Abstract
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/PGE2 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/PGE2 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/PGE2 and downregulation of Filaggrin in mouse lungs. Corresponding dysregulation of COX-2/PGE2 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/PGE2 and Filaggrin. Moreover, pretreatment of HBECs with NS398, a specific molecular inhibitor of COX-2, and AH6809, a downstream PGE2 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 PGE2 and acted as a pivotal mediator in the downregulation of Filaggrin.
Highlights
As industrialization has progressed worldwide, atmospheric pollution is recognized to be the leading contributor to global disease burden (Huang 2014)
We report that particulate matter (PM) exposure upregulates COX-2 and downregulates Filaggrin via the PI3K/AKT signaling pathway
These results indicate that PM exposure induces conducting airway inflammation
Summary
As industrialization has progressed worldwide, atmospheric pollution is recognized to be the leading contributor to global disease burden (Huang 2014). The major atmospheric pollutant, particulate matter (PM), is a mixture of solid particles and liquid droplets, which primarily deposits in the lungs through inhalation (Mukherjee and Agrawal 2018; Traboulsi et al 2017). Substantial epidemiological investigations have revealed that PM exposure participates in the pathogenesis of airway diseases (Li et al 2018b; Wang et al 2018). Human bronchial epithelial cells (HBECs) act as the first line of defense against PM exposure, which leads to the malfunction of the cells (Chen et al 2016; De Grove et al 2018). Considering the pivotal role of HBECs in the pathogenesis of airway diseases, research into the relevant mechanism affecting these cells might contribute to an understanding of PM-related airway disease
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