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IN VITRO LUNG ALVEOLAR EPITHELIAL CELL INJURY AND INFLAMMATORY RESPONSE TO PARTICULATE MATTER-ASSOCIATED METALS - MODULATION BY EXPOSURE TO TNF-ALPHA, IL-BETA, OR IFN-GAMMA
Citation:
Dye, J A., K. Peoples, AND C. L. Hayes. IN VITRO LUNG ALVEOLAR EPITHELIAL CELL INJURY AND INFLAMMATORY RESPONSE TO PARTICULATE MATTER-ASSOCIATED METALS - MODULATION BY EXPOSURE TO TNF-ALPHA, IL-BETA, OR IFN-GAMMA. Presented at Symp. of ARDS and Acute Lung Injury, San Antonio, TX, Oct. 2-5, 2003.
Description:
IN VITRO LUNG ALVEOLAR EPITHELIAL CELL INJURY AND INFLAMMATORY RESPONSE TO PARTICULATE MATTER-ASSOCIATED METALS - MODULATION BY EXPOSURE TO TNF , IL-1 , OR IFN .
JA Dye, KE Peoples*, CL Hayes?. US EPA, ORD, Pulmonary Toxicology Branch, RTP, NC, *HHMI-SRI, NCSU, Raleigh, NC, and ?SEE Program, RTP, NC, USA.
Epidemiological studies have linked air pollution exposure to adverse respiratory health effects, especially in individuals with pre-existing inflammatory airways disease. C.A. Pope, for example, reported that increases in particulate matter (PM) levels in Utah Valley were positively associated with hospital admissions for respiratory disease, most notably in children and relating to bronchitis and asthma (1989). Furthermore, asthmatic/symptomatic children appeared to suffer the most acute health effects (Pope 1992). Using PM-derived materials extracted from filters collected in Utah Valley, we have demonstrated that rats intratracheally exposed to samples containing relatively high levels of metals [i.e., copper (Cu) and zinc (Zn)] developed significantly greater lung injury, neutrophilic inflammation, and moderately severe alveolitis (Dye et al 2001). In the present studies, we investigated specific Cu- or Zn-induced alveolar epithelial effects using the RLE-6TN cell line derived from rat type II pneumocytes. At Cu or Zn exposures that alone were minimally cytotoxic over a 24h period, data indicated that combined Cu+Zn exposure resulted in minor, but significantly greater epithelial injury. In like fashion, relative to saline-exposed controls, Cu+Zn exposure resulted in a significant (2.0-fold) increase in MIP-2 production; while Zn or Cu+Zn exposure resulted in 1.5- and 2.0-fold increases in RANTES, respectively. Analogous to the inflamed lungs of asthmatics, we next exposed cells under "inflammatory conditions" to determine whether metal-induced effects would be exaggerated. Using rat recombinant cytokines, dose-response studies demonstrated that RLE cell production of MIP-2 and RANTES can be acutely up-regulated by exposure to TNF , IL-1 , or IFN , with combined cytokine exposure resulting in still greater increases. Data also demonstrated that RLE "pre-inflammation" with either IL-1 or IFN prior to Zn or Cu+Zn exposure resulted in significantly greater RANTES production; with negligible effects on cytotoxicity or MIP-2 release. These studies support the possibility that exposure of asthmatics to emission-source PM containing Zn may result in enhanced chemokine (e.g., RANTES) production thus exacerbating eosinophilic inflammation and potentially contributing to relapse of asthmatic symptoms and disease. (This abstract does not reflect US EPA policy).