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

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.

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。

哮喘常被分为T2高表达、T2低表达的不同内型，其中T2低表达型哮喘通常以中性粒细胞性气道炎症为特征，通常由白细胞介素-17 (IL-17)和Th17介导，并往往表现出对糖皮质激素的不敏感性。糖皮质激素抵抗(SR)是哮喘控制的瓶颈，常表现出难于纠正的气道高反应性，但其机制尚不明确。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SR型哮喘中作用不详。.本研究揭示了STAT3/SOCS3分别在非SR型和SR型哮喘小鼠模型和人支气管上皮细胞中的表达情况，通过基因质粒转染、RNA干预技术及小分子抑制剂的应用，明确了SOCS3和STAT3的相互调节作用，及其通过对Th17相关细胞因子、中性粒细胞趋化因子以及气道重塑、小气道功能的调控，影响哮喘特别是SR型哮喘的中性粒细胞炎症、气道重塑进而影响其气道反应性的作用机制。本研究结合临床样本中观察到的STAT3在哮喘患者中表达更多，发现小分子STAT3抑制剂C188-9不仅可以改善SR型哮喘的气道炎症、气道重塑，还可以较糖皮质激素干预更为有效、显著地降低SR型哮喘的气道高反应性以及小气道功能障碍，STAT3抑制剂与激素的联用发挥协同作用，可使SR型哮喘小鼠获益；本研究还首次指出了SOCS3在哮喘激素抵抗的发病机制中不可忽视的作用，及其对中性粒细胞性炎症以及激素抵抗相关的酶、氧化应激相关损伤的保护作用，为SR型哮喘提供新的作用靶点。.项目研究成果在JACI-in practice等期刊发表SCI论文8篇，获得实用新型专利授权2项，培养研究生3名。