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We focused on the regulation of inflammatory mediator expression by adenovirus E1A in lung epithelial cells and the role of this viral protein in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously reported that E1A, a well-known regulator of host genes, increased ICAM-1 expression in human bronchial epithelial (HBE) and A549 cells in response to LPS stimulation. In this report, we clarified the mechanism of this regulation. We found NF-[kappa]B translocation to the nucleus after LPS stimulation in both E1A-positive and -negative HBE cells. ICAM-1 promoter reporter constructs revealed that a mutation in the proximal NF-[kappa]B binding site completely inhibited increased transcription, whereas the mutation in a distal site did not. We analyzed the participation of E1A in transcriptional complex formation at this promoter using chromatin immunoprecipitation. In E1A-positive HBE and A549 cells, LPS stimulation increased ICAM-1 promoter immunoprecipitation by NF-[kappa]B p65 and p300 but not activator protein-1 antibodies with a concomitant increase by the E1A antibody. No increase was found in E1A-negative cells except in HBE cells with p65 antibody. The association of E1A with the increased promoter immunoprecipitation with p300 was also observed after TNF-[alpha] stimulation of A549 cells. These results suggest that adenovirus E1A regulates the ICAM-1 promoter through its proximal NF-[kappa]B binding site, most likely by interacting with the transcriptional complex that forms at this site. E1A regulation of the LPS response may play a role in acute exacerbations as a consequence of bacterial infections in COPD. gene regulation; inflammation; nuclear factor-[kappa]B

Epidemiologic and animal studies have shown that exposure to particulate matter air pollution (PM) is a risk factor for the development of atherosclerosis. Whether PM-induced lung and systemic inflammation is involved in this process is not clear. We hypothesized that PM exposure causes lung and systemic inflammation, which in turn leads to vascular endothelial dysfunction, a key step in the initiation and progression of atherosclerosis. New Zealand White rabbits were exposed for 5 days (acute, total dose 8 mg) and 4 wk (chronic, total dose 16 rag) to either PM smaller than 10 [micro]m ([PM.sub.10]) or saline intratracheally. Lung inflammation was quantified by morphometry; systemic inflammation was assessed by white blood cell and platelet counts and serum interleukin (IL)-6, nitric oxide, and endothelin levels. Endothelial dysfunction was assessed by vascular response to acetylcholine (ACh) and sodium nitroprusside (SNP). [PM.sub.10] exposure increased lung macrophages (P < 0.02), macrophages containing particles (P < 0.001), and activated macrophages (P < 0.006). [PM.sub.10] increased serum IL-6 levels in the first 2 wk of exposure (P < 0.05) but not in weeks 3 or 4. [PM.sub.10] exposure reduced ACh-related relaxation of the carotid artery with both acute and chronic exposure, with no effect on SNP-induced vasodilatation. Serum IL-6 levels correlated with macrophages containing particles (P = 0.043) and ACh-induced vasodilatation (P = 0.014 at week 1, P = 0.021 at week 2). Exposure to [PM.sub.10] caused lung and systemic inflammation that were both associated with vascular endothelial dysfunction. This suggests that PM-induced lung and systemic inflammatory responses contribute to the adverse vascular events associated with exposure to air pollution. air pollution; alveolar macrophage; systemic inflammation; interleukin-6