苯并芘暴露通过激活上皮细胞中的AhR-GDF15通路加重哮喘气道重塑
2025/12/29
摘要
气道重塑，包括成纤维细胞活化和胶原沉积，是哮喘的一个标志。污染物苯并芘（BaP）是一种芳烃受体（AhR）活化剂，与哮喘严重程度增加有关，但其在重塑中的作用尚不清楚。本研究探讨了BaP是否通过AhR介导的途径通过增强上皮-成纤维细胞串扰而加剧重塑，并确定了关键介质。我们发现BaP暴露显著上调气道上皮细胞中生长分化因子15 （GDF15）的表达和分泌，以AhR依赖的方式，因为AhR直接与GDF15启动子结合。因此，来自BaP处理的上皮细胞的条件培养基促进了成纤维细胞的活化，其标志是α-平滑肌肌动蛋白（α-SMA）和I型胶原蛋白（COL1A1）水平升高，而GDF15敲低会降低这两种蛋白的水平。在体内，BaP共暴露加重了过敏原诱导的气道重塑，胶原沉积增加，GDF15、α-SMA和COL1A1表达增加。一致地，重组GDF15直接激活肺成纤维细胞并刺激胶原蛋白的产生。关键的是，表没食子儿茶素没食子酸酯（EGCG）对AhR的抑制减弱了AhR诱导的GDF15表达和体内重塑，这一效应与AhR表达的减少有关。总之，这些发现表明BaP通过AhR-GDF15轴介导的上皮-成纤维细胞串扰加重气道重塑，突出了治疗污染加重哮喘的潜在靶点。
Benzo(a)pyrene exposure aggravates airway remodeling in asthma by activating AhR-GDF15 pathway in epithelial cells
Cuiting Shan, Wenguan Li, Yipeng Sun, Jialu Ma, Qingge Chen, Xiayi Miao, Xuming Luo, Yue Wu, Xiongbiao Wang, Zhenhua Ni
Abstract
Airway remodeling, involving fibroblast activation and collagen deposition, is a hallmark of asthma. The pollutant Benzo(a)pyrene (BaP), an aryl hydrocarbon receptor (AhR) activator, is associated with increased asthma severity, but its role in remodeling remains unclear. This study investigates whether BaP exacerbates remodeling by enhancing epithelial-fibroblast crosstalk through an AhR-mediated pathway and identifies key mediators. We found BaP exposure significantly upregulated growth differentiation factor 15 (GDF15) expression and secretion from airway epithelial cells in an AhR-dependent manner, as AhR directly bound to the GDF15 promoter. Consequently, conditioned media from BaP-treated epithelial cells promoted fibroblast activation, marked by elevated α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) levels, which were reduced by GDF15 knockdown. In vivo, BaP co-exposure worsened allergen-induced airway remodeling, with greater collagen deposition and higher GDF15, α-SMA, and COL1A1 expression. Consistently, recombinant GDF15 directly activated lung fibroblasts and stimulated collagen production. Critically, inhibition of AhR by epigallocatechin gallate (EGCG) attenuated BaP-induced GDF15 expression and remodeling in vivo, a effect associated with reduced AhR expression. In conclusion, these findings demonstrate that BaP aggravates airway remodeling via epithelial-fibroblast crosstalk mediated by the AhR-GDF15 axis, highlighting a potential target for treating pollutant-exacerbated asthma.
气道重塑，包括成纤维细胞活化和胶原沉积，是哮喘的一个标志。污染物苯并芘（BaP）是一种芳烃受体（AhR）活化剂，与哮喘严重程度增加有关，但其在重塑中的作用尚不清楚。本研究探讨了BaP是否通过AhR介导的途径通过增强上皮-成纤维细胞串扰而加剧重塑，并确定了关键介质。我们发现BaP暴露显著上调气道上皮细胞中生长分化因子15 （GDF15）的表达和分泌，以AhR依赖的方式，因为AhR直接与GDF15启动子结合。因此，来自BaP处理的上皮细胞的条件培养基促进了成纤维细胞的活化，其标志是α-平滑肌肌动蛋白（α-SMA）和I型胶原蛋白（COL1A1）水平升高，而GDF15敲低会降低这两种蛋白的水平。在体内，BaP共暴露加重了过敏原诱导的气道重塑，胶原沉积增加，GDF15、α-SMA和COL1A1表达增加。一致地，重组GDF15直接激活肺成纤维细胞并刺激胶原蛋白的产生。关键的是，表没食子儿茶素没食子酸酯（EGCG）对AhR的抑制减弱了AhR诱导的GDF15表达和体内重塑，这一效应与AhR表达的减少有关。总之，这些发现表明BaP通过AhR-GDF15轴介导的上皮-成纤维细胞串扰加重气道重塑，突出了治疗污染加重哮喘的潜在靶点。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译 中日友好医院呼吸与危重症医学科 林江涛 审校）
（Environ Pollut. 2025 Dec 17:127557. doi: 10.1016/j.envpol.2025.127557. Online ahead of print.）
Benzo(a)pyrene exposure aggravates airway remodeling in asthma by activating AhR-GDF15 pathway in epithelial cells
Cuiting Shan, Wenguan Li, Yipeng Sun, Jialu Ma, Qingge Chen, Xiayi Miao, Xuming Luo, Yue Wu, Xiongbiao Wang, Zhenhua Ni
Abstract
Airway remodeling, involving fibroblast activation and collagen deposition, is a hallmark of asthma. The pollutant Benzo(a)pyrene (BaP), an aryl hydrocarbon receptor (AhR) activator, is associated with increased asthma severity, but its role in remodeling remains unclear. This study investigates whether BaP exacerbates remodeling by enhancing epithelial-fibroblast crosstalk through an AhR-mediated pathway and identifies key mediators. We found BaP exposure significantly upregulated growth differentiation factor 15 (GDF15) expression and secretion from airway epithelial cells in an AhR-dependent manner, as AhR directly bound to the GDF15 promoter. Consequently, conditioned media from BaP-treated epithelial cells promoted fibroblast activation, marked by elevated α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) levels, which were reduced by GDF15 knockdown. In vivo, BaP co-exposure worsened allergen-induced airway remodeling, with greater collagen deposition and higher GDF15, α-SMA, and COL1A1 expression. Consistently, recombinant GDF15 directly activated lung fibroblasts and stimulated collagen production. Critically, inhibition of AhR by epigallocatechin gallate (EGCG) attenuated BaP-induced GDF15 expression and remodeling in vivo, a effect associated with reduced AhR expression. In conclusion, these findings demonstrate that BaP aggravates airway remodeling via epithelial-fibroblast crosstalk mediated by the AhR-GDF15 axis, highlighting a potential target for treating pollutant-exacerbated asthma.
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