IL-19及其受体调控慢性鼻-鼻窦炎组织重塑的机制研究

Tissue remodeling is the prominent pathophysiologic characteristic of chronic diseases of the airways. It is the key factor that affects the severity and prognosis of chronic rhinosinusitis (CRS). Recent studies indicate that the IL-20 subfamily promotes tissue remodeling. However, the roles of this subfamily in tissue remodeling of chronic airway diseases remain unclear. Our previous studies demonstrated that IL-19 and its receptors IL-20R1 and IL-20R2 are upregulated in CRS. This upregulation is found in the nasal mucosa characterized by nasal mucosa edema, mucinous metaplasia, and eosinophil infiltration, which contribute to increased levels of extracellular matrix regulator metalloproteinase (MMP)-7 and eosinophil cationic protein. The proposed study intends to detect the activations of JAK-STAT/ERK and TGF-β pathways in the primary nasal epithelial cells and to study the development of fibroblasts and nasal polyps in vitro after treatments with or without IL-19 stimulation. These findings will be used to determine the effects of activated JAK-STAT/ERK and inhibited TGF-β pathways on the expression of fibronectin and collagen in nasal fibroblasts and the expression of MMP, mucin, eotaxin and RANTES in the epithelial cells. Ultimately, the study aims to explain how the mechanism of IL-19 contributes to the imbalance of extracellular matrix, increased mucin deposition, and Eos infiltration during the tissue remodeling phase of CRS. The proposed study will elucidate the tissue remodeling mechanisms of CRS, provide a platform to develop new treatments for this disease.

组织重塑是气道慢性炎症的主要病理特征，是决定慢性鼻-鼻窦炎（CRS）病变性质和预后的重要因素。IL-20亚家族调控JAK-STAT/ERK通路是介导组织重塑的关键，然其在上呼吸道炎症中的作用未见报道。我们前期研究发现IL-20亚家族主要成员IL-19及其受体IL-20R1/IL-20R2在以水肿、黏液化生和嗜酸性粒细胞（Eos）浸润为主要病理特征的CRS中高表达，并与细胞外基质调节因子MMP、Eos阳离子蛋白等表达相关。因此，本项目拟通过对鼻黏膜上皮细胞、成纤维细胞及鼻息肉组织块的培养，对比在IL-19激活与其受体封闭前后，JAK-STAT/ERK及TGF-β通路的活化差异，进一步分析上述通路对成纤维细胞合成纤维蛋白、胶原，鼻黏膜上皮细胞产生MMP及Eos趋化因子的作用，最终阐明IL-19及其受体调控水肿、黏液化生及Eos浸润的机制。为进一步完善CRS发病机制，寻找潜在治疗靶点提供理论依据

组织重塑是气道慢性炎症的主要病理特征，是决定慢性鼻-鼻窦炎（CRS）病变性质和预后的重要因素。IL-20亚家族调控JAK-STAT/ERK通路是介导组织重塑的关键，然其在上呼吸道炎症中的作用未见报道。我们培养原代鼻黏膜上皮细胞、成纤维细胞，对比在IL-19激活与其受体封闭前后，相关通路的活化差异，进一步分析上述通路对成纤维细胞合成纤维蛋白、胶原，鼻黏膜上皮细胞产生MMP及Eos趋化因子的作用机制。发现：（1）IL-19及其受体在CRSsNP，尤其是CRSwNP患者鼻黏膜中表达增高，且与细胞外基质调节因子MMP9的表达正相关，IL-19通过激活ERK/NF-κB通路促进原代鼻黏膜上皮细胞产生MMP9，参与促进CRSwNP患者鼻黏膜细胞外基质降解；（2）CRSsNP患者鼻黏膜中Col和FN沉积、成纤维细胞多；IL-19通过NF-κB-Smad2/3信号通路的激活促原代成纤维细胞产生Col 1和FN，参与促进纤维化；（3）CRSsNP和CRSwNP患者鼻黏膜中黏蛋白的表达显著高于对照组，且IL-19与黏蛋白MUC5AC的表达共定位在鼻黏膜上皮细胞，IL-19可以通过STAT3通路的激活促进鼻黏膜上皮细胞产生MUC5AC；（4）IL-19及其受体在CRSwNP，尤其是Eos CRSwNP患者鼻黏膜中表达增高，且与嗜酸性粒细胞阳离子蛋白表达正相关；IL-19与嗜酸性粒细胞趋化因子RANTES同定位在鼻黏膜上皮细胞，IL-19通过与其受体结合激活ERK/NF-κB通路促进原代鼻黏膜上皮细胞产生RANTES，诱导嗜酸性粒细胞浸润。如上结果提示：IL-19及其受体高表达参与促进慢性鼻窦炎组织间质水肿、纤维化、黏液产生及嗜酸性粒细胞浸润的调节。