title: Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells.
abstract: Occupational and environmental exposures to airborne asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathologic presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We hypothesized that effects of mineral exposure in the airway epithelium may dictate deviating molecular events that may explain the different pathologies of asbestosis versus silicosis. Using robust gene expression-profiling in conjunction with in-depth pathway analysis, we assessed early (24 h) alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells (NHBEs). Observations were confirmed in an immortalized line (BEAS-2B) by QRT-PCR and protein assays. Utilization of overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis revealed gene alterations that were common to both minerals or unique to either mineral. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. These findings illustrate the use of gene-profiling as a means to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. In addition, it is a useful approach for predicting the pathogenicity of potentially harmful materials.
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA, Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands, t.perkins@maastrichtuniversity.nl p.peeters@maastrichtuniversity.nl.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Perkins
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA, Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands, t.perkins@maastrichtuniversity.nl p.peeters@maastrichtuniversity.nl.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Peeters
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: Arti
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), and Gene Expression Unit, Department of Molecular Cell Biology, KU Leuven, Leuven, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Arijs
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Dragon
authors.affiliation: Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands.
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.affiliation: Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht University, Maastricht, The Netherlands.
authors.forename: Niki L
authors.initials: NL
authors.lastname: Reynaert
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: Brooke T
authors.initials: BT
authors.lastname: Mossman
mesh_terms: D017638:Asbestos, Crocidolite / Q000633:toxicity*; D063646:Carcinogenesis / Q000139:chemically induced; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D046228:Microarray Analysis; D015398:Signal Transduction; D012822:Silicon Dioxide / Q000633:toxicity*
chemical_list: D017638:Asbestos, Crocidolite; D012822:Silicon Dioxide