Plasminogen Binding and Activation at the Mesothelial Cell Surface Promotes Invasion through a Collagen Matrix.

Plasminogen (Plg) activation to the serine protease plasmin (Pla) plays a key role in regulating wound healing and fibrotic responses, particularly when bound to cell surface receptors. Our previous work suggested that mesothelial cells bind Plg at the cell surface, though no Plg receptors were described for these cells. Since mesothelial cells contribute to injury responses, including cellular differentiation to a mesenchymal-like phenotype and extracellular matrix remodeling, we hypothesized that Plg binding would promote these responses.

Late Inflammation Induced by Asbestiform Fibers in Mice Is Ameliorated by a Small Molecule Synthetic Lignan.

Exposure to Libby amphibole (LA) asbestos-like fibers is associated with increased risk of asbestosis, mesothelioma, pulmonary disease, and systemic autoimmune disease. LGM2605 is a small molecule antioxidant and free radical scavenger, with anti-inflammatory effects in various disease models. The current study aimed to determine whether the protective effects of LGM2605 persist during the late inflammatory phase post-LA exposure.

Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice.

Background: Exposure to the Libby amphibole (LA) asbestos-like fibers found in Libby, Montana, is associated with inflammatory responses in mice and humans, and an increased risk of developing mesothelioma, asbestosis, pleural disease, and systemic autoimmune disease. Flaxseed-derived secoisolariciresinol diglucoside (SDG) has anti-inflammatory, anti-fibrotic, and antioxidant properties. We have previously identified potent protective properties of SDG against crocidolite asbestos exposure modeled in mice.

Analysis of autoantibody profiles in two asbestiform fiber exposure cohorts.

An increased risk for Systemic Autoimmune Diseases (SAID) was reported in the population of Libby, Montana, where extensive exposure to asbestiform amphiboles occurred through mining and use of asbestiform fiber-laden vermiculite. High frequencies of antinuclear autoantibodies (ANA) were detected in individuals and mice exposed to Libby Asbestiform Amphiboles (LAA). Among the 6603 individuals who have undergone health screening at the Center for Asbestos Related Diseases (CARD, Libby MT), the frequencies of rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, and systemic sclerosis are significantly higher than expected prevalence in the United States.

Autoimmunity and asbestos exposure.

Despite a body of evidence supporting an association between asbestos exposure and autoantibodies indicative of systemic autoimmunity, such as antinuclear antibodies (ANA), a strong epidemiological link has never been made to specific autoimmune diseases. This is in contrast with another silicate dust, crystalline silica, for which there is considerable evidence linking exposure to diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Instead, the asbestos literature is heavily focused on cancer, including mesothelioma and pulmonary carcinoma.

Asbestos-associated mesothelial cell autoantibodies promote collagen deposition in vitro.

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.

Mesothelial cell and anti-nuclear autoantibodies associated with pleural abnormalities in an asbestos exposed population of Libby MT.

Despite data linking amphibole asbestos exposure with production of autoantibodies, the role of autoantibodies in subsequent disease is unknown. Residents of Libby, Montana have experienced significant exposure to amphibole asbestos due to the mining of asbestos-contaminated vermiculite near the community over several decades. This population predominantly exhibits pleural disease, and an autoimmune-like disorder that has yet to be well defined.

Development and validation of a rapid and sensitive HPLC method for the quantification of 5-fluorocytosine and its metabolites.

To study the intracellular metabolism of the prodrug 5-fluorocytosine (5FC), we developed a novel reverse-phase high-performance liquid chromatography method to simultaneously detect 5FC and its four major anabolic metabolites: 5-fluorouracil, 5-fluorouridine, 5-fluorouridine-monophosphate and 5-fluoro-2'deoxyuridine-5'-monophosphate. Separation of each compound was accomplished under isocratic conditions using a C(18) column and mobile phase of formic acid-water (1 : 99 v/v). The method was validated for both accuracy and reproducibility in cell culture media.