YKL-40诱导人支气管上皮细胞表达HMGB-1在哮喘气道重构中的作用

YKL-40 is one of the chitinase-like proteins. Recent years, a couple of researches showed its close relationship with asthma, especially its roles in the airway remodeling of asthma. However the exact mechanisms in the process of remodeling are still not very clear. HMGB-1 is a nonhistone protein which resides in the nucleus as a DNA binding protein. Cell stress can trigger passive or active release of HMGB1. The association between HMGB-1 and asthma was proved extensively these years by different researches. The purpose of this project is to investigate that whether there is any coordination or some kind of cause-effect between YKL-40 and HMGB-1 in mediating the airway remodeling of asthma. Our preliminary experiments showed that YKL-40 could induce human bronchial epithelial cells to express HMGB-1 on a dose-dependent manner. Based on that, the contents of this project includes: 1. To make it clear YKL-40 could induce human bronchial epithelial cells to express HMGB-1 through PAR-2 and investigate the signal pathways in it, to see whether they are PI3K-AKT, MAPK , or NF-κB dependent; 2. To make it clear that the HMGB-1 stimulated by YKL-40 could induce the migration and proliferation of bronchial smooth muscle cells in asthmatic patients and induce the expression of MMPs and ECM associated proteins including γ2-chain laminin-5, Fibronectin andα3-integrin. The results of this project would provide new evidences for the mechanisms of airway remodeling in asthma.

YKL-40是一种甲壳酶样蛋白，近年来的多项研究证实其与哮喘的发病密切相关，尤其是在哮喘的气道重构中发挥重要作用。HMGB-1是细胞核内的非组蛋白，应激状态时释放出来，其与哮喘发病的相关性近年来也得到多项研究的证实。探究两种蛋白在哮喘气道重构的发生、发展过程中是否存在协同作用和因果关系是此项目的主要研究目的。我们前期的预实验已经证实YKL-40可以诱导人支气管上皮细胞表达HMGB-1增加，所以本项目的主要内容包括1.明确YKL-40可以通过膜受体PAR-2诱导人支气管上皮细胞表达HMGB-1增加，并探索其中的信号途径，即是否为PI3K-AKT、MAPK或NF-κB途径依赖；2.明确产生的HMGB-1是否可以通过其特异性受体RAGE诱导哮喘患者支气管平滑肌细胞的增殖、迁移，以及诱导MMP和ECM相关蛋白的表达增加，从而介导气道重构。通过上述实验为哮喘患者气道重构的机制研究提供新的证据。

YKL-40是一种甲壳酶样蛋白，近年来的多项研究证实其与哮喘的发病密切相关，尤其是在哮喘的气道重构中发挥重要作用。HMGB-1是细胞核内的非组蛋白，应激状态时释放出来，其与哮喘发病的相关性近年来也得到多项研究的证实。探究两种蛋白在哮喘气道重构的发生、发展过程中是否存在协同作用和因果关系是此项目的主要研究目的。我们证实1、YKL-40诱导人支气管上皮细胞表达和分泌HMGB1增加，HMGB1促进人气道平滑肌细胞的迁移能力；2、YKL-40可以诱导人支气管平滑肌细胞的增殖和迁移，且这种诱导增殖的效应是依赖于CyclinD1的；3、YKL-40诱导气道上皮下纤维化的形成，FAK或MAPK抑制剂改善YKL-40介导的气道重塑；4、YKL-40和NGAL是哮喘及肾损害重要的生物标志物。上述实验为哮喘患者气道重构的机制研究提供新的证据。