HDM通过TLR4依赖的TSLP-TSLPR信号通道触发哮喘气道重塑机制研究

气道上皮细胞在启动哮喘气道重塑和炎症中起关键作用。我们前期研究证明气道上皮释放TSLP在哮喘气道炎症中起重要作用，同时发现TSLP高表达伴随哮喘气道重塑标志物α-SMA和I型胶原气道沉积。因此，气道上皮TLSP可能诱导哮喘气道重塑。本研究根据前期研究结果，拟通过HDM诱导哮喘小鼠模型和体外培养小鼠肺成纤维细胞方法，采用分子生物学、LCM 、免疫组织化学等技术，探讨TSLP诱导哮喘气道重塑的机制，证实HDM与气道上皮TLR4结合，高表达TSLP，进而与TSLPR结合，激活MAPKs (ERK1/2、P38、JNK)-STAT3 信号通道，形成α-SMA和I型胶原沉积，最终导致气道重塑。本研究以TSLP-TSLPR信号通道为切入点，旨在阐明HDM诱导TLR4依赖的TSLP-TSLPR-MAPK-STAT3气道重塑机制，奠定哮喘气道重塑理论基础，为早期防治哮喘病人固定性气流受限提供临床治疗思路。

Airway epithelial cells play a key role in the initiation of asthmatic airway remodeling and inflammation. Our previous studies have shown that thymic stromal lymphopoietin (TSLP) expressed in airway epithelium plays a significant part in airway inflammation of asthma, also found that TSLP was overexpressed accompanied by increased synthesis and airway deposition of early stage asthmatic airway remodeling markers including α-smooth muscle actin(α-SMA) and typeⅠcollagen. Therefore, TLSP released from airway epithelial may induce airway remodeling of asthma. According to preliminary research data, we intend to explore the mechanism of TSLP-induced airway remodeling on the basis of established the host dust mite (HDM)-triggered asthmatic mice model and culturing mice lung fibroblast cell line in vitro, through the molecular biology techniques, flow fluorescence microsphere technique, laser capture microdissection (LCM), immunohistochemistry and so on. In this study, we design to confirm the overexpression of TSLP induced by HDM binding to Toll-like receptor 4(TLR4) on airway epithelial cells, and then TSLP-TSLPR complex activated MAPKs (ERK1 / 2, P38, JNK)-STAT3 signal pathway followed by the deposition of α-SMA and typeⅠcollagen. In this study, we will clarify the mechanism of HDM-triggered asthmatic airway remodeling via the TLR4-dependent TSLP-TSLPR-MAPK-STAT3 signal pathway by taking TSLP-TSLPR signal pathway as key point. This research could pave the way for airway remodeling theoretical basis for preventing asthma patients from fixed airflow limitation, and developing the new therapeutic strategies in asthma.