Ambient particulate matter (PM) promotes the development and exacerbation of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma, by increasing inflammation and mucus hypersecretion. However, the biological mechanisms underlying PM-induced airway inflammation and mucus hypersecretion remain unclear. Amphiregulin (AREG) is an important ligand for epidermal growth factor receptor (EGFR) and participates in the regulation of several biological functions. Here, the PM-exposed human bronchial epithelial cell (HBEC) model was used to define the role of AREG in PM-induced inflammation and mucus hypersecretion and its related signaling pathways. The expression of AREG was significantly increased in a dose-dependent manner in HBECs subjected to PM exposure. Moreover, PM could induce inflammation and mucus hypersecretion by upregulating the expression of IL-1α, IL-1β, and Muc-5ac in HBECs. The EGFR, AKT, and ERK signaling pathways were also activated in a time- and dose-dependent manner. The AREG siRNA markedly attenuated PM-induced inflammation and mucus hypersecretion, and activation of the EGFR-AKT/ERK pathway. Exogenous AREG significantly increased the expression of IL-1α, IL-1β, and Muc-5ac, and induced activation of the EGFR-AKT/ERK pathway in HBECs. Further, under PM exposure, exogenous AREG significantly potentiated PM-induced inflammation and mucus hypersecretion, and activation of the EGFR-AKT/ERK pathway. Tumor-necrosis factor-alpha converting enzyme (TACE) and EGFR specific inhibitor pretreatment showed that AREG was secreted by TACE-mediated cleavage to regulate PM-induced inflammation and mucus hypersecretion by binding to the EGFR. Moreover, according to the inhibitory effect of specific inhibitors of the class I PI3K isoforms, AKT and ERK, PM-induced inflammation and mucus hypersecretion was regulated by PI3Kα activation and its downstream AKT and ERK pathways. This study strongly suggests the adverse effect of AREG in PM-induced inflammation and mucus hypersecretion via the EGFR-PI3Kα-AKT/ERK pathway. These findings contribute to a better understanding of the biological mechanisms underlying exacerbation of chronic respiratory diseases induced by PM exposure.

中文翻译：

---

两性调节蛋白通过EGFR-PI3Kα-AKT/ ERK途径增强城市颗粒物引起的气道炎症和粘液分泌过多。

环境颗粒物（PM）通过增加炎症和粘液分泌过多，促进包括慢性阻塞性肺疾病（COPD）和哮喘在内的慢性呼吸系统疾病的发展和恶化。但是，PM诱导的气道炎症和粘液分泌过多的生物学机制仍不清楚。双调蛋白（AREG）是表皮生长因子受体（EGFR）的重要配体，并参与多种生物学功能的调节。在这里，暴露于PM的人支气管上皮细胞（HBEC）模型用于定义AREG在PM诱导的炎症和粘液过度分泌及其相关信号通路中的作用。在暴露于PM的HBEC中，AREG的表达以剂量依赖性方式显着增加。而且，PM可通过上调HBEC中IL-1α，IL-1β和Muc-5ac的表达来诱导炎症和黏液分泌过多。EGFR，AKT和ERK信号通路也以时间和剂量依赖性方式被激活。AREG siRNA显着减轻了PM诱导的炎症和粘液过度分泌以及EGFR-AKT / ERK途径的激活。外源性AREG显着增加HBEC中IL-1α，IL-1β和Muc-5ac的表达，并诱导EGFR-AKT / ERK途径的激活。此外，在PM暴露下，外源性AREG可显着增强PM诱导的炎症和粘液分泌过多，并激活EGFR-AKT / ERK途径。肿瘤坏死因子-α转化酶（TACE）和EGFR特异性抑制剂预处理显示，AREG通过TACE介导的裂解分泌，通过与EGFR结合来调节PM诱导的炎症和黏液分泌过多。而且，根据I类PI3K同工型，AKT和ERK的特异性抑制剂的抑制作用，由PI3Kα激活及其下游AKT和ERK途径调节PM诱导的炎症和粘液分泌过多。这项研究强烈暗示了AREG通过EGFR-PI3Kα-AKT/ ERK途径对PM引起的炎症和黏液分泌过多的不利影响。这些发现有助于更好地理解由PM暴露引起的慢性呼吸道疾病加重的生物学机制。根据I类PI3K亚型的特定抑制剂AKT和ERK的抑制作用，PI3Kα激活及其下游AKT和ERK途径调节PM诱导的炎症和粘液分泌过多。这项研究强烈暗示了AREG通过EGFR-PI3Kα-AKT/ ERK途径对PM引起的炎症和黏液分泌过多的不利影响。这些发现有助于更好地理解由PM暴露引起的慢性呼吸道疾病加重的生物学机制。根据I类PI3K亚型的特定抑制剂AKT和ERK的抑制作用，PI3Kα激活及其下游AKT和ERK途径调节PM诱导的炎症和粘液分泌过多。这项研究强烈暗示了AREG通过EGFR-PI3Kα-AKT/ ERK途径对PM引起的炎症和黏液分泌过多的不利影响。这些发现有助于更好地理解由PM暴露引起的慢性呼吸道疾病加重的生物学机制。