In previous studies we have described the acute inflammatory response of the human airway to inhaled DE. This was characterized by neutrophil, mast cell, and lymphocyte infiltration into the bronchial mucosa with enhanced epithelial expression of IL-8, Gro-␣, and IL-13. In the present study, we investigated whether redox-sensitive transcription factors were activated as a consequence of DE exposure, consistent with oxidative stress triggering airway inflammation. In archived biopsies from 15 healthy subjects exposed to DE [particulates with a mass median diameter of Ͻ10 m, 300 g/m 3 ] and air, immunohistochemical staining was used to quantify the expression of the transcription factors NF-B (p65) and AP-1 (c-jun and c-fos), as well their upstream MAPKs, p38 and JNK, in the bronchial epithelium. In addition, phosphorylation of tyrosine residues was examined. DE induced a significant increase in the nuclear translocation of NF-B (P ϭ 0.02), AP-1 (P ϭ 0.02), phosphorylated JNK (P ϭ 0.04), and phosphorylated p38 (P ϭ 0.01), as well as an increase in total (cytoplasmic ϩ nuclear) immunostaining of phosphorylated p38 (P ϭ 0.03). A significant increase in nuclear phosphorylated tyrosine was also observed (P Ͻ0.05). These observations demonstrate that DE activates redox-sensitive transcription factors in vivo consistent with oxidative stress triggering the increased synthesis of proinflammatory cytokines.particulate matter EPIDEMIOLOGICAL STUDIES HAVE DEMONSTRATED a consistent association between the exacerbations of respiratory disease and concentrations of airborne particulate matter, especially with fine particles with an aerodynamic diameter of Ͻ2.5 m (PM 2.5 ) (22, 23). Particles derived from diesel engines are considered to comprise a significant proportion of PM 2.5 in urban areas, and both in vitro and in vivo studies have demonstrated that they have potent effects on the lung (20, 36). Exposure of human subjects to whole diesel exhaust (DE) (particulates and the associated gas phase) results in an acute inflammatory response characterized by neutrophil, lymphocyte, and mast cell influx into the airways. These cellular changes are associated with upregulation of vascular endothelial adhesion molecules as well as enhanced expression of IL-8, IL-6, Gro-␣, and IL-13 in the bronchial epithelium (24, 30, 31). Instillation of DE particle (DEP) extracts into the nose has also been shown to increase the production of mucosal T helper type 2 (Th2)-related cytokines in atopic volunteers (10). Similarly, bronchial epithelial and macrophage cell lines, as well as primary cultures of bronchial epithelial cells, have been shown to release a variety of chemokines and cytokines when treated with DEP or their organic extracts (2,4,6,7,14,15,18,26,37). The cellular and molecular mechanisms underlying these inflammatory responses remain unresolved.DE-induced cytokine release requires upregulation of signaling pathways modulating cytokine gene expression. Much attention has focused on the capacity of DEP to elicit oxidative stress ...