聚-L-精氨酸通过激活 mTORC1-STAT3 通路诱导气道上皮细胞中的 FGFBP1 促进哮喘血管生成
2021/08/24
摘要
血管生成是哮喘气道重塑的关键特征。活化的嗜酸性粒细胞通过释放阳离子颗粒蛋白，如主要碱性蛋白（MBP），在哮喘中发挥重要作用，但其潜在机制尚不完全清楚。在这项研究中，我们证明成纤维细胞生长因子结合蛋白1（FGFBP1）在由聚-L-精氨酸（PLA）（MBP的模拟物）处理的气道上皮细胞系中显着上调。在哮喘临床样品以及卵清蛋白（OVA）诱导的慢性哮喘小鼠模型中也检测到升高的FGFBP1表达。PLA通过激活雷帕霉素复合物1-信号转导和转录激活因子3（mTORC1-STAT3）信号通路的机制靶标来增强FGFBP1表达。STAT3通过直接结合FGFBP1基因的启动子反式激活FGFBP1。此外，我们发现PLA处理的气道上皮细胞分泌的FGFBP1为促血管生成因子。最后，我们发现mTORC1-STAT3-FGFBP1信号通路在具有气道重塑特征的OVA诱导的慢性哮喘模型中被激活。雷帕霉素治疗缓解了哮喘小鼠的呼吸道症状并减少了血管生成。因此，气道上皮中mTORC1-STAT3-FGFBP1途径的激活有助于血管生成的进展，并且应该靶向用于治疗哮喘。
Poly-L-arginine promotes asthma angiogenesis through induction of FGFBP1 in airway epithelial cells via activation of the mTORC1-STAT3 pathway
Xu Chen, Manli Miao, Meng Zhou, Jie Chen, Dapeng Li, Ling Zhang, Anjiang Sun, Minglong Guan, Zixi Wang, Ping Liu, Shengquan Zhang, Xiaojun Zha, Xiaoyun Fan
Abstract
Angiogenesis is a key characteristic of asthma airway remodeling. By releasing cationic granule proteins, such as major basic protein (MBP), activated eosinophils play a prominent role in asthma, but the underlying mechanisms are still not fully understood. In this study, we demonstrated that fibroblast growth factor-binding protein 1 (FGFBP1) was dramatically upregulated in airway epithelial cell lines treated by poly-L-arginine (PLA), a mimic of MBP. Elevated FGFBP1 expression was also detected in asthma clinical samples, as well as in ovalbumin (OVA)-induced chronic asthma mouse models. PLA enhanced FGFBP1 expression through activation of the mechanistic target of rapamycin complex 1-signal transducer and activator of transcription 3 (mTORC1-STAT3) signaling pathway. STAT3 transactivated FGFBP1 by directly binding to the promoter of the FGFBP1 gene. Furthermore, we identified that FGFBP1 secreted by PLA-treated airway epithelial cells served as a proangiogenesis factor. Lastly, we found the mTORC1-STAT3-FGFBP1 signaling pathway was activated in an OVA-induced chronic asthma model with airway remodeling features. Rapamycin treatment alleviated respiratory symptoms and reduced angiogenesis in asthmatic mice. Therefore, activation of the mTORC1-STAT3-FGFBP1 pathway in the airway epithelium contributes to the progress of angiogenesis and should be targeted for the treatment of asthma.
血管生成是哮喘气道重塑的关键特征。活化的嗜酸性粒细胞通过释放阳离子颗粒蛋白，如主要碱性蛋白（MBP），在哮喘中发挥重要作用，但其潜在机制尚不完全清楚。在这项研究中，我们证明成纤维细胞生长因子结合蛋白1（FGFBP1）在由聚-L-精氨酸（PLA）（MBP的模拟物）处理的气道上皮细胞系中显着上调。在哮喘临床样品以及卵清蛋白（OVA）诱导的慢性哮喘小鼠模型中也检测到升高的FGFBP1表达。PLA通过激活雷帕霉素复合物1-信号转导和转录激活因子3（mTORC1-STAT3）信号通路的机制靶标来增强FGFBP1表达。STAT3通过直接结合FGFBP1基因的启动子反式激活FGFBP1。此外，我们发现PLA处理的气道上皮细胞分泌的FGFBP1为促血管生成因子。最后，我们发现mTORC1-STAT3-FGFBP1信号通路在具有气道重塑特征的OVA诱导的慢性哮喘模型中被激活。雷帕霉素治疗缓解了哮喘小鼠的呼吸道症状并减少了血管生成。因此，气道上皮中mTORC1-STAT3-FGFBP1途径的激活有助于血管生成的进展，并且应该靶向用于治疗哮喘。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Cell Death Dis. 2021 Aug 2;12(8):761. doi: 10.1038/s41419-021-04055-2.)
(Cell Death Dis. 2021 Aug 2;12(8):761. doi: 10.1038/s41419-021-04055-2.)
Poly-L-arginine promotes asthma angiogenesis through induction of FGFBP1 in airway epithelial cells via activation of the mTORC1-STAT3 pathway
Xu Chen, Manli Miao, Meng Zhou, Jie Chen, Dapeng Li, Ling Zhang, Anjiang Sun, Minglong Guan, Zixi Wang, Ping Liu, Shengquan Zhang, Xiaojun Zha, Xiaoyun Fan
Abstract
Angiogenesis is a key characteristic of asthma airway remodeling. By releasing cationic granule proteins, such as major basic protein (MBP), activated eosinophils play a prominent role in asthma, but the underlying mechanisms are still not fully understood. In this study, we demonstrated that fibroblast growth factor-binding protein 1 (FGFBP1) was dramatically upregulated in airway epithelial cell lines treated by poly-L-arginine (PLA), a mimic of MBP. Elevated FGFBP1 expression was also detected in asthma clinical samples, as well as in ovalbumin (OVA)-induced chronic asthma mouse models. PLA enhanced FGFBP1 expression through activation of the mechanistic target of rapamycin complex 1-signal transducer and activator of transcription 3 (mTORC1-STAT3) signaling pathway. STAT3 transactivated FGFBP1 by directly binding to the promoter of the FGFBP1 gene. Furthermore, we identified that FGFBP1 secreted by PLA-treated airway epithelial cells served as a proangiogenesis factor. Lastly, we found the mTORC1-STAT3-FGFBP1 signaling pathway was activated in an OVA-induced chronic asthma model with airway remodeling features. Rapamycin treatment alleviated respiratory symptoms and reduced angiogenesis in asthmatic mice. Therefore, activation of the mTORC1-STAT3-FGFBP1 pathway in the airway epithelium contributes to the progress of angiogenesis and should be targeted for the treatment of asthma.
上一篇：
肥大细胞类糜蛋白酶影响原代人气道成纤维细胞的功能特性：对哮喘的影响
下一篇：
氧化磷脂酰胆碱诱导气道上皮细胞多功能缺陷
