title: Pulmonary inflammatory and fibrotic responses in Fischer 344 rats after intratracheal instillation exposure to Libby amphibole.
abstract: Increased incidences of asbestosis have been reported in workers from Libby, MT, associated with exposures to amphibole-contaminated vermiculite. In this study pulmonary and histopathological changes were investigated following Libby amphibole (LA) exposure in a rat model. Rat respirable fractions of LA and amosite (aerodynamic diameter <2.5 μm) were prepared by water elutriation. Male F344 rats were exposed to single doses of either saline (SAL), amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal instillation. At times from 1 d to 3 mo after exposure, bronchoalveolar lavage (BAL) was performed and right and left lungs were removed for reverse-transcription polymerase chain reaction (RT-PCR) and histopathological analysis, respectively. Data indicated that 0.65 mg amosite resulted in a higher degree of pulmonary injury, inflammation, and fibrotic events than LA at the same mass dose. Exposure to either amosite or high dose LA resulted in higher levels of cellular permeability and injury, inflammatory enzymes, and iron binding proteins in both BAL fluid and lung tissue at most time points when compared to SAL controls. However, mRNA expression for some growth factors (e.g., platelet-derived growth factor [PDGF]-A and transforming growth factor [TGF]-1β), which contribute to fibrosis, were downregulated at several time points. Furthermore, histopathological examination showed notable thickening of interstitial areas surrounding the alveolar ducts and terminal bronchioles. On a mass dose basis, amosite produced a greater acute and persistent lung injury for at least 3 mo after exposure. However, further testing and analysis of LA are needed with regard to the dose metric to fully evaluate its potential fibrogenicity and carcinogenicity.
authors.affiliation: Curriculum in Toxicology, UNC School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Padilla-Carlin
authors.forename: Mette C J
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Shannahan
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Lyle D
authors.initials: LD
authors.lastname: Burgoon
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gavett
mesh_terms: D000395:Air Pollutants, Occupational / Q000737:chemistry / Q000633:toxicity*; D000538:Aluminum Silicates / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D017636:Asbestos, Amphibole / Q000737:chemistry / Q000633:toxicity*; D001195:Asbestosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D019016:Mineral Fibers / Q000032:analysis / Q000633:toxicity; D010316:Particle Size; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000395:Air Pollutants, Occupational; D000538:Aluminum Silicates; D017636:Asbestos, Amphibole; D015415:Biomarkers; D033862:Iron-Binding Proteins; D019016:Mineral Fibers; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; C075278:platelet-derived growth factor A; C003760:vermiculite