气道重塑是影响哮喘患者远期疗效的重要因素，活化的上皮下肺成纤维细胞合成细胞外基质（ECM）是其关键环节之一，但机制尚不明确。既往研究报道，巨噬细胞极化能激活成纤维细胞，线粒体融合参与成纤维细胞活化。申请人筛选脂质代谢相关酶，发现在活化的成纤维细胞中硬脂酰辅酶A去饱和酶1（SCD1）显著增加，抑制SCD1可减少M2型巨噬细胞诱导的成纤维细胞线粒体融合及活化。并且，哮喘气道上皮分泌的长链胸腺基质淋巴细胞生成素（long-TSLP）可诱导巨噬细胞M2型极化，而短链TSLP（short-TSLP）抑制其M2型极化，但具体机制不清。因此，本研究利用基因敲除、液相二级质谱等技术，通过细胞和动物实验，探讨哮喘气道上皮分泌的long-TSLP和short-TSLP对巨噬细胞极化的影响和机制，阐明M2型巨噬细胞诱导上皮下肺成纤维细胞SCD1表达调控脂质代谢、线粒体融合和活化的机制，为哮喘的诊治提供新的靶点。

Airway remodeling is an important factor affecting the long-term efficacy of asthmatic patients. The synthesis of extracellular matrix (ECM) by activated subepithelial fibroblasts is one of the key links in asthmatic airway remodeling, but the mechanism is still unclear. It is reported that polarized macrophage fibroblasts, and mitochondrial fusion involved in fibroblast activation. Applicants screened lipid metabolism-related enzymes and found that stearoyl-CoA desaturase 1 (SCD1) was significantly increased in activated fibroblasts, and inhibiting SCD1 reduced M2 macrophage-induced fibroblast mitochondrial fusion and activation. Simultaneously, it was found that long-chain thymic stromal lymphopoietin (long-TSLP) secreted by epithelium from asthmatic airway induced M2 polarization of macrophages, while short-chain TSLP (short-TSLP) inhibited, yet the specific mechanism is still unclear. Therefore, this study will use gene knockout methods, liquid phase secondary mass spectrometry and other techniques to investigate the effects and mechanisms of long-TSLP and short-TSLP secreted by airway epithelial cells on macrophage polarization in vitro and vivo, and elucidate the effects of M2 macrophage-induced SCD1 expression on lipid metabolism and activation in subepithelial fibroblasts. These may provide a new target in diagnosis and treatment of asthma.