and goblet cell metaplasia was achieved through the use of hematoxylin-eosin and periodic acid-Schiff staining, respectively. The levels of TGF-β1, matrix metalloproteinases 2, 7, 9, and 12 (MMP2, MMP7, MMP9, MMP12), as well as tissue inhibitor of metalloproteinase-1 (TIMP-1) in nasal lavage fluid were determined by enzyme-linked immunosorbent assay (ELISA). Western blotting was employed to ascertain the expression of epithelial-to-mesenchymal transition (EMT) markers (E-cadherin, ZO-1, α-SMA, and vimentin), as well as the activity of the PI3K/AKT/NF-κB pathway. The expression of E-cadherin in nasal epithelium was determined through immunohistochemistry.
In the OVA+SEB or CS-exposed NP mouse model, osthole was observed to reduce the incidence of polypoid changes and goblet cells, while simultaneously increasing the expression of E-cadherin in the epithelium when compared to the CS-treated group. After treatment with osthole, the levels of TGF-β1, MMP2, MMP7, MMP9, and MMP12 in nasal lavage fluid were observed to decrease, while the levels of TIMP-1 were found to increase. In vitro, cigarette smoke extract was observed to downregulate the expression of E-cadherin and ZO-1, while simultaneously upregulating the expression of α-SMA and vimentin. Moreover, osthole upregulated the expression of E-cadherin and ZO-1 while downregulating the expression of α-SMA and vimentin. This effect of osthole was reversed by PI3K/AKT/NF-κB pathway agonists.
Osthole attenuates CS exposure-induced EMT via the PI3K/AKT/NF-κB pathway, providing a theoretical and experimental basis for its clinical application in the treatment of CRSwNP.
蛇床子素是一种天然存在的香豆素衍生物，已从传统中药蛇床中分离出来。该化合物具有一系列药理特性，包括抗癌、抗氧化、抗炎和免疫调节作用。本研究的目的是探讨蛇床子素在伴鼻息肉的慢性鼻-鼻窦炎（CRSwNP）组织重塑中的作用。
在香烟烟雾（CS）诱导的鼻息肉（NP）小鼠模型中研究蛇床子素对NP形成的影响。分别通过苏木精-伊红染色和过碘酸-希夫染色检测息肉样改变和杯状细胞化生。采用酶联免疫吸附测定（ELISA）法测定鼻灌洗液中转化生长因子-β1（TGF-β1）、基质金属蛋白酶2、7、9和12（MMP2、MMP7、MMP9、MMP12）以及金属蛋白酶组织抑制剂-1（TIMP-1）的水平。采用蛋白质免疫印迹法确定上皮-间质转化（EMT）标志物（E-钙黏蛋白、紧密连接蛋白1、α-平滑肌肌动蛋白和波形蛋白）的表达以及PI3K/AKT/NF-κB信号通路的活性。通过免疫组织化学法测定鼻上皮中E-钙黏蛋白的表达。
在卵清蛋白+葡萄球菌肠毒素B（OVA+SEB）或CS暴露的NP小鼠模型中，与CS处理组相比，观察到蛇床子素可降低息肉样改变和杯状细胞的发生率，同时增加上皮中E-钙黏蛋白的表达。用蛇床子素处理后，观察到鼻灌洗液中TGF-β1、MMP2、MMP7、MMP9和MMP12的水平降低，而TIMP-1的水平升高。在体外，观察到香烟烟雾提取物下调E-钙黏蛋白和紧密连接蛋白1的表达，同时上调α-平滑肌肌动蛋白和波形蛋白的表达。此外，蛇床子素上调E-钙黏蛋白和紧密连接蛋白1的表达，同时下调α-平滑肌肌动蛋白和波形蛋白的表达。PI3K/AKT/NF-κB信号通路激动剂可逆转蛇床子素的这种作用。
蛇床子素通过PI3K/AKT/NF-κB信号通路减轻CS暴露诱导的EMT，为其在CRSwNP治疗中的临床应用提供了理论和实验依据。
