Altered cytokine production in the lung follows the deposition of urban air particles. The present study was designed to measure changes in tumor necrosis factoralpha (TNFalpha) and endothelin-1 (ET-1) levels in rat lung after instilling various fractions of the dust EHC-93, while in vitro, alveolar macrophages (AMs) and type 2 epithelial cells were studied to determine relative production of these molecules in response to the same particles. Whole dust and its soluble and leached components were instilled into rat lung and the animals were killed at intervals to 2 weeks; they received tritiated thymidine by intraperitoneal injection 1 hour before death. All samples induced some inflammation, with the highest cellular efflux being found by bronchoalveolar lavage 1 day after leached particles. Lung injury, illustrated by protein levels in lavage fluid, was maximal after instilling the soluble fraction and subsequently epithelial regeneration was also maximal in this group. TNFalpha levels were highest after instilling whole dust or its leached fraction at 4 hours and 1 day, and cell culture studies indicated a predominant AM source for this cytokine. ET-1 levels were also increased in BAL from 4 hours to 3 days and were mostly associated with the instillation of leached particles. The results demonstrate that the rapid production/release of TNFalpha and ET-1 after particle deposition is largely due to the insoluble particulate fraction. There appears to be a differential response to whole dust where the soluble components cause some inflammation and epithelial cell necrosis, whereas the leached particles are more likely to react with macrophages to induce the production of proinflammatory cytokines such as TNFalpha.