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Asbestos-associated mesothelial cell autoantibodies promote collagen deposition in vitro
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    Fibrosis, characterized by excessive collagen protein deposition, is a progressive disease that can fatally inhibit organ function. Prolonged exposure to pathogens or environmental toxicants such as asbestos can lead to chronic inflammatory responses associated with fibrosis. Significant exposure to amphibole asbestos has been reported in and around Libby, Montana due to local mining of asbestos-contaminated vermiculite. These exposures have been implicated in a unique disease etiology characterized predominantly by pleural disorders, including fibrosis. We recently reported the discovery of mesothelial cell autoantibodies (MCAAs) in the sera of Libby residents and demonstrated a positive and significant correlation with pleural disease; however, a mechanistic link was not determined. Here we demonstrate that MCAAs induce pleural mesothelial cells to produce a collagen matrix but do not affect production of the pro-inflammatory cytokine tumor growth factor-β. While autoantibodies commonly induce a pro-fibrotic state by inducing epithelial-mesenchymal transition (EMT) of target cells, we found no evidence supporting EMT in cells exposed to MCAA positive human sera. Although implicated in other models of pulmonary fibrosis, activity of the protein SPARC (secreted protein, acidic and rich in cysteine) did not affect MCAA-induced collagen deposition. However, matrix formation was dependent on matrix metalloproteinase (MMP) activity, and we noted increased expression of MMP-8 and -9 in supernatants of mesothelial cells incubated with MCAA positive sera compared to control. These data suggest a mechanism by which MCAA binding leads to increased collagen deposition through altering MMP expression and provides an important mechanistic link between MCAAs and asbestos-related, autoimmune-induced pleural fibrosis.

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    P20 RR016454/RR/NCRR NIH HHS/United States
    P20 RR016454/RR/NCRR NIH HHS/United States
    R15 ES021884/ES/NIEHS NIH HHS/United States
    TS000099-01/TS/ATSDR CDC HHS/United States
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