哮喘气道上皮来源long-TSLP/short-TSLP失衡对气道重塑中成纤维细胞活化的分子机制研究

Expression imbalance between long-TSLP (thymic stromal lymphopoietin) and short-TSLP in asthmatic airway epithelial cells would promote airway inflammation, but its effects on airway remodeling are not clear. We found in our preliminary study that short-TSLP inhibited lung fibroblast proliferation and extracellular matrix (ECM) production induced by long-TSLP. So we come to the hypothesis that short-TSLP could inhibit airway remodeling by counteracting the effects of long-TSLP. This project is intended to investigate whether HDM/OVA induces expression imbalance between long-TSLP and short-TSLP through PAR2/TLR4/NF-κB pathway, and to illustrate that short-TSLP inhibits long-TSLP induced activation of STAT3/5-NOX4-ROS by binding to TSLPR/IL-7Rα receptor complex, resulting in decreased fibroblast proliferation, reduced ECM production, and finally ameliorated airway remodeling by CRISPR/Cas9, TSLP knockout mouse and other methods. This study would provide novel evidence for short-TSLP in prevention and treatment of asthma.

哮喘气道上皮细胞中长链TSLP（胸腺基质淋巴细胞生成素）（long-TSLP）和短链TSLP（short-TSLP）表达失衡促进气道炎症，但与气道重塑的关系尚不明确。我们前期研究表明short-TSLP抑制long-TSLP诱导的肺成纤维细胞增殖及细胞外基质（ECM）合成。因此，我们假设short-TSLP通过抑制long-TSLP的作用减轻哮喘气道重塑。本项目拟采用CRISPR/Cas9、TSLP基因敲除小鼠等方法，拟观察HDM/OVA通过PAR2/TLR4/NF-κB通路诱导气道上皮细胞long-TSLP和short-TSLP表达失衡；进一步探讨short-TSLP结合TSLPR/IL-7Rα复合体，抑制long-TSLP激活STAT3/5-NOX4-ROS通路，减少肺成纤维细胞增殖及ECM合成增多，减轻气道重塑的发生发展。为short-TSLP作为哮喘防治的新靶标提供理论依据。

背景：哮喘气道上皮细胞中长链TSLP（胸腺基质淋巴细胞生成素）（long-TSLP）和短链TSLP（short-TSLP）表达失衡促进气道炎症，但与气道重塑的关系尚不明确。.研究内容：阐明哮喘气道上皮细胞生成和分泌long-TSLP和short-TSLP失衡机制。明确气道上皮来源long-TSLP和short-TSLP失衡效应在气道重塑中的作用和机理。.结果：小泛素化（SUMOylation）E3连接酶CBX4通过RNA结合蛋白MEX-3B促进long-TSLP翻译，进而导致哮喘气道上皮细胞生成和分泌long-TSLP和short-TSLP失衡。long-TSLP一方面通过TSLPR/IL-7Rα-stat3/5-NOX4-ROS通路活化肺成纤维细胞，另一方面诱导巨噬细胞表型极化为M2型，后者分泌细胞因子促进肺成纤维细胞中CBX4表达而稳定SCD1，进而促进不饱和脂肪酸生成和线粒体融合，增强肺成纤维细胞乳酸代谢和ECM合成，参与哮喘气道重塑。而short-TSLP通过阻断long-TSLP的作用，而减少哮喘气道重塑。.科学意义：通过进一步阐明TSLP参与哮喘的机制及表达失衡的机制，为开发新的治疗小分子化合物药物提供理论基础，为哮喘的治疗提供更多价优的选择。并且，short-TSLP作为新的研究热点，及其在免疫调节中的重要作用，进一步阐明作用的机制，为进一步开发成治疗药物提供理论基础。