Evidence for the critical role of the PI3K signaling pathway in particulate matter-induced dysregulation of the inflammatory mediators COX-2/PGE2 and the associated epithelial barrier protein Filaggrin in the bronchial epithelium
Evidence for the critical role of the PI3K signaling pathway in particulate matter-induced dysregulation of the inflammatory mediators COX-2/PGE2 and the associated epithelial barrier protein Filaggrin in the bronchial epithelium
复制标题
PI3K 信号通路在颗粒物诱导的支气管上皮炎症介质 COX-2/PGE(2) 和相关上皮屏障蛋白聚丝蛋白失调中发挥关键作用的证据
DOI：
10.1007/s10565-019-09508-1
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发表时间：
2019-12-28
影响因子：
6.1
通讯作者：
Dong, Nian
中科院分区：
文献类型：
--
作者：
Song, Chenjian;Liu, Lingjing;Dong, Nian
颗粒物(PM)是一种与人体呼吸道炎症密切相关的环境污染物。然而，PM相关的呼吸道炎症的分子机制仍未完全阐明。已知COX-2/PGE(2)在呼吸道炎症的发病机制中起关键作用。微丝蛋白是一种参与紧密连接屏障功能的跨膜蛋白。因此，Filaggrin可防止输送的溶质泄漏，因此对维持上皮完整性是必要的。本研究的目的是探讨COX-2/PGE(2)和微丝蛋白在体内和体外对PM暴露的调节机制。C57BL/6小鼠气管内滴注PM，连续2天。同时，人支气管上皮细胞(HBECs)暴露于PM 24 h后，可引起小鼠肺组织COX-2/PGE(2)表达上调，微丝蛋白表达下调。PM时HBECs中COX-2/PGE(2)和微丝蛋白表达异常PM诱导ERK、JNK和PI3K信号通路的磷酸化呈时间依赖性，而用特异性分子抑制剂LY294002阻断PI3K部分逆转了COX-2/PGE(2)和微丝蛋白的异常调节。此外，用COX-2的特异性分子抑制剂NS398和下游的PGE(2)受体抑制剂AH6809预处理HBECs，可逆转微丝蛋白对PM暴露的下调作用。综上所述，这些数据表明，PI3K信号通路上调了COX-2和PGE(2)，并在微丝蛋白的下调中发挥了关键的中介作用。
Particulate matter (PM) is an environmental pollutant closely associated with human airway inflammation. However, the molecular mechanisms of PM-related airway inflammation remains to be fully elucidated. It is known that COX-2/PGE(2) play key roles in the pathogenesis of airway inflammation. Filaggrin is a transmembrane protein contributing to tight junction barrier function. As such, Filaggrin prevents leakage of transported solutes and is therefore necessary for the maintenance of epithelial integrity. The objective of the present study was to investigate the regulatory mechanisms of COX-2/PGE(2) and Filaggrin upon PM exposure both in vivo and in vitro. C57BL/6 mice received intratracheal instillation of PM for two consecutive days. In parallel, human bronchial epithelial cells (HBECs) were exposed to PM for 24 h. PM exposure resulted in airway inflammation together with upregulation of COX-2/PGE(2) and downregulation of Filaggrin in mouse lungs. Corresponding dysregulation of COX-2/PGE(2) and Filaggrin was also observed in HBECs subjected to PM. PM exposure led to the phosphorylation of ERK, JNK, and PI3K signaling pathways in a time-dependent manner, while blockade of PI3K with the specific molecular inhibitor LY294002 partially reversed the dysregulation of COX-2/PGE(2) and Filaggrin. Moreover, pretreatment of HBECs with NS398, a specific molecular inhibitor of COX-2, and AH6809, a downstream PGE(2) receptor inhibitor, reversed the downregulation of Filaggrin upon PM exposure. Taken together, these data demonstrated that the PI3K signaling pathway upregulated COX-2 as well as PGE(2) and acted as a pivotal mediator in the downregulation of Filaggrin.