The mechanisms of asbestos-induced pulmonary diseases are unclear to date. Reactive oxygen (ROS) or nitrogen species (RNS) may play an important role in asbestos-induced acute injury. We hypothesize that ROS and RNS may also be important in the activation of transcription factors or gene expression by asbestos. The goal of this proposal is to define the role of ROS and RNS in the activation of the transcription factors, activator protein 1 (AP-1) and nuclear factor kappa B (NFkB) by asbestos. Rat lung epithelial cells and rat pleural mesothelial cells, progenitor cell of asbestos-induced cancers will be evaluated comparatively after exposure to asbestos, ROS or RNS for phenotypic endpoints (apoptosis, proliferation cytotoxicity), gene expression of c-fos and c-jun and activation of AP-1 and NK-kb. Stress associated with ROS or RNS will be determined after asbestos exposure using oxidant-sensitive probes and antibodies recognizing nitrotyrosine or four-hydroxynonenal modified proteins. Savengers of ROS or RNS and blocking the production of RNS will confirm the role of these reactive species in asbestos-induced cell signalling. Knowledge of the critical reactive intermediates will provide avenues for therapeutic intervention in early phases of the disease process.
| Janssen-Heininger, Y M; Macara, I; Mossman, B T (1999) Cooperativity between oxidants and tumor necrosis factor in the activation of nuclear factor (NF)-kappaB: requirement of Ras/mitogen-activated protein kinases in the activation of NF-kappaB by oxidants. Am J Respir Cell Mol Biol 20:942-52 |
| Janssen, Y M; Driscoll, K E; Timblin, C R et al. (1998) Modulation of mitochondrial gene expression in pulmonary epithelial cells exposed to oxidants. Environ Health Perspect 106 Suppl 5:1191-5 |
