Abstract
Airborne particulate matter (PM) may induce or exacerbate neutrophilic airway disease by triggering release of inflammatory mediators such as CXCL8 from the airway epithelium. It is still unclear which PM-components are driving CXCL8-responses as most candidates occur at low concentrations in the dusts. We therefore hypothesized that different PM-constituents may contribute through common mechanisms to induce CXCL8.
Human bronchial epithelial cells (BEAS-2B) were exposed to different PM-components (zinc/iron salts, 1-nitropyrene, lipopolysaccharide, diesel exhaust/mineral particles). Gene-expression patterns were detected by real-time PCR-array. CXCL8-responses were measured by real-time PCR and ELISA. CXCL8-regulation was assessed with a broad inhibitor-panel and neutralizing antibodies. EGFR-phosphorylation was examined by immunoprecipitation and Western-blotting.
Component-induced gene-expression was mainly linked to NF-κB, Ca2+/PKC, PLC, LDL and mitogenic signalling. Many inhibitors attenuated CXCL8-release induced by all PM-components, but to varying extent. However, EGFR-inhibition strongly reduced CXCL8-release induced by all test-compounds and selected compounds increased EGFR-phosphorylation. Interference with TGF-α or TNF-α converting enzyme (TACE), which mediates TGF-α ectodomain-shedding, also attenuated CXCL8-release.
Different PM-constituents induced CXCL8 partly through similar signalling pathways but the relative importance of the different pathways varied. However, TACE/TGF-α/EGFR-signalling appears to be a convergent pathway regulating innate immune responses of airway epithelial cells upon exposure to multiple airborne pollutants.
- ERS