Asbestos Inhalation Nitrate Levels and Cellular Mutation

When asbestos fibers are broken into small pieces they can be swallowed or inhaled and lead to mesothelioma disease.  This disease is responsible for the deaths of thousands of people each year, and consequently is the subject of a great deal of research.  One important study is called, "Secreted extracellular domains of macrophage scavenger receptors form elongated trimers which specifically bind crocidolite asbestos" by D Resnick, N J Freedman, S Xu and M Krieger - February 15, 1993 The Journal of Biological Chemistry, 268, 3538-3545.  Here is an excerpt: "Abstract - Macrophage scavenger receptors, which have been implicated in the development of atherosclerosis and other macrophage-mediated events, are trimeric integral membrane glycoproteins whose extracellular domains have been predicted to include alpha-helical coiled-coil, collagenous and globular structures. To elucidate further the structural and functional properties of these receptors, we generated transfected Chinese hamster ovary cells which express secreted extracellular domains of the type I and type II bovine scavenger receptors and developed a solid-phase bead-binding assay to assess their ligand-binding properties. The secreted receptors exhibited the distinctive high-affinity, broad polyanionic ligand-binding specificity and the pH dependence of binding which characterize the membrane-anchored cell-surface forms of the receptors. Both the type I and type II secreted receptors were trimeric glycoproteins comprising disulfide-linked dimers and noncovalently associated monomers. Gel filtration and glycerol-gradient centrifugation established that the type II trimers were highly elongated and did not associate into higher order oligomers at the low concentrations used in these experiments. Crocilodite asbestos, which is phagocytosed by alveolar macrophages and can cause asbestosis and mesothelioma, bound efficiently to secreted type I receptors and less well to the type II receptors. This binding was specific in that it was competed by a variety of well established scavenger receptor ligands but not by negative controls. These studies have identified a new type of insoluble scavenger receptor ligand, and have raised the possibility that scavenger receptors may play a role in mediating the physiological and pathological interactions of inspired particles with alveolar macrophages."

A second article is called, "Mechanisms of Asbestos-induced Nitric Oxide Production by Rat Alveolar Macrophages in Inhalation and in vitro Models" by Timothy R. Quinlan, Kelly A. BeruBe, Miles P. Hacker, Douglas J. Taatjes A, Cynthia R. Timblin A, Jonathan Goldberg, Priscilla Kimberley, Patrick O'Shaughnessy, David Hemenway, Jennifer Torino, Luis A. Jimenez and Brooke T. Mossman - Free Radical Biology and Medicine Volume 24, Issue 5, 15 March 1998, Pages 778-788.  Here is an excerpt: "Abstract - To evaluate the contribution of reactive nitrogen species to inflammation by asbestos, Fischer 344 rats were exposed to crocidolite or chrysotile asbestos by inhalation to determine whether increases occurred in nitric oxide (NO•) metabolites from alveolar macrophages (AMs). AMs from animals inhaling asbestos showed significant elevations ( p < .05) in nitrite/nitrate levels which were ameliorated by NG-monomethyl-l-arginine (NMMA), an inhibitor of inducible nitric oxide synthase (iNOS) activity. Temporal patterns of NO• generation from AMs correlated with neutrophil influx in bronchoalveolar lavage samples after asbestos inhalation or bleomycin instillation, another model of pulmonary fibrosis. To determine the molecular mechanisms and specificity of iNOS promoter activation by asbestos, RAW 264.7 cells, a murine macrophage-like line, and AMs isolated from control rats were exposed to crocidolite asbestos in vitro. These cells showed increases in steady-state levels of iNOS mRNA in response to asbestos and more dramatic increases in both iNOS mRNA and immunoreactive protein after addition of lipopolysaccharide (LPS). After transfection of an iNOS promoter/luciferase reporter construct, RAW 264.7 cells exposed to LPS, crocidolite asbestos and its nonfibrous analog, riebeckite, revealed increases in luciferase activity whereas cristobalite silica had no effects. Studies suggest that NO generation may be important in cell injury and inflammation by asbestos."  If you found any of these excerpts interesting, please read the studies in their entirety.  We all owe a debt of gratitude to these researchers.