课题组前期证实呼吸道合胞病毒（RSV）感染后期小鼠支气管肺泡灌洗液中Th2类细胞因子（简称II类因子）显著增高, 导致慢性气道炎症与气道高反应性（AHR），预实验发现：以Club细胞为代表的上皮细胞可能通过产生内源性损伤相关分子模式家族成员——高迁移率族蛋白(HMGB1)介导II类因子产生。本课题拟采用HMGB1、TLR4基因敲除小鼠，通过特异性去除或促进Club细胞分化、抗体阻断等证明：1.RSV感染后期Club细胞通过产生HMGB1介导II类因子升高导致气道炎症与AHR；2.HMGB1激活TLR4信号通路，增强GATA3表达，促进II类因子产生；3.明确HMGB1作为预测RSV感染毛细支气管炎患儿严重程度及后期发生反复喘息的生物学指标可行性。本研究将进一步揭示RSV感染后发生慢性气道炎症性疾病的机制，为寻找预测RSV感染后发生反复喘息的生物学指标及干预靶点提供重要的理论依据。

In our previous study, Th2 cytokines increased significantly in broncholveolar lavage fluid induced by RSV at the late stage in Balb/c mice, which were associated with chronic airway inflammation and airway hyperresponsiveness. However, the mechanism of type 2 response is unclear. Given High Mobility Group Proteins (HMGB1) , an important member of endogenous injury associated molecular patterns, may be the key regulators of type 2 response. While our preliminary data showed that Club cell, a kind of epithelium with the function of self-renew, may generate HMGB1. Therefore, HMGB1, TLR4 knockout mice will be used and club cell depleting and promoting them to differentiate to ciliated cells will be done in this study to prove the following issues: 1) whether club cell was involved in type 2 response though HMGB1 production in the late stage of RSV infection; 2) whether HMGB1 could regulate transcription factor GATA3, mediating type 2 response though TLR4 signaling pathways; 3) effect of HMGB1 on severity of bronchiolitis and RSV-induced recurrent wheezing in clinical cases and evaluate the feasibility of HMGB1 being a biomarker. This study will further reveal the mechanism of RSV-induced chronic airway inflammatory disease, and identify a biomarker of RSV-induced recurrent wheezing and potential intervention targets.