CST1在嗜酸性粒细胞型慢性鼻窦炎伴鼻息肉组织重塑中的作用与机制研究

Tissue remodeling is one of the most important characteristics and involved in the pathogenesis and prognosis of chronic rhinosinusitis with nasal polyps (CRSwNP). Previous researches have divided CRSwNP into eosinophilic and noneosinophilic subtypes, the two demonstrating different remodeling characteristics and relative molecule profiles, indicating that the underlying mechanisms may be different. Our team has shown that 1）CST1, a cysteine protease inhibitor, was highly expressed in ECRSwNP compared with control and nonECRSwNP. Furthermore, the expression of CST1 was negatively correlated with collagen content; 2) CST1 could regulate MMP expression released by eosinophils; 3) Interleukin-5 (IL-5) was involved in the activation of eosinophils induced by CST1. This research will further investigate the role and mechanisms of CST1 in CRSwNP tissue remodeling, which will explore the different mechanisms between ECRSwNP and nonECRSwNP, providing a theoretical basis for precision medicine.

组织重塑是慢性鼻窦炎伴鼻息肉CRSwNP的显著特征与发病诱因，且与复发相关。CRSwNP依据病理特征可分为嗜酸性粒细胞型CRSwNP（ECRSwNP）与非嗜酸性粒细胞型CRSwNP（nonECRSwNP）。二者组织重塑特征不同、相关因子表达谱不同，提示二者组织重塑调控机制存在差异。本团队前期研究表明1）半胱氨酸蛋白酶抑制剂CST1在ECRSwNP中表达显著高于nonECRSwNP，其表达与胶原含量呈负相关；2）CST1能激活嗜酸性粒细胞释放MMP-1及MMP-9；3）白介素5（IL-5）参与CST1调控嗜酸性粒细胞，提示CST1在ECRSwNP组织重塑中发挥作用。本研究将以息肉细胞及嗜酸性粒细胞为研究对象，利用重组蛋白、酶活性模拟物、激酶特异性抑制剂及细胞因子中和抗体，探索CST1在组织重塑中的功能与机制。该研究有助于理解不同CRSwNP组织重塑差异的机制，为个体化治疗提供理论依据。

慢性鼻窦炎伴鼻息肉（Chronic rhinosinusitis with nasal polyps, CRSwNP）是鼻科常见慢性炎性疾病，世界范围内患病率约为4.3%，以鼻黏膜2型炎症及组织重塑为显著病理特征。胱抑素SN（Cystatin SN, CST1）是近年新发现的2型炎症标志物，能促进鼻黏膜嗜酸性粒细胞浸润与活化，其在鼻黏膜重塑中的作用尚不清楚。由于小鼠缺乏CST1基因，我们将人源化CST1基因敲入C57BL/6小鼠，获得CST1-KI鼠。并将小鼠鼻黏膜剥离提取总RNA后测序分析。与野生型小鼠相比，CST1-KI鼠鼻黏膜重塑相关通路显著改变。采用qPCR验证了测序结果，CST1-KI鼠中鼻黏膜重塑相关分子较野生型显著改变，2型炎症相关因子在其中发挥关键作用。经进一步共培养实验，CST1可通过调控鼻黏膜上皮细胞与基质细胞的相互作用调控鼻黏膜重塑。鼻黏膜重塑是2型CRSwNP的显著病理特征，与CRSwNP疾病严重程度显著相关，因此，进一步研究了CST1与CRSwNP疾病预后的相关性。回顾性分析了151位患者鼻分泌物中CST1水平，鼻分泌物CST1能作为标志物预测CRSwNP术后控制情况。高CST1患者预后差。而在两年内进行不少于3疗程的短疗程口服糖皮质激素干预有助于控制CRSwNP，推迟复发进程。