PDF(Pubmed)
Abstract：
BACKGROUND: Previous studies have shown that IL-25 levels are increased in patients with asthma with fixed airflow limitation (FAL). However, the mechanism by which IL-25 contributes to airway remodeling and FAL remains unclear. Here, we hypothesized that IL-25 facilitates pro-fibrotic phenotypic changes in bronchial epithelial cells (BECs) and circulating fibrocytes (CFs), orchestrates pathological crosstalk from BECs to CFs, and thereby contributes to airway remodeling and FAL.
METHODS: Fibrocytes from asthmatic patients with FAL and chronic asthma murine models were detected using flow cytometry, multiplex staining and multispectral imaging analysis. The effect of IL-25 on BECs and CFs and on the crosstalk between BECs and CFs was determined using cell culture and co-culture systems.
RESULTS: We found that asthmatic patients with FAL had higher numbers of IL-25 receptor (i.e., IL-17RB)+-CFs, which were negatively correlated with forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC). The number of airway IL-17RB+-fibrocytes was significantly increased in ovalbumin (OVA)- and IL-25-induced asthmatic mice versus the control subjects. BECs stimulated with IL-25 exhibited an epithelial-mesenchymal transition (EMT)-like phenotypic changes. CFs stimulated with IL-25 produced high levels of extracellular matrix (ECM) proteins and connective tissue growth factors (CTGF). These profibrotic effects of IL-25 were partially blocked by the PI3K-AKT inhibitor LY294002. In the cell co-culture system, OVA-challenged BECs facilitated the migration and expression of ECM proteins and CTGF in CFs, which were markedly blocked using an anti-IL-17RB antibody.
CONCLUSIONS: These results suggest that IL-25 may serve as a potential therapeutic target for asthmatic patients with FAL.
METHODS: Fibrocytes from asthmatic patients with FAL and chronic asthma murine models were detected using flow cytometry, multiplex staining and multispectral imaging analysis. The effect of IL-25 on BECs and CFs and on the crosstalk between BECs and CFs was determined using cell culture and co-culture systems.
RESULTS: We found that asthmatic patients with FAL had higher numbers of IL-25 receptor (i.e., IL-17RB)+-CFs, which were negatively correlated with forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC). The number of airway IL-17RB+-fibrocytes was significantly increased in ovalbumin (OVA)- and IL-25-induced asthmatic mice versus the control subjects. BECs stimulated with IL-25 exhibited an epithelial-mesenchymal transition (EMT)-like phenotypic changes. CFs stimulated with IL-25 produced high levels of extracellular matrix (ECM) proteins and connective tissue growth factors (CTGF). These profibrotic effects of IL-25 were partially blocked by the PI3K-AKT inhibitor LY294002. In the cell co-culture system, OVA-challenged BECs facilitated the migration and expression of ECM proteins and CTGF in CFs, which were markedly blocked using an anti-IL-17RB antibody.
CONCLUSIONS: These results suggest that IL-25 may serve as a potential therapeutic target for asthmatic patients with FAL.
摘要：
背景：先前的研究表明，患有固定气流受限（FAL）的哮喘患者中IL-25水平升高。然而,IL-25促进气道重塑和FAL的机制尚不清楚.这里,我们假设IL-25促进支气管上皮细胞（BECs）和循环纤维细胞（CFs）的促纤维化表型变化，协调从BEC到CF的病理串扰，从而有助于气道重塑和FAL。
方法：使用流式细胞术检测FAL哮喘患者和慢性哮喘小鼠模型的纤维细胞，多重染色和多光谱成像分析。使用细胞培养和共培养系统确定IL-25对BEC和CF以及对BEC和CF之间的串扰的影响。
结果：我们发现患有FAL的哮喘患者的IL-25受体数量较高（即，IL-17RB)+-CFs，与1s/用力肺活量（FEV1/FVC）的用力呼气量呈负相关。与对照组相比，卵清蛋白（OVA）和IL-25诱导的哮喘小鼠的气道IL-17RB纤维细胞数量显着增加。用IL-25刺激的BEC表现出上皮-间质转化（EMT）样表型变化。用IL-25刺激的CFs产生高水平的细胞外基质(ECM)蛋白和结缔组织生长因子(CTGF)。IL-25的这些促纤维化作用被PI3K-AKT抑制剂LY294002部分阻断。在细胞共培养系统中，OVA攻击的BECs促进ECM蛋白和CTGF在CFs中的迁移和表达，使用抗IL-17RB抗体明显阻断。
结论：这些结果表明IL-25可能作为FAL哮喘患者的潜在治疗靶点。
方法：使用流式细胞术检测FAL哮喘患者和慢性哮喘小鼠模型的纤维细胞，多重染色和多光谱成像分析。使用细胞培养和共培养系统确定IL-25对BEC和CF以及对BEC和CF之间的串扰的影响。
结果：我们发现患有FAL的哮喘患者的IL-25受体数量较高（即，IL-17RB)+-CFs，与1s/用力肺活量（FEV1/FVC）的用力呼气量呈负相关。与对照组相比，卵清蛋白（OVA）和IL-25诱导的哮喘小鼠的气道IL-17RB纤维细胞数量显着增加。用IL-25刺激的BEC表现出上皮-间质转化（EMT）样表型变化。用IL-25刺激的CFs产生高水平的细胞外基质(ECM)蛋白和结缔组织生长因子(CTGF)。IL-25的这些促纤维化作用被PI3K-AKT抑制剂LY294002部分阻断。在细胞共培养系统中，OVA攻击的BECs促进ECM蛋白和CTGF在CFs中的迁移和表达，使用抗IL-17RB抗体明显阻断。
结论：这些结果表明IL-25可能作为FAL哮喘患者的潜在治疗靶点。
