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

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.