National attention has been drawn to asbestos-related diseases (ARD) due to the serious health situation in Libby, Montana. For almost 60 years Libby miners and residents were exposed to asbestos- contaminated vermiculite from a mining operation near town. Both occupationally- and environmentally- exposed individuals have shown a much higher incidence of ARD than the rest of the population (ATSDR, 2003). However, exposure to the asbestos-contaminated vermiculite is not limited to Libby residents: distribution of this vermiculite nationwide and the long latent period for disease development make asbestos-related diseases (ARD) a continuing public health issue. We previously investigated gene expression changes in a mouse model of asbestos exposure and identified a candidate gene for study that we hypothesize plays a role in disease progression. SPARC (secreted protein acidic and rich in cysteine) demonstrates reproducibly increased expression in mouse lungs exposed to several types of asbestos fibers, including the Libby amphibole. SPARC is a matricellular protein involved in the regulation of extracellular matrix (ECM) - cell interactions through a hypothesized modulation of growth factor activity. The goal of this project is to delineate the role of SPARC in response to exposure to the Libby amphibole and crocidolite asbestos as a positive control. The hypothesis to be tested in our studies is that expression of SPARC is a significant step in the development of lung fibrosis after asbestos exposure. To test the hypothesis, the specific aims will 1) ssess the in vivo expression of SPARC and proteins in the TGF-? signaling cascade in SPARC-null and matched wild-type mice after induction of lung fibrosis through intratracheal asbestos instillation, and compare this with the effects of subsequent RNAi transduction to control SPARC expression in wild-type mice, and 2) establish the in vitro gene and protein expression of SPARC as well as extracellular matrix production in mouse primary lung fibroblasts and an immortalized human lung fibroblast cell line stimulated by TGF-? or amphiboles before and after Sparc expression inhibition by RNAi. The investigation proposed here will further determine the role of SPARC in fibrosis development after amphibole exposure, specifically targeting how inhibition of SPARC expression can regulate ECM production. Proteins involved in pathways regulated by SPARC could provide targets for potential therapies that might also be beneficial for the treatment of similar, non-asbestos caused diseases such as idiopathic pulmonary fibrosis.
Fibrotic lung diseases, including idiopathic pulmonary fibrosis (IPF), are suspected to be caused by a combination of environmental exposures and a state of chronic inflammation. Due to a lack of understanding of the molecular mechanisms underlying the disease, there are currently no successful therapies for fibrosis patients. These studies are designed to understand the role of a matricellular protein, SPARC, in the development of pulmonary fibrosis in order to identify potential new targets for therapy.
