Role of NF-kappaB in the oxidative stress-induced lung inflammatory response to iron and selenium at ambient levels

摘要

Metals enriched in ambient air fine particulate matter (PM_(2.5)) are thought to contribute to the pathogenesis of PM_(2.5)-induced inflammatory lung diseases. An important mechanism involved in metal-induced lung injury involves increased oxidative stress due to generation of reactive oxygen species. The redox sensitive transcription factor, nuclear factor kappa B (NF-kB) converts extracellular oxidative stress signals into changes in expression of genes associated with diverse cellular activities.The purpose of this study was to determine the mechanism by which exposure to Fe or Se, at environmentally relevant concentrations, leads to an increased release of chemokines by cultured human lung epithelial cells (A549). We tested the hypothesis thatNF-kB signaling pathway is involved in the metal induced IL-8 and MCP-1 release by Fe and Se. Exposure to Fe or Se induced an enhanced release of chemokines at 6 and 24 h, and mediated nuclear translocation of NF-kappaB. Levels of chemokines in responseto Fe were significantly suppressed in the presence of BMS-345541, a specific inhibitor of NF-kappaB. Similar effects were seen in response to Se, indicating the involvement of NF-kappaB in the metal-induced chemokine release, while not affecting the AP-1 c-Jun-DNA binding activity. Overall, results indicate that both Fe and Se, at ambient levels, possess the potential for inducing lung inflammation via an oxidative stress pathway in lung epithelial cells.