Occupational exposure to asbestos or silica is associated with the development of both non-malignant and malignant pulmonary disease. Considerable evidence indicates that the mechanism of mineral dust toxicity involves the production of active oxygen species (AOS) catalyzed directly on the mineral surface or by phagocytic cells within the lung. Production of AOS in excess of cellular defenses creates an environment of oxidative stress for the cell. The molecular response of cells to stress is a reprogramming of gene expression to meet the new challenges of its environment. Oxidant- induced genes include: genes encoding antioxidant enzymes, protooncogenes, hsp70, grp78, gadd45, and gad153. Detailed characterization of the molecular stress responses to asbestos or silica will aid in the understanding of the mechanisms of mineral dust mediated disease formation and may identify biomarkers of exposure and/or disease development. The focus of this proposal is to characterize the molecular stress response within target cells of asbestos or silica exposed lung, to compare this response to that elicited by other oxidants, and to related this response to known markers of disease in well-characterized inhalation models. The objectives of this grant are; 1) to evaluate in vitro and in vivo models of asbestos and silica exposure for changes in hsp70, grp78, gadd45, and gadd153 steady state mRNA; 2) to relate these changes in vitro to other oxidant stress inducing agents and 3) to modulate expression of c- jun in target cells using transfection techniques and to determine its role in mineral dust-mediated disease.
| Timblin, C R; Janssen, Y M; Goldberg, J L et al. (1998) GRP78, HSP72/73, and cJun stress protein levels in lung epithelial cells exposed to asbestos, cadmium, or H2O2. Free Radic Biol Med 24:632-42 |
| Timblin, C R; Janssen, Y W; Mossman, B T (1995) Transcriptional activation of the proto-oncogene c-jun by asbestos and H2O2 is directly related to increased proliferation and transformation of tracheal epithelial cells. Cancer Res 55:2723-6 |
