成纤维细胞生长因子 10 通过抑制 PI3K/AKT/NF-κB 通路减轻哮喘中的过敏性气道炎症。
FGF10 attenuates allergic airway inflammation in asthma by inhibiting PI3K/AKT/NF-κB pathway.
机构信息
Department of Allergy, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Pulmonary and Critical Care Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Department of Pulmonary and Critical Care Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
出版信息
Cell Signal. 2024 Jan;113:110964. doi: 10.1016/j.cellsig.2023.110964. Epub 2023 Nov 11.
BACKGROUND
The effect of fibroblast growth factor 10 (Fgf10) against allergic asthma has remained unclear, despite its importance in lung development and homeostasis maintenance. The purpose of this study was to investigate the protective effect and potential mechanism of Fgf10 on asthma.
METHOD
House Dust Mite (HDM)-induced asthma mice were administered recombinant Fgf10 intranasally during activation. Flow cytometry and ELISA were performed to determine type of inflammatory cells and type 2 cytokines levels in bronchoalveolar lavage fluid (BALF). Hematoxylin and eosin (H&E) and periodic acid - Schiff (PAS) staining of lung sections were conducted to evaluate histopathological assessment. Transcriptome profiling was analyzed using RNA-seq, followed by bioinformatics and network analyses to investigate the potential mechanisms of Fgf10 in asthma. RT-qPCR was also used to search for and validate differentially expressed genes in human Peripheral Blood Mononuclear Cells (PBMCs).
RESULTS
Exogenous administration of Fgf10 alleviated HDM-induced inflammation and mucus secretion in lung tissues of mice. Fgf10 also significantly inhibited the accumulation of eosinophils and type 2 cytokines (IL-4, IL-5, and IL-13) in BALF. The PI3K/AKT/NF-κB pathway may mediate the suppressive impact of Fgf10 on the asthma inflammation. Through RNA-seq analysis, the intersection of 71 differentially expressed genes (DEGs) was found between HDM challenge and Fgf10 treatment. GO and KEGG enrichment analyses indicated a strong correlation between the DEGs and different immune response. Immune infiltration analysis predicted the differential infiltration of five types of immune cells, such as NK cells, dendritic cells, monocytes and M1 macrophages. PPI analysis determined hub genes such as Irf7, Rsad2, Isg15 and Rtp4. Interestingly, above genes were consistently altered in human PBMCs in asthmatic patients.
CONCLUSION
Asthma airway inflammation could be attenuated by Fgf10 in this study, suggesting that it could be a potential therapeutic target.
背景
尽管成纤维细胞生长因子 10（Fgf10）在肺发育和维持内稳态中具有重要作用，但它对过敏性哮喘的影响仍不清楚。本研究旨在探讨 Fgf10 对哮喘的保护作用及其潜在机制。
方法
在激活过程中，用重组 Fgf10 经鼻内给药治疗屋尘螨（HDM）诱导的哮喘小鼠。通过流式细胞术和 ELISA 测定支气管肺泡灌洗液（BALF）中炎症细胞类型和 2 型细胞因子水平。对肺组织进行苏木精和伊红（H&E）及过碘酸-希夫（PAS）染色，评估组织病理学评估。使用 RNA-seq 分析转录组谱，然后进行生物信息学和网络分析，以研究 Fgf10 在哮喘中的潜在机制。还使用 RT-qPCR 搜索和验证人外周血单核细胞（PBMC）中差异表达的基因。
结果
外源性给予 Fgf10 可减轻 HDM 诱导的哮喘小鼠肺组织中的炎症和黏液分泌。Fgf10 还显著抑制 BALF 中嗜酸性粒细胞和 2 型细胞因子（IL-4、IL-5 和 IL-13）的积累。PI3K/AKT/NF-κB 通路可能介导 Fgf10 对哮喘炎症的抑制作用。通过 RNA-seq 分析，在 HDM 挑战和 Fgf10 治疗之间发现了 71 个差异表达基因（DEGs）的交集。GO 和 KEGG 富集分析表明，DEGs 与不同的免疫反应密切相关。免疫浸润分析预测了五种免疫细胞（如 NK 细胞、树突状细胞、单核细胞和 M1 巨噬细胞）的差异浸润。PPI 分析确定了 Irf7、Rsad2、Isg15 和 Rtp4 等关键基因。有趣的是，哮喘患者的人 PBMC 中上述基因均发生改变。
结论
本研究表明，Fgf10 可减轻哮喘气道炎症，提示其可能成为潜在的治疗靶点。
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