| Transcription Factor Activation Following Exposure of an Intact Lung Preparation to Metallic Particulate Matter James M. Samet,1 Robert Silbajoris,1 Tony Huang,1 and Ilona Jaspers2 1Human Studies Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; 2Center for Environmental Medicine and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Abstract
Metallic constituents contained in ambient particulate matter have been associated with adverse effects in a number of epidemiologic, in vitro, and in vivo studies. Residual oil fly ash (ROFA) is a metallic by-product of the combustion of fossil fuel oil, which has been shown to induce a variety of proinflammatory responses in lung cells. We have examined signaling pathways activated in response to ROFA exposure and recently reported that ROFA treatment activates multiple mitogen-activated protein (MAP) kinases in the rat lung. In the present study we extended our investigations on the mechanism of toxicity of ROFA to include transcription factors whose activities are regulated by MAP kinases as well as possible effectors of transcriptional changes that mediate the effects of ROFA. We applied immunohistochemical methods to detect ROFA-induced activation of nuclear factor- B (NFB) , activating transcription factor-2 (ATF-2) , c-Jun, and cAMP response element binding protein (CREB) in intact lung tissue and confirmed and characterized their functional activation using DNA binding assays. We performed these studies using a perfused rabbit lung model that is devoid of blood elements in order to distinguish between intrinsic lung cell effects and effects that are secondary to inflammatory cell influx. We report here that exposure to ROFA results in a rapid activation of all of the transcription factors studied by exerting direct effects on lung cells. These findings validate the use of immunohistochemistry to detect transcription factor activation in vivo and demonstrate the utility of studying signaling changes in response to environmental exposures. Key words: ATF-2, CREB, c-Jun, immunohistochemistry, NFB, particulate matter, transcription factors. Environ Health Perspect 110:985-990 (2002) . [Online 15 August 2002] http://ehpnet1.niehs.nih.gov/docs/2002/110p985-990samet/ abstract.html Address correspondence to J.M. Samet, U.S. EPA Human Studies Facility, 104 Mason Farm Road, Chapel Hill, NC 27599, USA. Telephone: (919) 966-0665. Fax: (919) 966-6271. E-mail: samet.jim@epa.gov The authors contributed equally to this manuscript. Received 15 November 2001 ; accepted 21 February 2002.
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