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4.
Inhal Toxicol ; 29(1): 10-17, 2017 01.
Article in English | MEDLINE | ID: mdl-28183202

ABSTRACT

Amphibole asbestos exposure is associated with the production of mesothelial cell autoantibodies (MCAA). These MCAA have been linked with pleural fibrotic disease in the asbestos exposed community of Libby, Montana, and induce collagen deposition by cultured mesothelial cells. However, the exact intracellular mechanism by which these autoantibodies cause an increase in collagen deposition remains unknown. This study sought to gain insight into the transcription factors involved in the collagen production after human mesothelial cells are exposed to MCAA. In this study, transcription factor activation profiles were generated from human mesothelial cells (Met5A) treated with serum from Libby subjects, and were compared to cells treated with serum cleared of IgG, and therefore containing no MCAA. Analysis of those profiles indicated C/EBP-beta and hypoxia inducible factor 1 alpha (HIF-1α) are significantly increased in the nucleus, indicating activation, due to MCAA exposure compared to controls. Inhibition of either of these transcription factors significantly reduced collagen 1 deposition by these cells following exposure to MCAA. These data suggest autoantibodies are directly involved in type I collagen deposition and may elucidate potential therapeutic targets for autoantibody mediated fibrosis.


Subject(s)
Autoantibodies/immunology , CCAAT-Enhancer-Binding Protein-beta/biosynthesis , Epithelial Cells/immunology , Fibrosis/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Asbestos, Amphibole , Cells, Cultured , Collagen/metabolism , Gene Expression , Humans , Occupational Exposure , Serum , Up-Regulation
5.
Am J Physiol Lung Cell Mol Physiol ; 310(11): L1071-7, 2016 06 01.
Article in English | MEDLINE | ID: mdl-27106292

ABSTRACT

Libby amphibole (LA) causes a unique progressive lamellar pleural fibrosis (LPF) that is associated with pulmonary function decline. Pleural fibrosis among the LA-exposed population of Libby, MT, has been associated with the production of anti-mesothelial cell autoantibodies (MCAA), which induce collagen production from cultured human mesothelial cells. We hypothesized that the progressive nature of LPF could be at least partially attributed to an autoimmune process and sought to demonstrate that LA-induced MCAA trigger collagen deposition in vivo. C57BL/6 mice were exposed to LA for 7 mo, and serum was tested for MCAA by cell-based ELISA on primary mouse mesothelial cells. When treated in vitro with serum from mice exposed to LA, mesothelial cells upregulated collagen matrix production. This effect was lost when the serum was cleared of IgG using protein G beads, implicating IgG autoantibodies. Using the peritoneal cavity as a surrogate for the pleural cavity, groups of naïve (non-asbestos-exposed) mice were injected intraperitoneally with 1) control serum, 2) one dose of serum from LA-exposed mice (LA serum), 3) two doses of LA serum, or 4) two doses of LA serum cleared of IgG. After 1 mo, analysis of collagen in peritoneal walls using two-photon confocal microscopy (SHG analysis) and a hydroxyproline assay demonstrated significant increases in collagen by LA serum but not control or cleared serum. These data support the hypothesis that MCAA in LA-exposed mice induce fibrotic responses in vivo, demonstrating that an autoimmune component may be contributing to the progressive pleural fibrosis seen in LA-exposed patients.


Subject(s)
Asbestos, Amphibole/toxicity , Asbestosis/immunology , Autoantibodies/immunology , Epithelial Cells/immunology , Fibrillar Collagens/metabolism , Animals , Asbestosis/metabolism , Cells, Cultured , Epithelium/immunology , Epithelium/pathology , Lung/immunology , Lung/pathology , Mice, Inbred C57BL , Pleural Diseases/immunology , Pleural Diseases/metabolism , Primary Cell Culture
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