受肺内微生物影响的NODAL分子在气道高反应性疾病中的作用及分子机制的研究

Airway hyperresponsiveness diseases such as asthma is chronic airway inflammation, is due to bacteria,virus infection, or irritability of dust, chemical stimulation reaction. Bronchial epithelial cells (BECs) function defects or integrity destruction is the primary factor and the starter of airway hyperresponsiveness.. NODAL molecules secreted by epithelial cells and plays an important role in the transformation of epithelial mesenchymal. The correlation of respiratory syncytial virus (RSV) and asthma has been a lot of documents to verify, our study found that RSV strongly promote the NODAL expression, suggest that NODAL expression up-regulation may be associated with airway hyperresponsiveness disease. We also found the expression of airway epithelial NODAL affected by different lung microbes, and there was a significant difference, suggest that the lung microbes play an important role in regulating the NODAL expression.. This study based on NODAL point, clear NODAL molecules in the role of airway hyperresponsiveness disease development, explore the possible regulatory mechanism by the lung microbes. NODAL as indicators of disease severity and disease treatment targets, has important clinical value.

哮喘等气道高反应性疾病是气道慢性炎症，是由于细菌、病毒的感染，或是对粉尘、化学刺激的应激性反应。支气管上皮细胞（BECs）功能缺陷或完整性破坏是气道高反应的原发因素和启动环节。. NODAL分子由上皮细胞分泌，在上皮间质转化中起重要作用。呼吸道合胞病毒（RSV）与哮喘的相关性已经得到大量的文献验证，我们实验发现RSV强烈促进NODAL表达，提示NODAL表达上调可能与气道高反应性疾病相关。我们实验中还观察到气道上皮NODAL的表达受肺内多种微生物的影响，且影响有显著差异性，提示肺内微生物在调控NODAL表达中发挥重要作用。. 因此本研究以NODAL为切入点，明确NODAL分子在气道高反应性疾病发生发展中的作用，探寻肺内微生物对NODAL调控的分子机制。NODAL作为气道高反应性疾病严重程度的分子指标及治疗靶点，具有重要的临床应用价值。

慢性气道高反应性疾病是一类严重危害人类健康的具有复杂性状的多基因遗传疾病，其发病率近年内随着社会发展呈现上升趋势。而哮喘的发生通常伴随着上皮间质转化一同发生。随着对EMT与气道高反应性疾病相关性的深入了解，我们发现了在不同微生物处理下，NODAL基因是调控EMT的关键靶点，本项目重点研究了Nodal在气道高反应性疾病中的作用及机制。我们应用生物信息学技术构建Nodal信号通路后，观察到RSV通过下调生理性抑制剂LEFTY，上调ACVR2B受体，并诱导Nodal启动子去甲基化激活Nodal信号通路，抑制增殖，促进EMT，并一定程度上促进了NFκB及AP-1 (Jun)等信号通路的激活，诱导炎症反应蛋白的表达；而灭活的金色葡萄球菌、铜绿假单胞菌、鲍曼不动杆菌具有相反的作用。建立Nodal基因敲除动物模型后，我们的结果也提示Nodal基因敲除显著减少了臭氧引起的气道阻力增加，及肺部炎症的发生及发展，具有良好的气道保护作用。我们进一步筛选了靶向NODAL的抗气道高反应性疾病的药物，该方案为临床上治疗气道高反应性疾病提高了新的思路。