DAMP分子－HMGB1在气道上皮对哮喘气道炎症关键介质TSLP的作用及机制研究

气道上皮细胞来源的TSLP是促发和维持哮喘慢性炎症的关键分子。我们已经证明哮喘病人诱导痰中损伤相关分子模式(DAMPs)分子-HMGB1水平越高，疾病越严重。那么HMGB1促进哮喘发病的分子机制是什么？进一步研究显示：呼吸道合孢病毒及卵蛋白诱导的哮喘小鼠气道粘膜HMGB1表达增强，体外多种哮喘致敏物可促进气道上皮细胞HMGB1表达及释放，且HMGB1可显著增加气道上皮细胞 TSLP的释放。由此，我们提出了HMGB1对哮喘气道上皮细胞 TSLP调控的新机制。本项目拟采用慢病毒载体感染技术，通过基因过表达及干扰等方法，分别在气道上皮细胞和哮喘小鼠模型进一步观察HMGB1协同IL-1β对气道上皮细胞调控炎症关键分子TSLP的影响及可能机制，探讨阻断HMGB1途径改善哮喘炎症的可行性。本项目为确立阻断HMGB1途径作为哮喘防治的新靶标提供科学依据。

Thymic stromal lymphopoietin (TSLP) derived from airway epithelial cells is a key pro-allergic cytokine that has recently been linked to chronic inflammation of asthma. Emerging evidence in the pathogenesis of asthma has attracted TSLP as a promising therapeutic target. However, the definite regulation mechanism of TSLP expression in airway epithelial cells of asthma remains to be resolved..In our previous study,we have indentified that sputum and plasma concentrations of damage-associated molecular patterns(DAMPs)-HMGB1 in patients with asthma were significantly higher than concentrations in control subjects and were significantly negatively correlated with forced expiratory volume in 1 s (FEV1)and FEV1(% predicted).Then,the levels of HMGB1 in the airway mucosa were significantly higher in OVA and RSV induced asthma groups than in the control group.Furthermore,we also found that asthma stimulus such as house dust mites (HDMs) and H202 can significantly induce HMGB1 expression in airway epithelial cells,and recombinant human HMGB1 can increase TSLP expression in airway epithelial cells in vitro. Therefore we propose a new mechainism that DAMP molecule-HMGB1 can influence the expression and release of key inflammation factor-TSLP in airway epithelial of asthma..This study will further explore in airway epithelial cells and asthma models by way of lentivirus infection, gene overexpression and RNA interference,and et al, focusing on whether and how HMGB1 collabration with IL-1β regulate the expression of TSLP in airway epithelial and proving the feasibility of targetting of HMGB1 in inprove airway inflammation of asthma model. Our study may further clarify the pathogenesis of asthma and provide new therapeutic targets for asthma.