The role of nitric oxide in the particulate matter (PM2.5)-induced NFκB activation in lung epithelial cells

NFkappaB is one of key transcription factors that are involved in the inflammatory responses to the particulate matter (PM) in the lungs. In order to further understand the molecular mechanism, the effects of antioxidants and an inducible nitric oxide synthase (iNOS) inhibitor on PM-induced NFkappaB activation were examined in A549 lung epithelial cells. NFkappaB activation by 2.5 mum particulates (PM2.5) was evident from the degradation of an NFkappaB inhibitory protein, IkappaBalpha, and a luciferase reporter assay for NFkappaB activity. In these experiments, a pre-treatment of the cells with antioxidants N-acetyl-L-cysteine (NAC) and dimethylthiourea (DMTU) or an iNOS inhibitor L-N-6-1-iminoethyl-lysine (L-NIL) clearly inhibited the NFkappaB activation by PM2.5. The inhibitory effect of L-NIL was also observed on the PM2.5-induced interleukin-8 (IL-8) gene expression both at the transcriptional and protein levels. These results suggest that PM2.5 induces NFkappaB activity via the pathways involving ROS and/or RNS generation. Considering the fact that NFkappaB also induces NO generation via iNOS expression, they might make a positive feedback loop that amplifies the downstream responses. (C) 2004 Elsevier Ireland Ltd. All rights reserved.