STAT3/SOCS3信号通路在氧化应激诱导激素抵抗型哮喘中的作用机制研究

糖皮质激素抵抗（SR）是哮喘控制的瓶颈，机制不明。氧化应激活化IL-17A致中性粒细胞性气道炎症在SR型哮喘中起重要作用。STAT3/SOCS3信号通路在部分慢性炎症疾病可调控IL-17A介导的炎症反应，但在氧化应激所致SR型哮喘中作用不详。我们发现SR型哮喘STAT3/SOCS3肺组织表达较正常或非SR型哮喘小鼠升高，且与IL-17A呈正相关，故推测其可能存在STAT3/SOCS3调控IL-17A导致SR。针对此假设，本课题拟在前期建立成熟SR型哮喘模型基础上，通过基因质粒转染及RNA干预技术，分别上调和沉默STAT3/SOCS3在体外肺组织T淋巴细胞和小鼠体内表达的方法，观察其对哮喘模型大小气道慢性炎症、气道重构及SR作用，并应用IL-17A基因敲除小鼠模型进一步探讨STAT3/SOCS3-IL-17A通路诱导SR的作用机制，深入明确SR型哮喘的免疫分子机制，为其干预提供新的作用靶点。

Steroid resistance is the bottleneck of bronchial asthma control and it remains mechanistically poorly understood. Neutrophil-dominated airway inflammation, which is mediated by high expressions of IL-17A induced by oxidative stress, plays a key role in steroid-resistant asthma. STAT3/SOCS3, an important inflammatory signaling pathway in many chronic inflammatory disorders, is reported to be involved in IL-17A associated inflammation, but the underlying mechanism in oxidative stress-induced steroid-resistant asthma is little known. We have found that STAT3/SOCS3 was markedly enhanced in steroid-resistant asthma model compared to the steroid-sensitive asthma model and control group, and was positively correlated with IL-17A levels. To test the hypothesis that STAT3/SOCS3 activates IL-17A and then causes steroid resistance in oxidative stress-asthma, we plan to overexpress or inhibit STAT3/SOCS3 in steroid-resistant models, in vitro and in vivo respectively, by gene transinfection and RNA interference, based on our previous established mature ozone-induced steroid-resistant asthma model, exploring the effects of STAT3/SOCS3 on airway inflammatory processes, airway remodeling, and gene/non-gene mechanisms of steroid resistance, and the role of IL-17A in STAT3/SOCS3 mediated inflammation and steroid resistance investigated by using IL-17A knockout mice. The study may further reveal the immunopathogenesis in steroid resistance asthmna, and may provide a novel target for the therapy of steroid resistance in asthma.