The barrier-protective effect of ß-eudesmol against type 2-inflammatory cytokine-induced tight junction disassembly in airway epithelial cells.

Allergic inflammation, which is the pathogenesis of allergic rhinitis and asthma, is associated with disruption of the airway epithelial barrier due to the effects of type 2 inflammatory cytokines, i.e. interleukin-4 and interleukin-13 (IL-4/13). The anti-allergic inflammatory effect of ß-eudesmol (BE) on the tight junction (TJ) of the airway epithelium has not previously been reported. Herein, the barrier protective effect of BE was determined by measurement of transepithelial electrical resistance and by paracellular permeability assay in an IL-4/13-treated 16HBE14o- monolayer. Pre-treatment of BE concentration- and time- dependently inhibited IL-4/13-induced TJ barrier disruption, with the most significant effect observed at 20 µM. Cytotoxicity analyses showed that BE, either alone or in combination with IL-4/13, had no effect on cell viability. Western blot and immunofluorescence analyses showed that BE inhibited IL-4/13-induced mislocalization of TJ components, including occludin and zonula occludens-1 (ZO-1), without affecting the expression of these two proteins. In addition, the mechanism of the TJ-protective effect of BE was mediated by inhibition of IL-4/13-induced STAT6 phosphorylation, in which BE might serve as an antagonist of cytokine receptors. In silico molecular docking analysis demonstrated that BE potentially interacted with the site I pocket of the type 2 IL-4 receptor, likely at Asn-126 and Tyr-127 amino acid residues. It can therefore be concluded that BE is able to prevent IL-4/13-induced TJ disassembly by interfering with cytokine-receptor interaction, leading to suppression of STAT6-induced mislocalization of occludin and ZO-1. BE is a promising candidate for a therapeutic intervention for inflammatory airway epithelial disorders driven by IL-4/13.

Fine particulate matter PM2.5 and its constituent, hexavalent chromium induce acute cytotoxicity in human airway epithelial cells via inflammasome-mediated pyroptosis.

PM2.5-induced airway injury contributes to an increased rate of respiratory morbidity. However, the relationship between PM2.5 toxicants and acute cytotoxic effects remains poorly understood. This study aimed to investigate the mechanisms of PM2.5- and its constituent-induced cytotoxicity in human airway epithelial cells. Exposure to PM2.5 resulted in dose-dependent cytotoxicity within 24 h. Among the PM2.5 constituents examined, Cr(VI) at the dose found in PM2.5 exhibited cytotoxic effects. Both PM2.5 and Cr(VI) cause necrosis while also upregulating the expression of proinflammatory cytokine transcripts. Interestingly, exposure to the conditioned PM, obtained from adsorption in the Cr(VI)-reducing agents, FeSO4 and EDTA, showed a decrease in cytotoxicity. Furthermore, PM2.5 mechanistically enhances programmed pyroptosis through the activation of NLRP3/caspase-1/Gasdermin D pathway and increase of IL-1ß. These pyroptosis markers were reduced when exposure to conditioned PM. These findings provide a deeper understanding of mechanisms underlying PM2.5 and Cr(VI) in acute airway toxicity.