Du Kun, Wang Min, Zhang Nan, Yu Pei, Wang Ping, Li Ying, Wang Xiangdong, Zhang Luo, Bachert Claus
Department of Otorhinolaryngology Head and Neck Surgery Beijing Tongren Hospital Capital Medical University Beijing China.
Beijing Key laboratory of Nasal Diseases Beijing Institute of Otorhinolaryngology Beijing China.
Clin Transl Allergy. 2021 Sep 6;11(7):e12059. doi: 10.1002/clt2.12059. eCollection 2021 Aug.
Tissue remodeling caused by increased MMPs is involved in the pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP). We previously found higher levels of periostin and tenascin C in CRSwNPs, but whether they are associated with the dysregulation of MMPs is unknown. Therefore, the present study aimed to investigate the regulatory roles of these two ECM proteins in the expression of MMPs in nasal polyps.
The concentrations of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, TIMP-1, TIMP-2, TIMP-3, TIMP-4, periostin, and tenascin C in tissue homogenates of 51 patients with chronic rhinosinusitis with and without nasal polyps and 15 control subjects were measured and were analyzed by adjusted logistic regression and spearman correlation test. Primary human nasal polyp fibroblasts and epithelial cells were stimulated ex vivo with periostin and tenascin C and the gene expression of MMPs and TIMPs was determined by means of real-time PCR.
The protein levels of MMP-3, MMP-7, MMP-8, MMP-9, TIMP-1, TIMP-2, periostin, and tenascin C were significantly higher in patients with CRSwNPs than in healthy control subjects. The adjusted logistic regression analyses showed that MMP-3, MMP-7, MMP-8, MMP-9, TIMP-2, periostin, and tenascin C were related to the occurrence of CRSwNP. Spearman correlation test showed periostin was positively correlated with MMP-3 and TIMP-2, and tenascin C was positively correlated with MMP-3, MMP-7, MMP-8, MMP-9, and TIMP-2. Periostin stimulated the gene expression of MMP-3, MMP-7, MMP-8, and MMP-9 in fibroblasts and MMP-9 in epithelial cells ex vivo. Tenascin C stimulated the expression of MMP-3, MMP-7, MMP-8, and MMP-9 in epithelial cells. The expression of TIMPs in fibroblasts and epithelial cells was affected by neither periostin nor tenascin C.
Periostin and tenascin C might be involved in the remodeling of nasal polyps by regulating the expression of different MMPs in epithelial cells and fibroblasts. Our findings have the potential to identify key factors of tissue remodeling in CRSwNPs.
基质金属蛋白酶（MMPs）增加所导致的组织重塑参与了伴鼻息肉的慢性鼻-鼻窦炎（CRSwNP）的发病机制。我们之前发现CRSwNP患者中骨膜蛋白和肌腱蛋白C的水平较高，但它们是否与MMPs的失调有关尚不清楚。因此，本研究旨在探讨这两种细胞外基质蛋白在鼻息肉中MMPs表达的调控作用。
检测了51例伴有和不伴有鼻息肉的慢性鼻-鼻窦炎患者以及15例对照者组织匀浆中MMP-2、MMP-3、MMP-7、MMP-8、MMP-9、MMP-12、MMP-13、TIMP-1、TIMP-2、TIMP-3、TIMP-4、骨膜蛋白和肌腱蛋白C的浓度，并通过校正逻辑回归和Spearman相关性检验进行分析。用骨膜蛋白和肌腱蛋白C对原代人鼻息肉成纤维细胞和上皮细胞进行体外刺激，并通过实时PCR测定MMPs和TIMPs的基因表达。
CRSwNP患者中MMP-3、MMP-7、MMP-8、MMP-9、TIMP-1、TIMP-2、骨膜蛋白和肌腱蛋白C的蛋白水平显著高于健康对照者。校正逻辑回归分析显示，MMP-3、MMP-7、MMP-8、MMP-9、TIMP-2、骨膜蛋白和肌腱蛋白C与CRSwNP的发生有关。Spearman相关性检验显示，骨膜蛋白与MMP-3和TIMP-2呈正相关，肌腱蛋白C与MMP-3、MMP-7、MMP-8、MMP-9和TIMP-2呈正相关。骨膜蛋白在体外刺激成纤维细胞中MMP-3、MMP-7、MMP-8和MMP-9以及上皮细胞中MMP-9的基因表达。肌腱蛋白C刺激上皮细胞中MMP-3、MMP-7、MMP-8和MMP-9的表达。骨膜蛋白和肌腱蛋白C均未影响成纤维细胞和上皮细胞中TIMPs的表达。
骨膜蛋白和肌腱蛋白C可能通过调节上皮细胞和成纤维细胞中不同MMPs的表达参与鼻息肉的重塑。我们的研究结果有可能识别CRSwNP中组织重塑的关键因素。
